When might hemispheric favouring of epileptiform discharges begin?

PURPOSE: EEG studies based on adult populations report interictal epileptiform discharges (EDS) favour the left hemisphere. It is not clear when favouring becomes apparent as similar paediatric studies have not been performed. METHODS: The authors reviewed 1,579 paediatric EEG interpretations for evidence of hemispheric favouring of focal epileptiform discharges. Analysis focused on first-time EEG results. RESULTS: Right hemispheric favouring of interictal epileptiform discharges occurs in childhood, it remits around 5 years of age whereupon left-sided favouring occurs more frequently (P=0.004, Fisher's Exact). CONCLUSION: Hemispheric vulnerabilities to interictal focal epileptiform activity may display discrete age-related favouring. These findings are discussed in context of normal hemispheric maturation.

Age at focal epilepsy onset varies by sex and hemispheric lateralization.

BACKGROUND: Previous studies have shown that interictal epileptiform discharges favor the left hemisphere in adults but the right side in children up until age 5. This may be due to sex-influenced asymmetric brain maturation. To clarify this relationship, the authors analyzed age at epilepsy onset by sex and by lateralization of epileptiform activity. METHODS: An adult epilepsy center long-term monitoring database was used to define patients with exclusively unilateral epileptiform findings. Three groups were studied: any epileptiform activity (n = 404), ictal activity (n = 287), and interictal activity (n = 265). The second and third groups were drawn from the first group and the second and third groups overlapped with each other. Side of lateralized finding and sex were analyzed via factorial two-way analysis of variance with the outcome variable being age at epilepsy onset. Comparison analysis included patients with generalized epilepsy (n = 114), nonepileptic seizures (NES, n = 232), and surgical mesial temporal sclerosis (MTS, n = 116). RESULTS: Patients with unilateral epileptiform activity displayed bimodal epilepsy onset ages with infant and adolescent peaks. For patients with a right-sided focus, epilepsy onset was earlier in men (14.4 years) than women (20.7 years). In contrast, among patients with a left-sided focus, epilepsy began earlier in women (18.2 years) than men (19.9 years, p < 0.01). Parallel results were found in unilateral ictal (p < 0.01) and unilateral interictal activity (p = 0.01). Patients with surgical MTS, NES, or generalized seizure showed no similar patterns. CONCLUSIONS: In adult patients with focal epilepsy, sex and lateralized epileptiform abnormalities may be related to age at epilepsy onset.

Ictal patterns of neocortical seizures monitored with intracranial electrodes: correlation with surgical outcome.

PURPOSE: Numerous factors have been analyzed in attempts to predict the outcome of surgical resections in patients with neocortical epilepsy. We examined the correlation between surgical outcome and electrocorticographic features of neocortical ictal patterns. METHODS: Twenty six patients with neocortical epilepsy underwent monitoring with subdural grid electrodes before surgery. Ictal patterns were analyzed retrospectively and correlated with three types of outcome: seizure free, worthwhile improvement (>75% reduction of seizure frequency), and no worthwhile improvement. The duration of follow-up was 2-5 years. RESULTS: Ictal patterns were divided according to the size of epileptogenic zone (focal, regional, multifocal); velocity and type of seizure propagation (fast contiguous, slow contiguous, noncontiguous); pattern of the onset of ictal activity; part of the cortex involved in the origin of the seizure (frontal, frontocentroparietal, etc.). Spread to medial temporal structures (as assessed by subtemporal strips) also was evaluated in selected cases. Statistically significant correlation with surgical outcome (p = 0.026) was shown for only one variable: type of spread. Patients with slow spread (n = 8) demonstrated the best outcomes (five are seizure free), whereas patients with noncontiguous spread (n = 5) demonstrated the worst outcomes (four did not improve significantly). Patients with fast contiguous spread (n = 13) showed intermediate outcomes. CONCLUSIONS: Types of propagation of ictal neocortical activity correlate with surgical outcome. Analysis of ictal pattern during intracranial recordings may help to predict surgical outcome for neocortical epilepsy.

Human cerebrocortical potentials evoked by stimulation of the dorsal nerve of the penis.

Cortical evoked potentials resulting from stimulation of the dorsal nerve of the penis (DNP) provide a unique opportunity to document the cortical localization of sexual sensory representation in man. The DNP supplies sensory axons to the major portion of the human phallus, including the penile shaft and glans. Animal and human studies indicate that this nerve plays a crucial role in erection and ejaculation. Direct cortical evoked responses to DNP electrical stimulation were recorded in patients undergoing preoperative evaluation for resection of epileptic foci. These studies provided evidence that the primary sensory cortex contains a large area of cortex devoted to the afferent fibers of the DNP and that the sensory field is in a different location than previously described. The location and distribution of this response indicated the need for revision of the traditional concept of the sensory cortical homunculus.

X-linked adrenoleukodystrophy: adult cerebral variant.

We report a unique case of a 43-year-old architect with adult-onset adrenoleukodystrophy who presented primarily with intellectual decline and no evidence of adrenal insufficiency. Serial MRIs taken over a number of months demonstrated the evolution of demyelination starting in the frontal white matter then shifting to the occipital white matter and finally resolving without any therapeutic intervention. Clinically, over this same period of time, the patient's symptoms resolved and he was able to return to work. The proband, his brother, and his nephew were found to have a color-vision defect. Each of these individuals had a red/green gene array that contained a 5' green-red 3' hybrid known to be associated with deutan color-vision defects. The proband's brother and nephew were otherwise normal. The gene that causes adrenoleukodystrophy appears not to be as close to the red/green color vision gene array on the X chromosome as previously reported.

Retinol esterification in bovine retinal pigment epithelium: reversibility of lecithin:retinol acyltransferase.

Esterification of all-trans-retinol is a key reaction of the vertebrate visual cycle, since it produces an insoluble, relatively non-toxic, form of the vitamin for storage and supplies substrate for the isomerization reaction. CoA-dependent and -independent pathways have been described for retinol esterification in retinal pigment epithelium (RPE). The CoA-independent reaction, catalysed by lecithin:retinol acyltransferase (LRAT) was examined in more detail in this study. Addition of retinol to RPE microsomes results in a burst of retinyl ester synthesis, followed by a rapid apparent cessation of the reaction. However, [3H]retinol, added when retinyl ester synthesis has apparently ceased, is rapidly incorporated into retinyl ester without a net increase in the amount of ester. The specific radioactivities of [3H]retinol and [3H]retinyl ester reach the same value. [14C]Palmitate from palmitoyl-CoA is incorporated into preexisting retinyl ester in the absence of net ester synthesis, too. These exchange reactions suggest that the reaction has reached equilibrium at the plateau of the progress curve and that only the accumulation of retinyl ester, and not its synthesis, has stopped during this phase of the reaction. Studies with geometrical isomers of retinol revealed that the rate of exchange of all-trans-retinol with all-trans-retinyl esters was about 6 times more rapid than exchange of 11-cis-retinol with 11-cis-retinyl ester. This is the first demonstration of the reversibility of LRAT and the first example of stereospecificity of retinyl ester synthesis in the visual system. Reversal of the LRAT reaction could contribute to the mobilization of 11-cis-retinol from 11-cis-retinyl ester pools.

Gaucher's disease in the presence of normal glucocerebrosidase activity.

We encountered an infant with clinical and histopathologic features of Gaucher's disease (infantile, type 2) with normal glucocerebrosidase (D-glucosyl-N-acylsphingosine glucohydrolase, E.C.3.2.1.45) activity. Biochemical analysis was performed on leukocytes, cultured skin fibroblasts, and liver. Normal activity of glucocerebrosidase previously has been reported in an older child with juvenile onset (type 3) Gaucher's disease and attributed to a deficiency of a sphingolipid activator protein. These rare cases illustrate and expand our concept of Gaucher's disease and may have both diagnostic and therapeutic implications.

Connatal Pelizaeus-Merzbacher disease: an autosomal recessive form.

An infant female had connatal Pelizaeus-Merzbacher disease with neonatal onset of developmental failure, seizures, nystagmus, visual impairment, abnormal movements, and spasticity. There was nearly complete absence of central myelin with preservation of peripheral myelin. The 17 reported patients with connatal Pelizaeus-Merzbacher disease are summarized. Evidence of autosomal recessive inheritance is provided by our patient, 3 previously described girls, and 1 family with both boys and girls affected equally. This possible form of inheritance is important to consider in genetic counseling.

Lymphoma and leukemia manifested by steroid-responsive polyneuropathy.

Subacute polyneuropathy that responded to prednisone was the initial symptom in two patients, one of whom was later found to have histiocytic lymphoma and the other, chronic lymphocytic leukemia. Sural nerve biopsy specimens in both showed extensive segmental demyelination. In the first patient, there was invasion of the myelinated axons by macrophage processes, and the later course of the neuropathy appeared to parallel that of the lymphoma. In the second patient, there was diffuse lymphocytic infiltration of the perineurium and endoneurium, lymphocytes were found beneath the basal lamina, and the demyelination was characterized by extensive vesicular degeneration of the myelin sheath. The demyelination appeared to be cell mediated in the first patient. This was probably the mechanism in the second patient as well, but simple mechanical compression by infiltrating leukemic cells was another possible explanation.

Adult dystonic lipidosis: clinical, histologic, and biochemical findings of a neurovisceral storage disease.

A 43-year-old man presented with splenomegaly and a 20-year history of a neurologic disorder that included vertical supranuclear ophthalmoplegia, mild dementia, and a movement disorder. Adult dystonic lipidosis was diagnosed from the clinical picture and demonstration of foamy and sea-blue histiocytes in bone marrow. Ultrastructural patterns in cytolysosomes suggested accumulation of neutral fat and phospholipids. Liver content of bis-(monoacylglycerol) phosphate was increased, probably because the number of lysosomes had increased. Sphingomyelinase activity was normal in cultured skin fibroblasts. Juvenile and adult dystonic lipidosis form a clinically, histologically, and biochemically distinct neurovisceral storage disease that differs from Niemann-Pick disease.

Clinical and biochemical heterogeneity of globoid cell leukodystrophy.

The residual galactosylceramide beta-galactosidase activity in cultured skin fibroblasts from a child with late-onset globoid cell leukodystrophy (GLD) was distinctly different from that found in the typical infantile form of the disease. The residual enzyme activity and maximum velocity of the enzyme reaction were higher in this patient, while the Michaelis constant was similar in controls and in the two forms of GLD. The pH optimum of enzyme activity from the patient was similar to that of controls and a more acidic pH optimum was found in the infantile form. Cultured skin fibroblasts from the patient accumulated less [6(3)H]-galactosylceramide than did cells from the infantile form. These various biochemical measurements correlated well with the age of onset of the disease and suggest that different allelic mutations of the galactosylceramide beta-galactosidase locus are responsible for the different clinical forms of GLD.

Genetic control of developmental patterns of cerebral enzyme activities: further differences between C3H and ICR strains of mice.

We have investigated developmental changes in activity for five enzymes associated with different cerebral metabolic systems in two separate strains of mice. The enzymes studied were acid beta-galactosidase, arylsulfatase A, cerebroside beta-galactosidase, cerebroside sulfotransferase, and glutamate decarboxylase. The two strains of mice were C3H/SWV and ICR/SWV. We confirm the experiments of Meisler, Paigen, and colleagues showing higher acid beta-galactosidase activity throughout development in C3H mice. In addition we have demonstrated higher arylsulfatase A activity throughout development in C3H mice. The shape of the developmental curve for arylsulfatase A activity in brain in the two strains was similar. There were no differences in developmental changes of activity between the two strains for the other three enzymes studied.

GM1 gangliosidosis: phenotypic variation in a single family.

Infantile, juvenile, and adult forms of GM1 gangliosidosis have been well characterized. Certain genetic and biochemical studies have suggested that the phenotypic variation found in GM1 gangliosidosis results from different allelic mutations affecting the GM1 ganglioside beta-galactosidase locus and that different combinations of these mutations accounts for the clinical heterogeneity of this illness. A family in which both the infantile and juvenile forms of GM1 gangliosidosis occurred, the children sharing a common mutation of their acid beta-galactosidase activity, supports the allelic nature of these different clinical forms of the disease. From the observations made in this unique family, additional phenotypes of GM1 gangliosidosis might be anticipated.

GM1 gangliosidosis: enzymatic variation in a single family.

Acid beta-galactosidase activity can be separated into multiple molecular forms by isoelectric focusing on cellulose acetate membranes. The residual acid beta-galactosidase in the juvenile form of GM1 gangliosidosis has three bands of enzyme activity with an apparent isoelectric pH (pI) range from 4.9 to 5.2, whereas that in the infantile form has a single band with an apparent pI of 5.2. Separation of residual acid beta-galactosidase into multiple molecular forms by analytical isoelectric focusing demonstrates enzymatic differences that can be correlated with the allelic mutations that affect the GM1 ganglioside beta-galactosidase locus.

Heterozygote detection in MLD. allelic mutations at the ARA locus.

The detection of heterozygotes for MLD based on enzyme assays of a general population is highly unreliable. Twenty-three percent of controls and ARA activities below the levels found in some obligate heterozygotes for MLD. This serious overlap problem precludes the use of ARA determinations in large screening programs to assign individuals into specific genetic categories. On the other hand, intrafamily analysis of ARA activity offers the possibility of accurately determining heterozygotes for MLD. Sixteen children of parents heterozygous for MLD had ARA activities which clearly categorized them as either homozygous affected, heterozygous, or normal. The wide range of ARA activity found in controls and heterozygotes for MLD appeared to result from the presence of multiple allelic mutations at the ARA locus. One of these mutations leads to a low ARA activity and when present in an individual who is heterozygous for MLD may lead to overlap of his total activity with that of some homozygous affected individuals. This low ARA activity mutation can be recognized by alterations in the multiple molecular forms of ARA activity separated by analytical isoelectric focusing electrophoresis.

Developmental dissociation of myelin synthesis and "myelin-associated" enzyme activities in the shiverer mouse.

Developmental changes in three enzymes associated with myelin lipids were studied in the shiverer mouse, a murine mutant showing a severe deficiency of CNS myelin. Age-related changes in cerebroside sulfotransferase (measured in brain) and arylsulfatase A and cerebroside B-galactosidase (measured in brain and liver) were the same for shiverer and control mice. The shiverer mouse, therefore, demonstrates a dissociation between the genetic mechanisms regulating myelination in the CNS and developmental changes in enzyme activities thought to be closely related to the synthesis of myelin. In addition, we found no defect in the shiverer mouse in the incorporation of glycine-labeled basic protein into CNS myelin, indicating an important metabolic difference between the morphologically similar shiverer and quaking mutants.

Multiple molecular forms of arylsulfatase A in different forms of metachromatic leukodystrophy (MLD).

Arylsulfatase A (ARA) can be separated into six to eight individual enzymatic bands of activity by isoelectric focusing on cellulose acetate membranes. The residual ARA activity in juvenile metachromatic leukodystrophy (MLD) has a single band of activity with apI of 5.5, whereas the residual ARA in the late infantile form of MLD has three bands of activity with pI range of from 5.4 to 5.8. The technique of isoelectric focusing on cellulose acetate membranes demonstrates enzymatic differences which can be correlated with the clinical form of the disease.

Multiple molecular forms of certain lysosomal enzymes separated by isoelectric focusing on cellulose acetate membranes.

Analytical isoelectric focusing on cellulose acetate membranes offers greater resolution of the enzyme pattern than does standard electrophoresis and offers numerous advantages over other support media in isoelectric focusing. A series of lysosomal enzymes, deficiencies of which cause lethal storage diseases in infants and children, can be shown to exist as multiple molecular forms by analytical isoelectrical focusing on cellulose acetate membranes. This analytical technique should be a valuable tool in the investigation of enzyme polymorphism and genetically determined enzyme deficiency diseases.