Myelinoclastic diffuse sclerosis (Schilder's disease): cliniconeuroradiologic correlations.

We report a 17-year-old boy with myelinoclastic diffuse sclerosis (Schilder's disease) presenting with left leg paresis, visual loss, and behavioral changes. CT and MRI showed two large lesions in the subcortical white matter of the occipital and parietal lobes of both hemispheres and increased intracranial pressure. Histology disclosed large areas of demyelination and perivascular infiltrates. The patient improved with coincident oral prednisolone treatment.

Glutathione depletion potentiates MPTP and MPP+ toxicity in nigral dopaminergic neurones.

Glutathione levels are decreased in the substantia nigra of patients with Parkinson's disease. We studied whether glutathione depletion contributes to dopaminergic cell death using a specific inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (BSO). We found no significant reduction of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta (SNpc) when BSO was administered systemically to preweanling mice or locally to the SNpc of adult rats. However, the combination of BSO with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) in preweanling mice and the combination of nigral injections of BSO with intrastriatal injections of MPP+ (1-methyl-4-phenylpyridinium), the active metabolite of MPTP in adult rats, potentiated the toxic effects of MPTP and MPP+ on nigral neurones. Our data show that glutathione depletion can result in cell death if the nigrostriatal system is metabolically compromised.

Lamotrigine has no antiparkinsonian activity in rat models of Parkinson's disease.

In rodent models of Parkinson's disease such as reserpinized or 6-hydroxydopamine substantia nigra lesioned rats, blockade of glutamate receptors of the NMDA (N-methyl-D-aspartate) or the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptor subtypes and concomitant treatment with L-DOPA (L-3,4-dihydroxyphenylalanine) or direct dopamine agonists restores locomotor activity and induces rotations. An alternative approach to interfere with glutamatergic transmission would involve the inhibition of glutamate release resulting in functional glutamate antagonism. The novel antiepileptic drug lamotrigine blocks the veratridine-evoked release of the excitatory transmitters L-glutamate and L-aspartate. Due to its presumed antiglutamatergic action it has been suggested that lamotrigine may be useful in the treatment of Parkinson's disease. In a preliminary open-label study in patients with Parkinson's disease some favourable effects were reported. The present study was undertaken to systematically investigate the effects of lamotrigine in rat models of Parkinson's disease. However, lamotrigine failed to exert antiparkinsonian activity in reserpinized rats when administered alone or in combination with the dopamine receptor agonist apomorphine. In rats bearing 6-hydroxydopamine lesions of the substantia nigra lamotrigine did not induce rotations when given alone and did not modify rotations induced by apomorphine or the preferential dopamine D2 receptor agonist lisuride. On the basis of these negative results it is predicted that lamotrigine will not have significant favourable effects on akinesia and rigidity in Parkinson's disease patients.

Effects of 7-nitroindazole, NG-nitro-L-arginine, and D-CPPene on harmaline-induced postural tremor, N-methyl-D-aspartate-induced seizures, and lisuride-induced rotations in rats with nigral 6-hydroxydopamine lesions.

The present behavioral study was undertaken to investigate whether neuronal nitric oxide (NO) synthase mediates the abnormal consequences of increased NMDA receptor-mediated synaptic transmission in models of postural tremor, Parkinson's disease and epilepsy. We used 7-nitroindazole, a selective inhibitor of neuronal NO synthase, and NG-nitro-L-arginine (L-NAME), an unspecific NO synthase inhibitor, and compared their action with that of the competitive NMDA receptor antagonist 3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-1-phosphonic acid (D-CPPene). In both mice and rats, 7-nitroindazole, L-NAME and D-CPPene dose dependently reversed the harmaline-induced increase of cerebellar cyclic guanosine-5'-monophosphate (cGMP) levels. For subsequent behavioral experiments we used doses of 7-nitroindazole, L-NAME and D-CPPene which were equipotent in preventing harmaline-induced cGMP increase. Harmaline-induced tremor in mice and rats was suppressed by D-CPPene, but not by 7-nitroindazole or by L-NAME. This effect of D-CPPene was not due to unspecific suppression of motor activity, since D-CPPene did not affect locomotor activity at doses which reduced tremor. D-CPPene, but not 7-nitroindazole and L-NAME potentiated the antiparkinsonian action of the dopamine agonist lisuride in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. D-CPPene antagonized seizures induced by intracerebroventricular injection of NMDA in mice. In contrast, 7-nitroindazole and L-NAME had only a tendency to prevent seizures and to delay the latency to onset of seizures. We conclude from these results that neuronal NO synthase does not serve as a major mediator of increased NMDA receptor-mediated synaptic transmission in animal models of Parkinson's disease, postural tremor and epilepsy. The novel observation that D-CPPene suppresses harmaline-induced tremor leads us to suggest that NMDA receptor antagonists should be considered as novel therapeutics for postural tremor.

NMDA-mediated toxicity to striatal neurons is not reversed by 7-nitroindazole, an inhibitor of neuronal nitric oxide synthase.

L-glutamate itself and compounds activating glutamate receptor subtypes such as N-methyl-D-aspartate (NMDA) can produce excitotoxic lesions similar to neuronal cell damage following ischemia, traumatic brain injury or as seen in human neurodegenerative disorders. Competitive and non-competitive NMDA-receptor antagonists have neuroprotective properties in a number of in-vitro and in-vivo models for these disorders. The discovery of nitric oxide (NO) in the central nervous system (CNS) and the demonstration of the link between glutamate receptor activation and NO formation led to the hypothesis that NMDA toxicity may be mediated by NO because of its ability to promote free radical generation. Three isoforms of nitric oxide synthase (NOS) have been described, one of which is expressed constitutively in neuronal tissues (nNOS) and is perferentially inhibited by 7-nitroindazole (7-NI). One day after intrastriatal injection of NMDA, systemic pretreatment of rats with 7-NI had no effect on lesion volumes. It is concluded that formation of NO subsequent to NMDA receptor stimulation is not critically involved in excitotoxicity seen in this model.

Highly restricted origin of prefrontal cortical inputs to striosomes in the macaque monkey.

The prefrontal cortex is made up of neocortical areas thought to mediate aspects of the temporal and spatial organization of behavior. One of the prime output targets of the prefrontal cortex is the striatum, which is thought to operate in series with the prefrontal cortex in some neural computations. We have analyzed this prefronto-striatal projection in cynomolgus monkeys by combining anterograde neuronal tract tracing methods with neurochemical markers for the striosome and matrix compartments of the striatum. Our results single out two parts of the frontal cortex as projecting densely to the striosome compartment of the striatum: the posterior orbitofrontal/anterior insular cortex and the mediofrontal prelimbic/anterior cingulate cortex. These areas jointly innervated striosomes in the anterior and ventromedial striatum, mainly in the caudate nucleus. Striosomes in the dorsolateral striatum were never labeled. Thus, the anatomical subsystem defined by striosome affiliation includes three cortical and striatal regions that, in humans, have been implicated in obsessive-compulsive disorder. Nearly all of the remaining parts of the prefrontal cortex studied projected preferentially to the matrix compartment. Most of these prefrontal inputs were also patchy, and many of the patches (matrisomes) were selectively paired with nearby striosomes. The highly fractionated organization of prefrontal inputs to striosomes and matrisomes could form a template for computational networks in the striatum that redistribute prefrontal corticostriatal inputs to serve in context-dependent behavioral planning.

Repertoires of autoantibodies against homologous eye muscle in ocular and generalized myasthenia gravis differ.

If weakness of the eye muscles remains the only symptom of myasthenia gravis (MG) for more than 2 years, the condition is operationally defined as ocular MG (OMG). A number of clinical, genetic, and immunological differences between this variant and generalized MG (GMG) have been described. We analyzed repertoires of autoantibodies against proteins of skeletal and extraocular muscle in sex- and age-matched groups of patients with either GMG or OMG (n = 10 in each group). All GMG sera detected a group of three proteins larger than 200 kDa which were not detected by any of the OMG sera. Two components with apparent molecular weights of 50 and 60 kDa were stained by seven of the ten OMG sera but by none of the GMG group. These antigens are probably soluble, cytoplasmatic proteins of the eye muscle. OMG sera, furthermore, detected a protein of about 45 kDa in the pellet fraction of eye muscle but failed to do so after adsorption with skeletal muscle fractions. We conclude that OMG and GMG sera contain autoantibodies of different specificities. Our findings further support immunological heterogeneity in MG.

Automatic-voluntary dissociation: an unusual facial paresis in a patient with probable multiple sclerosis.

A patient with multiple sclerosis is described who presented with a unilateral loss of voluntary function of his lower face muscles. However, in an emotional situation, there was strong involuntary innervation of these muscles: automatic-voluntary dissociation. The subcortical afferents to the facial motor nucleus are discussed. It is hypothesized that cortical disinhibition of midbrain nuclei underlies the accentuated involuntary innervation.

The diagnostic value of serum autoantibodies in endocrine orbitopathy and idiopathic ocular myositis.

Sera of patients with Graves' orbitopathy (GOP) often contain antibodies against retroorbital tissue components. The presence of such autoantibodies has been considered to indicate an autoimmune pathogenesis of the disease. However, their specificity has not been conclusively tested, because studies demonstrating autoantibodies used controls with no lesion in the extraocular eye muscles. Although ocular myositis (OM) is clinically distinct from GOP, damage to the retroorbital muscles is a common histopathological finding in both conditions. Using an immunoblot technique, reactions of sera from patients suffering from either disease were compared. Sera from both groups contained antibodies against a variety of antigenic determinants recognized by both sera. These autoantibodies may have been induced secondary to tissue damage and should be considered to be nonspecific. Because the role of tissue damage was not accounted for in previous studies, evidence concerning antigens supposedly specific for GOP should be reevaluated. The reaction patterns of OM and GOP sera were slightly different. These differences were specific enough to suggest that sera from patients with GOP contain antibodies against eye muscle components that are not present in the sera of patients with idiopathic OM. These findings support the assumption that GOP is an autoimmune disease. However, the major autoimmune targets remain to be identified and their pathogenic relevance is still unclear.