How are we doing with the treatment of essential tremor (ET)?: Persistence of patients with ET on medication: data from 528 patients in three settings.

BACKGROUND: The pharmacological treatment of essential tremor (ET) is not optimal. There are only two first-line medications and troublesome side effects are common. It is not uncommon for patients to simply stop taking medication. Yet, no published data substantiate or quantify this anecdotal impression. OBJECTIVES: To determine, amongst patients with ET who were prescribed medication for tremor, what proportion are still taking medication and what proportion have stopped? METHODS: Five hundred and twenty-eight patients with ET from three distinct study settings (clinical, brain donors, population) were interviewed. RESULTS: A clear pattern that emerged across settings was that the proportion of patients with ET who had stopped medication was sizable and consistently similar (nearly one-third): 31.4% (clinical), 24.3% (brain donors), 30.0% (population), 29.8% (overall). A similarly high proportion of cases with severe tremor had stopped their medication: 31.9% (clinical), 36.4% (brain donors). For the four most commonly used medications (propranolol, primidone, diazepam, topiramate), one-half or more of the treated patients had stopped the medication; amongst the less commonly used medications, the proportion who stopped was even higher. CONCLUSIONS: Nearly one of every three patients with ET who had been prescribed medication for tremor had discontinued pharmacotherapy. Even more revealing was that a similar proportion of cases with severe tremor had stopped medication. These data make tangibly evident that there is a sizable population of patients with ET who are untreated and disabled, and underscore the inadequacy of current pharmacotherapeutic options for this common neurological disease.

Intravascular lymphoma: magnetic resonance imaging correlates of disease dynamics within the central nervous system.

BACKGROUND: Intravascular lymphoma (IVL) is a rare non-Hodgkin's lymphoma with relative predilection for the central nervous system. In the absence of extraneural manifestations, the disease is not recognised until autopsy in the majority of cases underlining the need for new clinical markers. METHODS: This is a retrospective series of five patients with IVL seen at a single institution over three years. An advanced magnetic resonance imaging (MRI) protocol was performed at various time points prior to diagnosis and during treatment. RESULTS: MRI revealed multiple lesions scattered throughout the cerebral hemispheres; the brainstem, cerebellum, and spinal cord were less frequently involved. On initial presentation, hyperintense lesions were seen on diffusion weighted images suggestive of ischaemia in three of four patients in whom the images were obtained at that time point. In four patients lesions were also identifiable as hyperintense areas on fluid attenuated inversion recovery (FLAIR) sequences. Initial contrast enhancement was encountered in three cases. Diffusion weighted imaging lesions either vanished or followed the typical pattern of an ischaemic small vessel stroke with evolution of abnormal FLAIR signal followed by enhancement with gadolinium in the subacute stage and tissue loss in the chronic stage. Diffusion weighted imaging and FLAIR abnormalities proved to be partially reversible, correlating with the response to chemotherapy. CONCLUSION: We provide the first detailed description of the dynamic pattern of diffusion weighted MRI in IVL. These patterns in combination with systemic findings may facilitate early diagnosis and serve as a new tool to monitor treatment response.

Expression of c-fos, c-jun, and c-jun N-terminal kinase (JNK) in a developmental model of induced apoptotic death in neurons of the substantia nigra.

The transcription factors c-fos and c-jun have been proposed to play a role in the initiation of programmed cell death in neurons. We have shown that programmed cell death, with the morphology of apoptosis, occurs in dopamine neurons of the substantia nigra (SN) during normal postnatal development and that this death event can be induced by early striatal target injury. We have investigated the relationship between c-fos and c-jun protein expression and induced death in neurons of the SN. Although c-fos is induced, it is unlikely to play a role in cell death, because its expression is not well correlated with apoptotic death either temporally or at a cellular level. Expression of c-jun, however, is both temporally and regionally correlated with induction of death, and, at a cellular level, it colocalizes with apoptotic morphology. The increased expression of c-jun is likely to be functionally significant, because it is associated with increased c-jun N-terminal kinase (JNK) and phosphorylated c-jun expression. JNK expression also colocalizes with apoptotic morphology. We conclude that c-jun is likely to play a role in the initiation of apoptotic cell death in these neurons.

Increased expression of cyclin-dependent kinase 5 in induced apoptotic neuron death in rat substantia nigra.

We reported previously that striatal excitotoxic lesion with quinolinic acid of rat pups during the first 2 weeks of postnatal life results in loss of dopaminergic neurons of the substantia nigra (SN) due to induced apoptosis. Here we demonstrate by immunohistochemistry that, following such a lesion, high levels of cyclin-dependent kinase 5 (cdk5) protein are present exclusively in apoptotic cells over and above basal levels of diffuse axonal staining. Furthermore, localization of high levels of cdk5 is associated also with normal developmental programmed cell death in the SN and other regions of the central nervous system, including the cerebral cortex. These findings suggest a novel role for cdk5 during neuron apoptosis and may provide insight into mechanisms of loss of dopaminergic neurons in Parkinson's disease.

Neuron death in the substantia nigra of weaver mouse occurs late in development and is not apoptotic.

Weaver is a spontaneous mutation in mice characterized by the postnatal loss of external granule cells in the cerebellum and dopaminergic neurons of the midbrain, especially in the substantia nigra. We have shown previously that natural cell death with the morphology of apoptosis occurs in the substantia nigra of normal rodents during postnatal development. We therefore sought to determine whether the loss of dopaminergic neurons in homozygous weaver mice occurs during the period of natural cell death in the substantia nigra and whether it has the morphology of apoptosis. We have found, using a silver stain technique, that although apoptotic cell death does occur early postnatally in homozygous weaver substantia nigra, it also does so with equal magnitude in wild-type and heterozygous weaver littermates. Unique to homozygous weavers is the occurrence of degenerating neurons in the nigra that are not apoptotic. These degenerating neurons are observed at postnatal day 7, and they are most abundant on postnatal days 24-25. The nonapoptotic nature of this cell death is confirmed by negative in situ end labeling of nuclear DNA fragmentation and by ultrastructural analysis. Ultrastructural studies reveal irregular chromatin aggregates in the nucleus, as well as marked cytoplasmic changes, including the formation of vacuoles and distinctive stacks of dilated cisternae of endoplasmic reticulum. We interpret these changes as indicative of either a variant morphology of programmed cell death or a pathological degenerative process mediated by an as yet unknown mechanism related to the recently described mutation in the GIRK2 potassium channel.

Apoptosis in substantia nigra following developmental hypoxic-ischemic injury.

We have previously observed that either hypoxic-ischemic or excitotoxic striatal injury during development is associated with a reduction in the adult number of dopaminergic neurons in the substantia nigra. This decrease occurs in the presence of preserved striatal dopaminergic markers and in the absence of direct nigral injury. We have also observed that natural cell death, with the morphology of apoptosis, occurs in the substantia nigra, and that there is an induced apoptotic cell death event following early striatal excitotoxic injury. We now report that forebrain hypoxic-ischemic injury is also associated with an induced cell death event in the substantia nigra, with both morphological and histochemical features of apoptosis. Induced apoptotic cell death occurs in immunohistochemically defined dopaminergic neurons. While the mechanisms for this induced cell death are not yet known, in the case of the pars compacta it may be related to the loss of normal striatal target-derived developmental support. Since dopaminergic neurons are postmitotic at the time of the injury, we conclude that this induced cell death is responsible for the diminished adult number of dopaminergic neurons. We also conclude that hypoxic-ischemic injury to the developing brain in general causes not only direct, necrotic injury to vulnerable regions, but also induced apoptotic death at remote sites. The significance of this finding is that apoptosis is a distinct death mechanism, with unique regulatory pathways, which can potentially be modified by approaches different from those which might influence cell death in regions of direct injury. In view of the present finding that apoptosis can occur in the setting of hypoxic-ischemic injury, and our previous work demonstrating its occurrence following excitotoxic injury, it seems likely that it may occur following other forms of injury to the immature brain in which excitotoxic injury plays a role, such as seizures, head trauma and hypoglycemia.

Genetic analysis of laminin A reveals diverse functions during morphogenesis in Drosophila.

In order to dissect the functions of laminin A in vivo, we have undertaken a molecular and genetic characterization of the laminin A subunit (lamA) gene in Drosophila. Sequence analysis predicts a multidomain structure similar to mammalian homologs. We generated a series of complete and partial loss-of-function mutant alleles of the lamA gene; complete loss-of-function mutations lead to late embryonic lethality. Certain combinations of partial loss-of-function lamA alleles give rise to escaper adults, which have rough eyes associated with changes in cell fate and pattern, misshapen legs and defects in wing structure. These phenotypes suggest that laminin A has diverse functions during morphogenesis in Drosophila.

Cell type specific trans-acting factors are involved in alternative splicing of human fibronectin pre-mRNA.

ED-A and ED-B are facultative type III homologies of fibronectin, encoded by alternatively spliced exons, described in man and in rat. A hybrid alpha-globin-fibronectin minigene containing the ED-B region from the human gene has been transfected in human cell lines derived from various tissues, in order to study the processing of the generated precursor RNA in the different cell environments. In most tested lines the pre-RNA is alternatively spliced and produces two mature RNAs, with and without the ED-B exon, in different ratios that closely resemble the corresponding endogenous fibronectin RNAs. In a hepatoma cell line, Hep 3B, only one RNA is produced, in which the ED-B exon is absent; the same pattern of splicing is observed in liver. The data show that all the information required to produce accurate and regulated alternative splicing of the ED-B exon is contained in the fragment used and cell specific factors are necessary for the pre-RNA to be differentially spliced in the various cell lines. In contrast, expression in Hep 3B of a similar gene containing the ED-A area failed to reproduce the liver specific splicing pattern. Therefore regulation of ED-A processing is likely to involve different mechanisms to those responsible for control of ED-B splicing.

Sequence analysis and in vivo expression show that alternative splicing of ED-B and ED-A regions of the human fibronectin gene are independent events.

The structure of two alternatively spliced regions. ED-A and ED-B, of human fibronectin gene, was determined, in order to show whether any similarity was present between the two. Although some interesting features are present in each, no obvious common structure or sequence homology was found. Functional analysis of the alternative splicing events was carried out by transient expression in Hela cells. A hybrid gene was constructed by inserting the ED-B region into the third exon of the human alpha 1-globin gene. The transfected hybrid gene is expressed and produces, in Hela cells, two alternatively spliced RNAs, showing a pattern very similar to that observed for the endogenous fibronectin gene in fibroblasts. Cotransfection of this gene with a similar gene containing the ED-A region, shows that no interference is present between the two alternative splicing processes.