bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilateral parasagittal parietooccipital polymicrogyria and epilepsy
Authors: Guerrini R. , Dubeau F. , Dulac O. , Barkovich A. J. , Kuzniecky R. , Fett C. , Jones‐Gotman M. , Canapicchi R. , Cross H. , Fish D. , Bonanni P. , Jambaqué I. , Andermann F.
Published: January 2005

We describe 9 patients with a bilateral malformation of cortical development, centered around the parasagittal and mesial aspects of the parietooccipital cortex, with magnetic resonance imaging findings suggestive of polymicrogyria. No familial distribution or etiologic factors were identified. Location in a watershed area between anterior and posterior cerebral arteries suggests postmigratory perfusion failure as the underlying cause. In most patients the malformation was detected by magnetic resonance imaging after computed tomography scans with 10‐mm‐thick sections were considered normal. Seizures, present in all, had started between the ages of 20 months and 15 years (mean, 9 years) and were only intractable in 7. Complex partial seizures with or without minor automatisms were the most frequent ictal pattern. In only 4 patients these were preceded by symptoms indicating posterior onset. Interictal electroencephalograms showed both diffuse and bilateral parietooccipital or temporal abnormalities. The range of IQ scores indicated average intelligence to mild retardation. Several patients presented deficits on neuropsychological tasks requiring performance under time constraints, suggesting that the malformation may result in cognitive slowing. Early diagnosis of this malformation may be difficult because of the lack of neurological signs, relatively late seizure onset, difficulty in localizing seizure onset, and inability to recognize the cortical abnormality on computed tomography scans.
Patients homozygous for the 17p 11.2 duplication in charcot‐marie‐tooth type 1A Disease
Authors: LeGuern E. , Gouider R. , Mabin D. , Tardieu Bs S. , Birouk N. , Parent P. , Bouche P. , Brice A.
Published: January 2005

Charcot‐Marie‐Tooth type 1A disease is an inherited sensorimotor neuropathy that is most often associated with a duplication of chromosome 17p11.2. This region contains the gene of the peripheral myelin protein 22 (PMP22), which is responsible by a gene dosage effect for the Charcot‐Marie‐Tooth type 1A phenotype with 17p11.2 duplication. We performed a clinical, electrophysiological, and genetic study of a consanguinous Charcot‐marie‐Tooth type 1A family with 4 affected siblings, 3 of whom were homozygous for the 17p11.2 duplication, the other a heterozygote. Comparison of phenotypes showed that the severity of the disease was more severely affected than the heterozygous sibling who was pausiymptomatic. These results suggest that the severity of the disease is not determined solely by the number of copies of the PMP22 gene.
Adult‐onset Krabbe's disease in siblings with novel mutations in the galactocerebrosidase gene
Authors: Bernardini Gary L. , Herrera Daniel G. , Rn Debbie Carson , DeGasoperi Rita , Sosa Miguel A. Gama , Kolodny Edwin H. , Trifiletti Rosario
Published: January 2005

Krabbe's disease or globoid cell leukodystrophy is a rare demyelinating disorder of the central and peripheral nervous systems, the diagnosis of which is based on clinical findings and the determination of low to absent functional activiry of athe enzyme β‐galactocerebrosidase. We report the presentation of late‐onset Krabbe's disease in 2 siblings, a 17‐year‐old boy and his 16‐year‐old sistem both with marked deficiency of the enzyme β‐galactocere‐brosidase. Only the older sibling manifested clinical signs and symptoms of the disease, while the younger sister remained asymptomatic to date. Molecular analyses disclosed the presence in this family of two novel single point mutations within the gene for galactocerebrosidase.
Motion direction discrimination in blind hemifields
Authors: Barton Jason J. S. , Sharpe James A.
Published: January 2005

We tested motion direction discrimination with random dot cinematograms (RDCs) projected into the contralateral homonymous visual field defects of 10 patients with unilateral cerebral hemispheric lesions. Five patients had medial occipital lesions that spared the putative motion area in lateral occipitotemporal cortex and the optic radiations and other white matter tracts proximal to this site. The other 5 had lesions involving this area or the proximal optic radiations. Eye position was monitored to ensure fixation. No patient in either group discriminated motion direction in signal/noise RDCs at a level better than chance, and the performance of those with lesions restrited to medial occipital lobe did not differ from those with lateral occipital or optic radiation lesions. A subgroup of patients with medial occipital lesions also performed a „frequency of discrimination”︁ experiment, using 100% coherent dot motion with stimulus velocities ranging as high as 79.4°/sec. Their results on these tests were also no better than chance. Sparing of the putative motion area in lateral occipitotemporal cortex and its input fibers is not a sufficient condition for residual direction discrimination (blindsight) with RDCs in homonymous visual field defects.
Oculomotor nerve and muscle abnormalities in congenital fibrosis of the extraocular muscles
Authors: Engle Elizabeth C. , Goumnerov Boyan C. , McKeown Craig A. , Schatz Martha , Johns Donald R. , Porter John D. , Beggs Alan H.
Published: January 2005

Congenital fibrosis of the extraocular muscles is an autosomal dominant congenital disorder characterized by bilateral ptosis, restrictive external ophthalmoplegia with the eyes partially or completely fixed in an infraducted (downward) and strabismic position, and markedly limited and aberrant residual eye movements. It has been generally thought that these clinical abnormalities result from myopathic fibrosis of the extraocular muscles. We describe the intracranial and orbital pathology of 1 and the muscle pathology of 2 other affected members of a family with chromosome 12‐linked congenital fibrosis of the extraocular muscles. There is an absence of the superior division of the oculomotor nerve and its corresponding alpha motor neurons, and abnormalities of the levator palpebrae superioris and rectus superior (the muscles innervated by the superior division of the oculomotor nerve). In addition, increased numbers of internal nuclei and central mitochondrial clumping are found in other extraocular muscles, suggesting that the muscle pathology extends beyond the muscles innervated by the superior division of cranial nerve III. This report presents evidence that congenital fibrosis of the extraocular muscles results from an abnormality in the development of the extraocular muscle lower motor neuron system.
Differential effects of levodopa on dopaminergic function in early and advanced Parkinson's disease
Authors: Torstenson Richard , Hartvig Per , Långström Bengt , Westerberg Göran , Tedroff Joakim
Published: January 2005

The effect of levodopa on L‐[11C]DOPA influx rate was evaluated in patients with early and advanced Parkinson's disease (PD) by using positron emission tomography (PET). The patients were scanned both drug‐free and after a subsequent therapeutic levodopa infusion. Regional analysis of striatal L‐[11C]DOPA influx rate showed a correlation to the degenerative loss of nerve terminals reported at postmortem analysis in PD. Levodopa induced markedly differential effects on the striatal L‐[11C]DOPA influx rate in early and advanced patients. In patients with mild PD, levodopa infusion decreased L‐[11C]DOPA influx, whereas in patients with advanced PD, levodopa induced significant upregulation of L‐[11C]DOPA influx. These changes were confined to the putamen and were, in both patient categories, most prominent in the dorsal part of the region. The present investigation demonstrates a marked shift in the modulatory action of levodopa with the advancement of PD and suggests the induction of positive feedback in advanced PD. These findings could help explain the less graded clinical response to levodopa in advanced PD and would thus have importance for the understanding of the pathogenesis underlying motor fluctuations.
Increased apolipoprotein E ϵ4 in epilepsy with senile plaques
Authors: Gouras Gunnar K. , Relkin Norman R. , Sweeney David , Munoz David G. , Mackenzie Ian R. , Gandy Sam
Published: January 2005

Inheritance of the apolipoprotein E (ApoE) ϵ4 allele is a risk factor for Alzheimer's disease (AD) and is associated with increased deposition of β‐amyloid (Aβ) in AD, Down's syndrome, and normal aging. Aβ deposition in the form of senile plaques (SPs) has recently been described in patients with temporal lobe epilepsy (TLE). We studied the relationship between ApoE ϵ4 genotype and the deposition of Aβ in temporal lobe tissue from patients who underwent temporal lobectomy for intractable epilepsy. TLE patients with SPs had a 70% ApoE ϵ4 carrier frequency compared with a 27% carrier frequency among age‐matched TLE controls without SPs. Our data suggest that the association between ApoE ϵ4 and intracerebral Aβ accumulation is not unique to the elderly or to those with dementia, and may be a feature of conditions in which there is both an ApoE ϵ4 allele and over‐production of Aβ precursor protein, and, presumably, Aβ.
Clinical and pathological phenotype of the original family with Charcot‐Marie‐Tooth type 1B: A 20‐year study
Authors: Bird Thomas D. , Kraft George H. , Lipe Hillary P. , Kenney Kimbra L. , Sumi S. Mark
Published: January 2005

Charcot‐Marie‐Tooth type 1B is an uncommon form of hereditary motor and sensory neuropathy caused by mutations in the Po myelin protein gene on chromosome 1. We report here a 20‐year observation of 13 members of the first family with Charcot‐Marie‐Tooth disease to demonstrate linkage to chromosome 1 and now known to have a C270A mutation in the Po gene altering the extracellular domain of the protein. Affected individuals generally show an early age at onset, often indicated by delayed ability to walk. Proximal muscle weakness of the lower extremities is common and often marked, but the individuals remain ambulatory and there is no decrease in life span. Motor nerve conduction velocities of the fastest fibers are severely slowed (mean, 9–11 m/sec), even when compared with 3 families having Charcot‐Marie Tooth type 1A (mean, 19–21 m/sec). Variability of disability between family members suggests that genetic and environmental factors in addition to the Po mutation play a role in the final phenotype. Nerve biopsy specimens demonstrate hypertrophy, onion bulb formation, loss of myelinated fibers, and occasional myelin thickening similar to that described in Po myelin knockout mice. Autopsy of the 92‐year‐old great‐grandmother in this family demonstrated diffuse involvement of sensory and motor nerves, with loss of myelin in the posterior columns of the spinal cord and loss of anterior horn neurons but without other involvement of the central nervous system. This family demonstrates the long‐term phenotypic consequences on the peripheral nervous system system of a specific point mutation in the Po myelin gene.
Magnetic resonance imaging of periventricular leukomalacia and its clinical correlation in children
Authors: Olsén Päivi , Pääkkö Eija , Vainionpää Leena , Pyhtinen Juhani , JÄRvelin Marjo‐Riitta
Published: January 2005

The prevalence of periventricular leukomalacia and its association with clinical neurological signs in school‐age preterm children are unknown. We matched 42 eight‐year‐old children who were born before term with birth weights lower than 1,750 gm (mean, 1,410 gm; gestational age, 31 weeks) with 42 children who were born at term and of normal birth weight, to compare clinical neurological status and magnetic resonance imaging findings. Of the children born prematurely, 9.5% had cerebral palsy and 31% had minor neurological dysfunction whereas 9% of the children born at term had minor neurological dysfunction and none had cerebral palsy. Deviations in tongue movements, heel walking, Fogs test results, and finger opposition, as well as behavioral disturbances, differentiated the preterm from the full‐term group. The prevalence of periventricular leukomalacia among all children born prematurely was 32%. It was observed in all children with cerebral palsy, in 25% with minor neurological dysfunction, and in 25% of the clinically healthy preterm children. None of the children born at term had evidence of periventricular leukomalacia. Children with periventricular leukomalacia especially demonstrated poor performance on heel walking and Fogs test. Though commonly found in preterm children, periventricular leukomalacia is not uniformly associated with abnormal neurological findings. A through neurological examination is a better predictor of later developmental problems than is magnetic resonance imaging.
A novel presenilin‐1 mutation: Increased β‐amyloid and neurofibrillary changes
Authors: Gómez‐Isla T. , Wasco W. , Pettingell W. P. , Gurubhagavatula S. , Schmidt S. D. , Jondro P. D. , McNamara M. , Rodes L. A. , Diblasi T. , Growdon W. B. , Seubert P. , Schenk D. , Growdon J. H. , Hyman B. T. , Tanzi R. E.
Published: January 2005

The prevalence of known mutations in presenilin genes (PS1 and PS2) causing early‐onset familial Alzheimer's disease (FAD) was assessed in a population of 98 singleton early‐onset AD cases, 29 early‐onset FAD cases, and 15 late‐onset FAD cases. None of the cases tested positive for the eight mutations initially reported, and none of these mutations were observed in 60 age‐matched controls. A novel mutation (R269H) in PS1 was found in a single case of early‐onset AD but not in any other AD or control case. Thus, the PS mutations tested are quite rare in early‐onset AD. Amyloid β protein (Aβ) deposition was investigated in the temporal cortex of the R269H mutation case using end‐specific monoclonal antibodies to detect the presence of Aβx−40 and Aβx−42 subspecies. Stereologically unbiased tangle and neuropil thread counts were obtained from the same region. R269H PS1 mutation was associated with early age of dementia onset, higher amounts of total Aβ and Aβx−42, and increased neuronal cytoskeletal changes. Thus, if the changes observed on this case prove to be typical of PS1 mutations, PS1 mutations may impact both amyloid deposition and neurofibrillary pathology.
Friedreich‐like ataxia with retinitis pigmentosa caused by the His101Gln mutation of the α‐Tocopherol transfer protein gene
Authors: Yokota Takanori , Shiojiri Toshiaki , Gotoda Takanari , Arita Makoto , Arai Hiroyuki , Ohga Tatsuhide , Kanda Takashi , Suzuki Junichi , Imai Tomihiro , Matsumoto Hiroyuki , Harino Seiyo , Kiyosawa Motohiro , Mizusawa Hidehiro , Inoue Keizo
Published: January 2005

The α‐tocopherol transfer protein (α‐TTP) is a cytosolic liver protein that is presumed to function in the intracellular transport of α‐tocopherol, the most biologically active form of vitamin E. We studied 4 unrelated patients with autosomal recessive Friedreich‐like ataxia who had isolated vitamin E deficiency. A point mutation was identified in all of them at position 101 of the gene for α‐TTP, where histidine (CAT) was replaced with glutamine (CAG). Three of the 4 patients developed retinitis pigmentosa subsequent to the onset of ataxia. Neurological symptoms included ataxia, dysarthria, hyporeflexia, and decreased proprioceptive and vibratory sensations. Electrophysiological and pathological examinations showed that the cardinal sites affected were the central axons of dorsal root ganglion cells and the retina, with minor involvement of the peripheral sensory nerve, optic nerve, and pyramidal tract. The vitamin E tolerance test performed showed that the absorption of vitamin E was normal but that its decrease from the serum was accelerated. Oral administration of vitamin E appeared to halt the progression of visual and neurological symptoms. We propose a new treatable syndrome of Friedreich‐like ataxia and retinitis pigmentosa caused by a defect in the α‐TTP gene.
Accumulation of β‐amyloid precursor protein in HIV encephalitis: Relationship with neuropsychological abnormalities
Authors: Giometto Bruno , An Shu F. , Groves Mike , Scaravilli Tomaso , Geddes Jennian F. , Miller Robert , Tavolato Bruno , Beckett Andrew A. J. , Scaravilli Francesco
Published: January 2005

The pathogenesis of neuropsychological abnormalities in patients with human immunodeficiency virus type 1 (HIV‐1) encephalitis is obscure because neurons are not the target of infection and severe neuronal loss occurs only late during the disease. Moreover, there is evidence indicating that HIV dementia is not a homogeneous entity and could partially reverse after treatment with zidovudine. The finding that impaired axonal flow, evidenced by β‐amyloid precursor protein immunoreactivity, could contribute to the neuropsychological deficits prompted the present study. Brains of patients with full‐blown acquired immunodeficiency syndrome (AIDS) were studied and findings compared with those of normal and abnormal control subjects. The presence of HIV‐1 DNA was investigated by nested polymerase chain reaction; axonal abnormalities were detected by β‐amyloid precursor protein, ubiquitin immunohistochemistry, and silver staining. Accumulation of β‐amyloid precursor protein was observed in all the HIV encephalitis brains studied; the appearance of the immunostaining varied from globular structures to bundles of parallel formations. In 2 AIDS brains without pathological abnormalities, only the latter pattern was detected. The brains with trauma were strongly reactive with β‐amyloid precursor protein antibody and the different reactivity within them correlated with posttrauma survival, only globular structures being detected in the older cases. No correlation was found between the different pattern of β‐amyloid precursor protein reactivity and dementia in AIDS patients. These results show that widespread axonal injury is a constant feature in AIDS brains and suggest that it could play a role in the pathogenesis of the neuropsychological abnormalities of these patients.
Extensive DNA deletion associated with severe disease alleles on spinal muscular atrophy homologues
Authors: Wang Ching H. , Carter Todd A. , Das Kamna , Xu Jin , Ross Barbara M. , Penchaszadeh Graciela K. , Gilliam T. Conrad
Published: January 2005

Spinal muscular atrophy (SMA) is a motor neuron disease presenting with a wide spectrum of phenotypic variations. The primary cause of most, if not all, forms of childhood‐onset spinal muscular atrophy appears to be the homozygous loss of the telomeric copy of the survival motor neuron (SMNT) gene. It is interesting that approximately half of all affected patients are likewise homozygous nulls for the neuronal apoptosis inhibitory protein (NAIP) gene and a somewhat lessor fraction for the basal transcription factor, p44 subunit (BTFP44) gene. It has been proposed that homozygous loss of SMNT is the primary cause of spinal muscular atrophy while the loss of NAIP and perhaps other genes primarily affects the severity of disease manifestation. We explored this hypothesis by evaluating the extent of gene deletions in three multigenerational families with spinal muscular exhibiting dramatic intrafamilial phenotypic variation. Using somatic cell hybrid lines to sequester individual spinal muscular atrophy homologues, we show that homologues missing several contiguous genes correlate with “severe” disease alleles and homologues missing only SMNT correlate with “mild” disease alleles. These observations support the hypothesis that phenotypic severity among the childhood‐onset spinal muscular atrophies is directly correlated with the extent of disease‐specific deletions.
Circulating tumor necrosis factor‐α correlates with electrodiagnostic abnormalities in Guillain‐Barré syndrome
Authors: Sharief M. K. , Ingram D. A. , Swash M.
Published: January 2005

Autoimmune damage to peripheral nerves, mediated by activated T lymphocytes and macrophages, underlies the pathogenesis of inflammatory demyelination in Guillain‐Barré syndrome. Both T lymphocytes and macrophages secrete tumor necrosis factor‐α, a cytokine that exerts toxic effects on myelin, Schwann cells, and endothelial cells. The reportedly high serum levels of this cytokine in patients with Guillain‐Barré syndrome may reflect the degree of immune activation rather than a direct pathogenic effect. We compared serum levels of tumor necrosis factor‐α, interleukin‐1β, and soluble interleukin‐2 receptor with well‐established electrodiagnostic criteria for primary demyelination in 23 patients with Guillain‐Barré syndrome, to assess the relationship between these cytokines and peripheral myelin damage. High serum levels of tumor necrosis factor‐α were associated with prolonged distal motor latencies and slowed motor conduction velocities, prolonged or absent F‐wave responses, and reduced amplitude of distal compound muscle action potentials. No significant correlation was observed between electrodiagnostic criteria for primary demyelination and serum levels of interleukin‐1β or soluble interleukin‐2 receptor. These findings suggest a putative role of tumor necrosis factor‐α in the pathogenesis of peripheral nerve demyelination in Guillain‐Barré syndrome.
Multiple sclerosis: Oligodendrocytes display cell death–related molecules in situ but do not undergo apoptosis
Authors: Bonetti Bruno , Raine Cedric S.
Published: January 2005

To investigate whether apoptosis is involved in the fate of oligodendrocytes in chronic multiple sclerosis lesions, the pro‐apoptotic molecules fas and tumor necrosis factor receptors and the anti‐apoptotic molecule bcl‐2 were examined by immunohistochemistry, and DNA fragmentation was assessed by an end labeling technique. Fas and both tumor necrosis factor receptors were preferentially expressed on oligodendrocytes in multiple sclerosis lesions, this phenotype being more evident at the lesion edge. The ligand for fasL, was constitutively present at high levels on microglia. The anti‐apoptotic molecule bcl‐2 was selectively expressed on oligodendrocytes in silent lesions and on astrocytes in active lesions. These molecules were also detected in control material, albeit at lower levels. In chronic active lesions, a few inflammatory cells displayed fas reactivity, whereas the majority expressed bcl‐2. DNA fragmentation was found in a number of infiltrating cells and some microglia, whereas, with one possible exception, oligodendrocytes showed no evidence of apoptosis. Thus, while apoptosis is involved in the elimination of infiltrating cells, it plays little or no role in oligodendrocyte depletion in multiple sclerosis, a process that may be related to a lytic pathway. In addition, microglia constitutively displayed the ligand for fas, and appeared to be the major effector cell population in the central nervous system.
Presenilin‐I polymorphism and hereditary cerebral hemorrhage with amyloidosis, Dutch type
Authors: Bornebroek M. , Haan J. , Backhovens H. , Deutz P. , Van Buchem M. A. , van den Broeck M. , Bakker E. , Roos R. A. C. , Van Broeckhoven C.
Published: January 2005

Hereditary cerebral hemorrhage with amyloidosis, Dutch type, caused by a mutation at codon 693 of the amyloid β precursor protein gene, is characterized by amyloid β deposition resulting in recurrent strokes and dementia. Recent data suggest that presenilin‐1 may be biologically linked to cerebral amyloid β deposition. The intronic presenilin‐1 polymorphism published by Wragg and colleagues (1996) was analyzed in 65 carriers of the hereditary cerebral hemorrhage with amylodosis, Dutch type, mutation. We found that the presenilin‐1 genotype was not correlated with age at first stroke, number of recurrences, dementia, and age at death or with white matter hyperintensities and focal lesions on magnetic resonance images. From our data we conclude that amyloid β deposition in this disease is most likely not influenced by presenilin‐1.
Familial spongiform encephalopathy associated with a novel prion protein gene mutation
Authors: Nitrini Ricardo , Rosemberg Sergio , Passos‐Bueno Maria Rita , da Silva Luís S. Teixeira , Iughetti Paula , Papadopoulos Maria , Carrilho Paulo M. , Caramelli Paulo , Albrecht Steffen , Zatz Mayana , LeBlanc Andrea
Published: January 2005

Human prion diseases include Creutzfeldt‐Jakob disease, Gerstmann‐Sträussler‐Scheinker disease, fatal familial insomnia, and kuru. Each of these diseases has a specific clinical presentation while spongiform encephalopathy, neuronal loss, and gliosis are their neuropathological hallmarks. We studied a Brazilian family with an autosomal dominant form of dementia. Nine members of the family were affected by a dementia with frontotemporal clinical features, with a mean age at onset of 44.8 ± 3.8 years and a mean duration of symptoms of 4.2 ± 2.4 years. Neuropathological examination of 3 patients showed severe spongiform change and neuronal loss in the deep cortical layers and in the putamen, but minimal gliosis in the most severely affected areas. The putamen and cerebellum, but not other areas of the affected brain, displayed prion protein immunoreactivity. A novel prion protein gene mutation causing a nonconservative substitution at codon 183 was identified in 2 neuropathologically confirmed affected individuals (mother and son). The mutation was transmitted in a mendelian fashion to 12 members of the family. Therefore, we identified a novel prion disease variant characterized by an early onset and long duration of the symptoms, severe spongiform change with minimal gliosis, associated with a prion protein gene mutation at codon 183.
Long‐duration response to levodopa influences the pharmacodynamics of short‐duration response in Parkinson's disease
Authors: Zappia Mario , Colao Rosanna , Montesanti Rita , Rizzo Milena , Aguglia Umberto , Gambardella Antonio , Oliveri Rosario Lćno , Quattrone Aldo
Published: January 2005

The long duration response (LDR) to chronic levodopa treatment may mask the short‐duration response (SDR) to a single dose of the drug in Parkinson's disease (PD). As a result, the measurement of SDR may be inaccurate for establishing levodopa dosing regimen in individual patients. To evaluate the possible contamination of SDR by LDR, we investigated in 16 patients with PD the characteristics of SDR to a single dose of levodopa administered after a prolonged washout from chronic therapy and after a 15‐day treatment period with levodopa. Levodopa treatment produced a sustained LDR, and the SDR, measured on the 15th day of treatment, had lower magnitude and shorter duration than the response recorded after washout. Moreover, after treatment, SDR did not vary between patients with mild and severe PD, whereas, after washout, severely affected patients had larger but shorter SDR than mildly affected patients. The evaluation of SDR without the interference of LDR is critical in defining the characteristics of the therapeutic response to levodopa.
High‐frequency unilateral thalamic stimulation in the treatment of essential and parkinsonian tremor
Authors: Koller William , Pahwa Rajesh , Busenbark Karen , Hubble Jean , Wilkinson Steve , Lang Anthony , Tuite Paul , Sime Elspeth , Lazano Andres , Hauser Robert , Malapira Teresita , Smith Donald , Tarsy Daniel , Miyawaki Edison , Norregaard Thorkild , Kormos Theresa , Olanow C. Warren
Published: January 2005

Pharmacologic treatment for essential tremor and the tremor of Parkinson's disease is often inadequate. Stereotaxic surgery, such as thalamotomy, can effectively reduce tremors. We performed a multicenter trial of unilateral high‐frequency stimulation of the ventral intermedius nucleus of the thalamus in 29 patients with essential tremor and 24 patients with Parkinson's disease, using a blinded assessment at 3 months after surgery to compare clinical rating of tremor with stimulation ON with stimulation OFF and baseline and a 1‐year follow‐up. Six patients were not implanted because of lack of intraoperative tremor suppression (2 patients), hemorrhage (2 patients), withdrawal of consent (1 patient), and persistent microthalamotomy effect (1 patient). A significant reduction in both essential and parkinsonian tremor occurred contralaterally with stimulation. Patients reported a significant reduction in disability. Measures of function were significantly improved in patients with essential tremor. Complications related to surgery in implanted patients were few. Stimulation was commonly associated with transient paresthesias. Other adverse effects were mild and well tolerated. Efficacy was not reduced at 1 year. Chronic high‐frequency stimulation is safe and highly effective in ameliorating essential and parkinsonian tremor.
The X‐linked infantile spasms syndrome (Mim 308350) maps to Xp 11.4–Xpter in two pedigrees
Authors: Claes S. , Devriendt K. , Lagae L. , Ceulemans B. , Dom L. , Casaer P. , Raeymaekers P. , Cassiman J. J. , Fryns J. P.
Published: January 2005

We report 2 families with X‐linked infantile spasms syndrome (X‐linked West syndrome). Data from clinical examination, biochemical analysis, neuroimaging, and neuropathology are discussed. In these families, genetic linkage analysis was able to locate the disease gene to the distal part of the short arm of the X chromosome, between Xpter and Xp11.4. This is the first report of linkage with genetic markers in this disorder. Although most cases are sporadic, further unraveling of the genetic background of the familial cases might greatly improve our understanding of infantile spasms.
Human immunodeficiency virus infection of dorsal root ganglion neurons detected by polymerase chain reaction in situ hybridization
Authors: Brannagan Thomas H. , Nuovo Gerard J. , Hays Arthur P. , Latov Norman
Published: January 2005

A predominantly sensory peripheral neuropathy is common with human immunodeficiency virus (HIV) infection, but the cause is unknown. Formalin‐fixed dorsal root ganglia (DRG), obtained at postmortem from patients with neuropathy and HIV infection and from control subjects, were examined for the presence of HIV DNA by using polymerase chain reaction (PCR)‐amplified in situ hybridization. Viral message RNA was detected using reverse transcription in situ PCR with gag‐specific primers. HIV DNA and RNA sequences were detected in many satellite cells, mononuclear cells, and occasional neurons in 5 of 5 patients with HIV and neuropathy. HIV DNA was detected only in rare interstitial and satellite cells from 3 of 4 patients with HIV infection without neuropathy and was not detected in 6 patients without HIV infection. HIV infection of DRG neurons and supporting cells may contribute to the HIV‐associated sensory neuropathy.
A Bcl‐2 antisense oligonucleotide increases α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) toxicity in cortical cultures
Authors: White Melissa J. , Chen Jun , Li Zhu R. , Irvin Stacy , Sinor Amy , DiCaprio Michael J. , Jin Kunlin , Greenberg David A.
Published: January 2005

Both α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptor–mediated neurotoxicity and the induction of death‐regulatory genes have been implicated in the pathophysiology of delayed ischemic neuronal injury. To assess the role of the antiapoptotic gene Bcl‐2 in the modulation of AMPA toxicity, we exposed neuron‐enriched cultures from rat cerebral cortex to AMPA, in the absence or presence of an antisense oligodeoxynucleotide (ODN) directed against Bcl‐2. AMPA produced concentration‐dependent toxicity detected by a decrease in fluorescence of the redox indicator Alamar blue and by an increase in lactic acid dehydrogenase release. This effect was accompained by the induction of Bcl‐2 protein expression, with maximal induction at 100 μM AMPA. A phosphorothioate antisense ODN against Bcl‐2 reduced the AMPA‐stimulated induction of Bcl‐2 protein levels, detected by western blotting, by about 70%. In the presence of the antisense ODN, but not sense or scrambled ODNs, the toxicity of 100 μM AMPA was increased by about 60%. These findings suggest that induction of Bcl‐2 expression by AMPA may have a protective role to limit AMPA receptor–mediated neuronal damage and that modifying Bcl‐2 expression could have therapeutic potential in ischemia.
Pallidotomy for hemiballismus: Efficacy and characteristics of neuronal activity
Authors: Suarez J. I. , Metman L. Verhagen , Reich S. G. , Dougherty P. M. , Hallet M. , Lenz F. A.
Published: January 2005

A patient with unremitting, medically intractable hemiballismus underwent a pallidotomy that abolished his involuntary movements. Firing rates of cells in the internal segment of the globus pallidus (GPi) recorded during this procedure were significantly lower than those observed during pallidotomy for Parkinson's disease, either “on” or “off” medication. Firing patterns in hemiballismus were characterized by low‐frequency modulation of the firing rate. These results are consistent with the hyperkinetic model, which suggests that hemiballismus results from decreased inhibition of the pallidal relay nucleus of the thalamus by the GPi. The efficacy of surgery in the case of hemiballismus demonstrates that pallidotomy can be an effective treatment for this condition and suggests that patterned neuronal activity in the GPi is important in the mechanism of hyperkinetic disorders.
Outcome after temporal lobectomy in bilateral temporal lobe epilepsy
Authors: Sirven Joseph I. , Malamut Barbara L. , Liporace Joyce D. , O'Connor Michael J. , Sperling Michael R. , O'Connor Michael J.
Published: January 2005

We determined how noninvasive presurgical data relate to prognosis after temporal lobectomy in patients with independent bilateral temporal lobe (IBTL) complex partial seizures on the intracranial electroencephalogram (EEG). Between 1986 and 1994, 28 patients had IBTL seizures on intracranial EEG. Fifteen of these 28 patients underwent temporal lobectomy and 13 were not offered surgery. Of the 15 patients who had surgery, 10 patients became seizure‐free. Magnetic resonance imaging (MRI) and the Wada test were the only variables associated with a seizure‐free outcome. Seven of 10 seizure‐free patients had a lateralized Wada result or the presence of unilateral hippocampal sclerosis, whereas none of the patients with persistent seizures had either of these findings. Variables not found to be predictive of a seizure‐free outcome included location of scalp interictal spikes, degree of seizure‐onset laterality, presence of early epilepsy risk factor, duration of epilepsy, and full‐scale intelligence quotient. We conclude that MRI and the Wada test provide information of prognostic value in patients with bilateral temporal seizures independent of intracranial EEG data.
Unilateral cerebellar lesions affect initiation of ipsilateral smooth pursuit eye movements in humans
Authors: Straube A. , Scheuerer W. , Eggert T.
Published: January 2005

To clarify the role of the cerebellum in pursuit initiation (first 100 msec), we used infrared oculography to examine the effect of unilateral cerebellar lessions on the initial (0–20 msec) and later (80–100 msec) periods as well as the steady‐state response (200–300 msec) of horizontal smooth pursuit in 10 patients with unilateral cerebellar lesions. These results were compared with those of 17 age‐matched healthy subjects. Smooth pursuit was elicited with a step‐ramp target movement with randomized horizontal directions and velocities of 10/sec and 30/sec. In the first 20‐msec pursuit, velocity was 22% lower toward the side of the cerebellar lesion than away from it and 16% lower in the period 80 to 100 msec (normal differences, 2% and 3%). Later (200–300 msec), the ipsiversive/contraversive difference was smaller, but pursuit velocity in both directions was significantly lower in patients than in normals. No lesion affected the floccular region and/or the nodulus/uvula. Five lesions extended so far medially that they could have affected the medial deep cerebellar nucleus (fastigial nucleus). The remaining five were in the lateral hemisphere in areas previously considered uninvolved in pursuit generation. Our findings prove that the cerebellum participates in human pursuit initiation and that lesions in the lateral cerebellum possibly affect smooth puröit.
Butyrylcholinesterase in the life cycle of amyloid plaques
Authors: Guillozet A. L. , Mesulam M.‐M. , Smiley J. F. , Mash D. C.
Published: January 2005

Deposits of diffuse β‐amyloid (Aβ) may exist in the brain for many years before leading to neuritic degeneration and dementia. The factors that contribute to the putative transformation of the Aβ amyloid from a relatively inert to a pathogenic state remain unknown and may involve interactions with additional plaque consituents. Matching brain sections from 2 demented and 4 nondemented subjects were processed for the demonstration of Aβ immunoreactivity, butyrylchlinesterase (BChE) enzyme activity, and thioflavine S binding. Additional sections were processed for the concurrent demonstration of two or three of these markers. A comparative analysis of multiple cytoarchitectonic areas processed with each of these markers indicated that Aβ plaque deposits are likely to undergo three stages of maturation, ie, a “diffuse” thioflavine S–negative stage, a thioflavine S–positive (ie, compact) but nonneuritic stage, and a compact neuritic stage. A multiregional analysis showed that BChE‐positive plaques were not found in cytoarchitectonic areas or cortical layers that contained only the thioflavine S–negative, diffuse type of Aβ plaques. The BChE‐positive plaques were found only in areas containing thioflavine S–positive compact plaques, both neuritic and nonneuritic. Within such areas, almost all ( > 98%) BChE‐containing plaques bound thioflavine S, and almost all (93%) thioflavine S plaques contained BChE. These results suggest that BChE becomes associated with amyloid plaques at approximately the same time that the Aβ deposit assumes a compact β‐pleated conformation. BChE may therefore participate in the transformation of Aβ from an initially benign form to an eventually malignant form associated with neuritic tissue degeneration and clinical dementia.
Treatment of gustatory sweating with botulinum toxin
Authors: Toyka Klaus V. , Reiners Karlheinz , Naumann Markus , Zellner Max
Published: January 2005

Gustatory sweating is an autonomic disorder that frequently occurs after parotid gland surgery. We investigated the action of intracutaneous injections of botulinum toxin (BTX) (1.0–2.0 mouse units/2.25‐cm2 skin area) in 45 patients (mean age, 52 years) with gustatory sweating. The area of hyperhidrosis was determined by Minor's iodine test before and up to 24 weeks after the injection. The effect of BTX was assessed by measuring the hyperhidrotic area. The maximum BTX‐induced reduction of gustatory sweating was seen at 7.4 · 4.5 days after injection. The area of sweating decreased from 17.6 · 8.6 cm2 before BTX to 1.3 · 1.6 cm2 after BTX (p < 0.0001). Half the patients rated gustatory sweating subjectively as completely abolished, and the remainder felt pronounced improvement. No toxic effects were observed. In none of the patients did hyperhidrosis recur over a 6‐month follow‐up. We conclude that BTX is a safe and effective treatment that can be recommended as the therapy of choice in gustatory sweating.
Are portable folding chairs useful to combat orthostatic hypotension?
Authors: Smit Adrianus A. J. , Hardjowijono Mireille A. , Wieling Wouter
Published: January 2005

The effect of sitting on a derby chair (height, 48 cm), fishing chair (38 cm), and footstool (20 cm) on the improvement of postural hypotension was studied serially in 8 patients with autonomic failure. The increment in blood pressure during sitting was higher by using a lower portable chair. This was related to an increasing cardiac output at lower sitting heights. The fishing chair was, according to our patients' experience, most useful.
Guidelines for using quantitative measures of brain magnetic resonance imaging abnormalities in monitoring the treatment of multiple sclerosis
Authors: Filippi M. , Horsfield M. A. , Adèr H. J. , Barkhof F. , Bruzzi P. , Evans A. , Frank J. A. , Grossman R. I. , McFarland H. F. , Molyneux P. , Paty D. W. , Simon J. , Tofts P. S. , Wolinsky J. S. , Miller D. H.
Published: January 2005

The change of brain lesion load, measured on T2‐weighted magnetic resonance imaging (MRI) using computer‐assisted techniques, is a widely used secondary endpoint for phase III clinical trials in multiple sclerosis (MS). Collections, transfer, and analysis of the electronic data across multiple centers have all proved challenging and give rise to potential errors. However, many new acquisition schemes and postprocessing techniques have been developed; these may reduce scan times and result in better lesion conspicuity or lessen the human interaction needed for data analysis. This review considers many aspects of the use of MRI in clinical trials for MS and provides international consensus guidelines, derived from a task force of the European Magnetic Resonance Networks in Multiple Sclerosis (MAGNIMS) together with a group of North American experts. The main points considered are the organization of correctly powered trials and selection of participating sites; the appropriate choice of pulse sequences and image acquisition protocol given the current state of technology; quality assurance for data acquisition and analysis; accuracy and reproducibility of lesion load assessments; and the potential for the application of quantitative methods to other MRI‐derived measures of disease burden.
Adenosine A2A Antagonist: A novel antiparkinsonian agent that does not provoke dyskinesia in Parkinsonian monkeys
Authors: Kanda Tomoyuki , Jackson Michael J. , Smith Lance A. , Pearce Ronald K. B. , Nakamura Joji , Kase Hiroshi , Kuwana Yoshihisa , Jenner Peter
Published: January 2005

Treatment of Parkinson's disease with L‐dopa therapy leads to long‐term complications, including loss of drug efficacy and the onset of dyskinesia. Adenosine A2A receptors in striatum are selectively localized to GABAergic output neurons of the striato‐pallidal pathway and may avoid such problems. The novel adenosine A2A receptor antagonist KW‐6002 has been examined for antiparkinsonian activity in MPTP‐treated primates. Oral administration of KW‐6002 reversed motor disability in MPTP‐treated common marmosets in a dose‐dependent manner. However, KW‐6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW‐6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW‐6002 induced little or no dyskinesia in MPTP‐treated primates previously primed to exhibit dyskinesia by prior exposure to L‐dopa. These results suggest that selective adenosine A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.
Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions
Authors: Murer M. Gustavo , Dziewczapolski Gustavo , Menalled Liliana B. , García M. Carmen , Agid Yves , Gershanik Oscar , Raisman‐Vozari Rita
Published: January 2005

Orally administered levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD). The introduction of levodopa therapy is often delayed, however, because of the fear that it might be toxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxicity is scarce. We have evaluated the effects of a 6‐month oral levodoapa treatment on several dopaminergic markers, in rats with moderate or severe 6‐hydroxydopamine‐induced lesions of mesencephalic dopamine neurons and sham‐lesioned animals. Counts of tyrosine hydroxylase (TH)‐immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopa‐treated and vehicle‐treated rats. In addition, for rats of the sham‐lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly defferent between rats treated with levodopa or vehicle. It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Furthermore, the density of TH‐positive fibers observed in moderately lesioned rats was higher in those treated chronically with levodopa than in those receiving vehicle. Last, that chronic levodopa administration reversed the up‐regulation of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically effective 6‐month oral levodopa treatment is not toxic for remaining dopamine neurons in a rat model of PD but instead promotes the recovery of striatal innervation in rats with partial lesions.
Pathogenesis of cortical myoclonus studied by magnetoencephalography
Authors: Mima Tatsuya , Nagamine Takashi , Ikeda Akio , Yazawa Shogo , Kimura Jun , Shibasaki Hiroshi
Published: January 2005

Myoclonus‐associated cortical activities were studied by simultaneous recording of a magnetoencephalogram and an electroencephalogram in 6 patients with cortical myoclonus due to various causes. Cortical activities were averaged, with respect to the precise onset of the myoclonic jerk, to evaluate the myoclonus‐associated cortical magnetic fields. The estimated generator of their earliest peak was localized at the contralateral precentral gyrus in all patients. As judged from the direction of the electrical current, surface positive activity preceding the electromyographic discharge was detected in 3 patients with cortical reflex myoclonus and in 1 patients with possible corticobasal degeneration. In contrast, in the remaining 2 patients (Lennox‐Gastaut syndrome and Alzheimer's disease), magnetic fields time‐locked to the myoclonic jerk were associated with surface negative activity at the precentral cortex. The present study, applying for the first time an off‐line jerk‐locked back‐averaging analysis to magnetoencephalography, demonstrated the important role of the precentral cortex in generating spontaneous myoclonus. It is most likely that the differing polarity of the electromagnetic activity reflects the differing activation pattern within the cortical laminar structure in the precentral area, underlying the generation of various types of myoclonus.
Association between centromeric deletions of the SMN gene and sporadic adult‐onset lower motor neuron disease
Authors: Moulard Bruno , Salachas Francois , Chassande Bénédicte , Briolotti Valerie , Meininger Vincent , Malafosse Alain , Camu William
Published: January 2005

The telomeric copy (t) of the survival motor neuron (SMN) gene is homozygously deleted in more than 90% of patients with infantile motor neuron disease (MND). In the general population, no homozygous SMNt deletion has been found, whereas 5% of centromeric SMN (SMNc) deletions can be observed. Although SMNt deletions appear causal for infantile and at least some adult‐onset spinal muscular atrophy (SMA) (type IV), the respective role of SMN deletions remains unclear in adult‐onset MNDs. We studied SMN gene in three different groups of patients with adult‐onset MNDs. In sporadic amyotrophic lateral sclerosis (ALS; n = 177) ands familial ALS (n = 66), no SMNt deletion had been found, and the frequency of SMNc deletions was not increased. Converesly, among the 14 patients with sporadic pure lower MND (LMND), we found 2 patients with homozygous SMNt deletions (14%) and 5 patients with homozygous SMNc deletions (36%). These data suggest that (1) SMNt deletions do not account for the major part, if any, of adult‐onset LMND cases; and (2) SMNc deletions act as a susceptibility factor for LMNDs in adults. The clinical and gentic heterogeneity of LMND cases, including SMA type IV, are yet to be unexplained. Further studies on large groups of adult‐onset LMND patients are warranted to refine its nosology.