Frederick Andermann

Familial agenesis of the cerebellar vermis A syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and retardation

SOME TWO YEARS AGO we investigated a child with profound psychomotor retardation who had had an occipital meningoencephalocele removed at birth. Contrast studies were carried out which showed a large midline defect in the posterior fossa and absence of the vermis. At the time we disregarded the nurses’ comments about the child’s abnormal breathing. A year later, Dr. P. P. Demers referred this patient’s baby brother to us because he was concerned about his abnormal breathing and xetarded development. It was then found that a third and older child in this family was Tetarded, ataxic, and breathing abnormally. Finally we were able to trace yet another sibling who had died in fancy and who, at autopsy, proved to have agenesis of the vermis. This .diagnosis was then confirmed in the two affected living children by contrast studies. From this investigation there emerged a familial syndrome of episodic hyperpnea, abnormal eye movements, ataxia, and mental retardation associated with a common malformation in the four affected siblings, agenesis of the vermis. This syndrome has not previously been described in the literature. The affected children will be presented in the order in which the abnormality was identified, which happens to be in reverse to the birth order (Fig. 1).

Neuroimaging evidence of progressive neuronal loss and dysfunction in temporal lobe epilepsy

Whether temporal lobe epilepsy is the result of an isolated, early injury or whether there is ongoing neuronal dysfunction or loss due to seizures is often debated. We attempt to address this issue by using magnetic resonance techniques. Proton magnetic resonance spectroscopic imaging can detect and quantify focal neuronal dysfunction or loss based on reduced signals from the neuronal marker N‐acetylaspartate (NAA), and magnetic resonance imaging (MRI)‐based measurements of hippocampal volumes (MRIvol) can quantify the amount of atrophy in this structure. We performed magnetic resonance spectroscopic imaging and MRIvol in 82 consecutive patients with medically intractable temporal lobe epilepsy to determine whether there was a correlation between seizure frequency, or type or duration of epilepsy, with NAA to creatine (Cr) values or hippocampal volumes. Volumes and spectroscopic resonance intensities were categorized as to whether they were measured from the temporal lobe ipsilateral or contralateral to the predominant electroencephalographic focus. Ipsilateral and contralateral NAA/Cr was negatively correlated with duration of epilepsy. Hippocampal volumes were negatively correlated with duration ipsilaterally but not contralaterally. Frequency of complex partial seizures was not correlated with any of the magnetic resonance measures. However, patients with frequent generalized tonic–clonic seizures had lower NAA/Cr bilaterally and smaller hippocampal volumes ipsilaterally than patients with none or rare generalized tonic–clonic seizures. The results suggest that although an early, fixed injury may cause asymmetric temporal lobe damage, generalized seizures may also cause progressive neuronal dysfunction or loss. Ann Neurol 1999;45:568–576

Learning and retention of words and designs following excision from medial or lateral temporal-lobe structures

We sought to elucidate the contributions of the amygdala, hippocampus and temporal neocortex to learning and memory for verbal and visuospatial material. Two matched learning tasks, using abstract words versus abstract designs, were administered to patients with unilateral neocorticectomy (NCE; Dublin), selective amygdalohippocampectomy (AHE; Zurich) or anterior temporal-lobe resection invading the amygdala and hippocampus (ATL; Montreal). Data were analysed according to side and type of resection. Learning and recall for words was impaired in groups with resection from the left temporal lobe, irrespective of whether mediobasal structures were spared or temporal neocortex was spared. All right-resection groups were unimpaired. Learning for abstract designs was impaired across all trials in the right AHE and NCE groups, and on the last two trials in the right ATL group. Restricted deficits of lower magnitude were observed on some trials in left-resection groups. These results show a partial dissociation between side of excision and type of material, but the finding of similar deficits in all resection types was unexpected. We propose that excision from either the hippocampal region or temporal neocortex may result in a disconnection, giving a similar functional outcome, as both types of resection interrupt a circuit likely to be essential for normal storage and retrieval of information.

Progressive myoclonus epilepsies: specific causes and diagnosis.

RECENT advances in the diagnosis and classifcxation of epileptic seizures and epileptic syndromes, together with improvemenss in anticonvulsant therapy, have enabled the great majority of patients ...

Concepts of absence epilepsies Discrete syndromes or biological continuum

There are two current approaches to the clinical conceptualization of the generalized epilepsies. The syndromic approach attempts to subdivide the patient population into relatively homogeneous groups, largely on the basis of clinical and EEG criteria. In contrast, the neurobiological approach aims to formulate a unique profile for each patient by incorporating particulars of the patient onto the background of knowledge regarding the etiologic factors important in generalized epilepsy. The value of these two approaches is discussed with regard to the dual aims of, first, improving the understanding of generalized epilepsy, and second, providing a precise diagnosis, an accurate prognosis, and optimal treatment for the patient.

Frequency and characteristics of dual pathology in patients with lesional epilepsy

We studied 167 patients who had identifiable lesions and temporal or extratemporal partial epilepsy. Pathology included neuronal migration disorders (NMDs) (48), low-grade tumors (521, vascular malformations (34), porencephalic cysts (16), and gliotic lesions as a result of cerebral insults early in life (17). MRI volumetric studies using thin (1.5-or 3-mm) coronal images were performed in all patients and in 44 age-matched normal controls. An atrophic hippocampal formation (HF), indicating dual pathology, was present in 25 patients (15%). Abnormal HF volumes were present in those with lesions involving temporal (17%) but also extratemporal (14%) areas. Age at onset and duration of epilepsy did not influence the presence of HF atrophy. However, febrile seizures in early childhood were more frequently, although not exclusively, found in patients with hippocampal atrophy. The frequency of hippocampal atrophy in our patients with low-grade tumors (2%) and vascular lesions (9%) was low. Dual pathology was far more common in patients with NMDs (25%), porencephalic cysts (31%), and reactive gliosis (23.5%). Some structural lesions, such as NMDs, are more likely to be associated with hippocampal atrophy, independent of the distance of the lesion from the HF. In other types of lesions, such as vascular malformations, dual pathology was found when the lesion was close to the HF. A common pathogenic mechanism during pre- or perinatal development may explain the occurrence of concomitant mesial temporal sclerosis and other structural lesions because of either (1) associated developmental abnormalities or (2) predisposition to prolonged febrile convulsions. Further clarification of this issue would improve our understanding of the pathogenesis of mesial temporal sclerosis and lead to more efficient planning of surgical treatment for lesional epilepsy.

Magnetic resonance scanning and epilepsy

Practitioners and researchers from a broad range of disciplines and three continents review the status of magnetic resonance imaging and scanning in epilepsy, and the current research and where is it likely to lead. The 53 papers, from a workshop in Chalfont St Peter, England, October 1992, discuss

fMRI Activation in Continuous and Spike-triggered EEG-fMRI Studies of Epileptic Spikes

Summary:  Purpose: To evaluate functional magnetic resonance imaging (fMRI) with simultaneous EEG for finding metabolic sources of epileptic spikes. To find the localizing value of activated regions and factors influencing fMRI responses.

Gelastic seizures and hypothalamic hamartomas Evaluation of patients undergoing chronic intracranial EEG monitoring and outcome of surgical treatment

We retrospectively studied 12 consecutive patients with gelastic seizures and hypothalamic hamartomas who, because of intractable epilepsy, underwent chronic intracranial EEG monitoring or epilepsy surgery. All patients had medically refractory seizures that included laughter as an ictal behavior (gelastic seizures). The hypothalamic hamartomas were identified with neuroimaging studies (12 of 12) and by pathologic verification (four of 12). Associated clinical features included behavioral disorders (n = 5), developmental delay (n = 4), and precocious puberty (n = 2). Interictal extracranial EEG predominantly showed bihemispheric epileptiform changes suggesting a secondary generalized epileptic disorder. Intracranial EEG recordings, performed in eight patients, indicated the apparent focal onset of seizure activity (anterior temporal lobe [n = 7] and frontal lobe [n = 1]). None of the seven patients who underwent a focal cortical resection, however, experienced a significant reduction in seizure tendency. An anterior corpus callosotomy, performed in two patients with symptomatic generalized epilepsy, resulted in a worthwhile reduction in drop attacks. Results of this study may modify the surgical strategies in patients with gelastic seizures and hypothalamic hamartomas.

Array-Based Gene Discovery with Three Unrelated Subjects Shows SCARB2/LIMP-2 Deficiency Causes Myoclonus Epilepsy and Glomerulosclerosis

Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.