bluuebunny/crossref_metadata_2025 huggingface dataset:
Apolipoprotein E and alzheimer's disease: Ethnic variation in genotypic risks
Authors: Maestre Gladys , Ottman Ruth , Stern Yaakov , Gurland Barry , Chun Michael , Tang Ming‐Xin , Shelanski Michael , Tycko Benjamin , Mayeux Richard
Published: January 2005

The presence of the apolipoprotein ε4 (apo ε4) allele significantly increases the risk of Alzheimer's disease. Whether this is due to biological effects of the apo ε4 protein or reflects linkage disequilibrium with an as yet unidentified Alzheimer's disease susceptibility gene is of critical importance. In a community study in northern Manhattan we found a fivefold increase in the risk of Alzheimer's disease among African‐Americans, Hispanics, and whites homozygous for apo ε4. Overall, the risk between Alzheimer's disease and apo ε4 heterozygosity was also increased by twofold, but the association was somewhat weaker for African‐Americans than for Hispanics and whites. In contrast, the apo ε2/ε3 genotype was associated with an eightfold increased risk of Alzheimer's disease in African‐Americans but it was associated with reduced risk in whites. Variability in the strength and type of association between Alzheimer's disease and the apo E polymorphisms in the three ethnic groups could not be fully explained by age differences. The allelic frequency of apoε*4 was significantly higher in patients than control subjects in all ethnic groups at age 70 or younger, reflecting the higher proportion of apo ε4 homozygotes, but this difference diminished with increasing age. The allelic frequency of apoε*2 for African‐Americans and Hispanics, but not whites, was significantly higher in patients than control subjects, but only after age 70. Though these findings need confirmation, they suggest that modifier genes or environmental factors may interact selectively with apo ε4 in African‐Americans to weaken the association with Alzheimer's disease or that the apo E allelic system is in linkage disequilibrium with a nearby, as yet unidentified Alzheimer's disease susceptibility locus.
Reduced expression of preproenkephalin in striatal neurons from huntington's disease patients
Authors: Richfield Eric K. , Maguire‐Zeiss Kathleen A. , Cox Christopher , Gilmore Jennifer , Voorn Pieter
Published: January 2005

Differential loss of neurons and terminals occurs in Huntington's disease. Neurons expressing preproenkephalin (PPE) appear to be more vulnerable than neurons expressing preprotachykinin and terminals in the lateral pallidum (containing enkephalin) are more affected than terminals in the medial pallidum (containing substance P). We used in situhybridization histochemistry and emulsion autoradiography to quantify the number of PPE expressing neurons and the neuronal levels of PPE mRNA in striatum of individuals who died with Huntington's disease and normal controls. We found a grade‐related decline in the number of PPE‐labeled neurons per field in the striatum of individuals with Huntington's disease compared with controls. Three measures of the neuronal level of PPE mRNA, the mean number of silver grains per PPE neuron, the median number of grains per PPE neuron, and the percentage of PPE neurons with more than 30 grains, were all significantly reduced (41 to 80% of control) in Huntington's disease striatum. The magnitude of the reduction in levels of PPE mRNA per neuron was related to the grade of lesions. These data support the notion that decreased levels of PPE mRNA may account, in part, for the greater loss of enkephalin staining in lateral pallidal terminals compared with substance P staining in medial pallidal terminals. Decreased levels of PPE mRNA may result in clinical symptoms prior to the loss of neurons. The reduction in expression of PPE mRNA suggests that surviving striatal neurons may be affected by the expression of the Huntington's disease gene prior to their imminent cell death.
Hyperkalemic periodic paralysis with cardiac dysrhythmia: A novel sodium channel mutation?
Authors: Baquero Jaime L. , Ayala Ricardo A. , Wang Jianzhou , Curless Richard G. , Feero W. Gregory , Hoffman Eric P. , Ebeid Makram R.
Published: January 2005

A patient is presented with hyperkalemic periodic paralysis (HyperPP) and a cardiac dysrhythmia. An amino acid substitution (Val783Ile) in the adult skeletal muscle sodium channel gene was detected. Although lack of available family members precluded rigorous genetic tests, the sodium channel change may be responsible for HyperPP in this patient and could also be responsible for the associated cardiac dysrhythmia.
Activated T cells of nonneural specificity open the blood‐nerve barrier to circulating antibody
Authors: Pollard J. D. , Westland K. W. , Harvey G. K. , Jung S. , Bonner J. , Spies J. M. , Toyka K. V. , Hartung H.‐P.
Published: January 2005

Recent studies from our laboratory and by other investigators have shown that autoreactive CD4+ cells specific for peripheral nerve P2 protein have a powerful effect on blood‐nerve barrier permeability. In this study we injected CD4+ T cells reactive to a nonneural antigen (ovalbumin) systemically and achieved their accumulation in the tibial nerve of Lewis rats by previous intraneural injection of ovalbumin. Selected rats were given systemic demyelinating antibody (antigalactocerebroside) to provide an indicator of changes in the permeability of the blood‐nerve barrier, and the animals were monitored by sequential neurophysiological studies and histology. Circulating ovalbumin‐specific T cells accumulated at sites of intraneural ovalbumin injection without inducing demyelination in control animals. In rats with circulating galactocerebroside antibodies, local conduction block and demyelination were seen in the region of T‐cell accumulation. Electron microscopy demonstrated dissolution of some tight junctions between endothelial cells in areas of T‐cell accumulation, and T cells traversing the endothelium between endothelial cells and through their cytoplasm. Endothelial cell damage was evident in these areas. This study demonstrates breakdown of the blood‐nerve barrier by activated T cells, even of nonneural specificity, allowing the development of focal conduction block and demyelination in the presence of circulating antimyelin antibodies.
Ocular neuromyotnia: Clinical features, physiological mechanisms, and response to therapy
Authors: Frohman Elliot M. , Zee David S.
Published: January 2005

Ocular neuromyotonia (ONM) is a rare disorder characterized by episodic diplopia, occurring either spontaneously or following sustained eccentric gaze. Most patients have had prior radiation therapy to the sellar and parasellar region. ONM is thought to reflect impaired muscle relaxtion due to inappropriate discharges from oculomotor, trochlear, or abducens neurons or axons with unstable cell membranes. Patients with ONM often benefit from membrane stabilizing agents such as carbamazepine. Here we describe a 71‐year‐old man, with no history of radiation therapy, who for 18 months had had transient episodic diplopia that occurred after down gaze. Clinical examination indicated ONM in muscles supplied by the right oculomotor nerve. Binocular scleral search coil eye movement recordings revealed a defect not only of muscle relaxation but also of maximal muscle contraction. The patient was treated with carbamazepine 200 mg per day with complete resolution of his symptoms. ONM may be more common than previously recognized, and patients with unexplained transient episodic diplopia should be specifically tested for diplopia and ocular misalignment following sustained eccentric gaze.
Comparison of ictal SPECT and interictal PET in the presurgical evaluation of temporal lobe epilepsy
Authors: Ho Susan S. , Berkovic Samuel F. , Berlangieri Salvatore U. , Newton Mark R. , Egan Gary F. , Tochon‐Danguy Henri J. , McKay W. John
Published: January 2005

We retrospectively compared ictal technetium 99m hexamethylpropyleneamineoxime single‐photon emission computed tomography (SPECT) and interictal 18F‐fluorodeoxyglucose positron emission tomography (PET) in 35 patients with well‐lateralized temporal lobe epilepsy (TLE). Based on SPECT scans the two observers correctly lateralized seizure foci with certainty in 89% of patients; interobserver agreement was excellent. Both observers incorrectly lateralized the seizure focus on two SPECT scans; one error was explained by rapid electroencephalographic spread to the contralateral side and for the other patient, isotope was injected during a brief aura. Based on PET scans, observers correctly lateralized the foci with certainty in 63% and with lesser confidence in 83%; four incorrect lateralizations were made by one observer and none by the other. PET interobserver disagreement was explained by differences between observers in weighting the relative hypometabolism in medial and lateral temporal regions. The detection rate for PET was lower in the absence of structural imaging abnormalities (60 vs 87%). PET yielded correct lateralizations in the 2 patients for whom SPECT interpretation was difficult. We conclude that both ictal SPECT and interictal PET are sensitive methods for the lateralization of TLE, but SPECT can be interpreted with greater certainty and is more sensitive when magnetic resonance imaging findings are negative. False lateralization is rare with ictal SPECT and can be explained when interpreted in conjunction with electroclinical data. Both investigations have complementary roles when localization is difficult.
Encephalopathy with parkinsonian features in children following bone marrow transplantations and high‐dose amphotericin B
Authors: Mott Stephen H. , Packer Roger J. , Vezina L. Gilbert , Kapur Sudesh , Dinndorf Patricia A. , Conry Joan A. , Pranzatelli Michael R. , Quinones Ralph R.
Published: January 2005

Encephalopathy, leukoencephalopathy, and secondary parkinsonism occurred in 3 children with refractory leukemia undergoing allogenic bone marrow transplantation (BMT) who were treated with high‐dose amphotericin B for pulmonary aspergillosis or sinus aspergillosis that did not involve the nervous system. Treatment included high‐dose cytosine arabinoside, cyclophosphamide, and total body irradiation prior to the BMT. The children developed a progressively worsening encephalopathy and parkinsonian features, characterized by resting tremor, cogwheel rigidity, and masklike facies. Neuroimaging studies showed cerebellar, cerebral, and basal ganglia atrophy, as well as frontal and temporal lobe white matter involvement. Two of the 3 patients recovered, although 1 has residual intellectual impairment. The third succumbed to non–central nervous system Epstein‐Barr virus–lymphoproliferative disease and had autopsy‐confirmed leukoenephalopathy.
Cephalosporin‐induced recurrent aseptic meningitis
Authors: Creel George B. , Hurtt Mark
Published: January 2005

A 66‐year‐old woman had several episodes of aseptic meningitis associated with exposure to cephalexin, cefazolin, and ceftazidime. The cerebrospinal fluid IgG index was elevated, specific IgG‐ceftazidime binding was shown, and skin allergy testing with cefazolin provoked a recurrence of meningitis. We postulate an acute hypersensitivity reaction involving an antigen‐specific humoral immune response.
Intracerebral hemorrhage versus infarction: Stroke severity, risk factors, and prognosis
Authors: Jørgensen Henrik Stig , Nakayama Hirofumi , Raaschou Hans Otto , Olsen Tom Skyhøj
Published: January 2005

The purpose of this study was to compare stroke severity, risk factors, and prognosis in patients with intracerebral hemorrhage versus infarction. We prospectively studied 1,000 unselected patients with acute stroke of a verified type in the Copenhagen Stroke Study. Neurological deficits and functional disabilities were evaluated weekly from the time of acute admission throughout the rehabilitation period. Eighty‐eight (9%) had intracerebral hemorrhage. The relative frequency of intracerebral hemorrhage rose exponentially with increasing stroke severity. In multivariate analyses, stroke type had no influence on mortality, neurological outcome, functional outcome, or the time course of recovery. Initial stroke severity was the all‐important prognostic factor. The relative importance of hypertension and blood pressure on admission was not greater for intracerebral hemorrhage than for infarction. No preponderance was found between type of stroke and sex, age, and smoking. Diabetes, ischemic heart disease, and elevated serum total cholesterol level all favored cerebral infarction as opposed to intracerebral hemorrhage. We conclude that the type of stroke per se has no influence on stroke prognosis in general; the extent of the injury is decisive. The poorer prognosis in patients with intracerebral hemorrhage is due to the increase in frequency of intracerebral hemorrhage with increasing stroke severity. The likelihood of cerebral infarction occuring as opposed to intracerebral hemorrhage seems increased fivefold in stroke patients with diabetes. Hypertension and blood pressure on admission were not predictors of stroke type.
Anti‐GM1 IgG antibodies and campylobacter bacteria in Guillain‐Barré syndrome: Evidence of molecular mimicry
Authors: Oomes Peter G. , Jacobs Bart C. , Hazenberg Maarten P. H. , Bänffer John R. J. , van der Meché Frans G. A.
Published: January 2005

In Guillain‐Barré syndrome antibodies to GM1 and the presence of an antecedent Campylobacter jeJunei infection are correlated with a more severe course of the disease. From a group of 137 consecutive GBS patients, 11 sera had elevated titers of anti‐GM1 IgG antibodies during the acute stage of disease. Each serum sample was preincubated with three different Penner serotypes of whole C. jeJunei (PEN O:4/59, PEN O:41) and Campylobacter coli (PEN O:22) bacteria. The PEN O:4/59 serotype, isolated from the stools of a Guillain‐Barré syndrome patient, inhibited 63 to 93% of the anti‐GM1 activity in 6 of 11 patients. The PEN O:41 inhibited 63 to 100% of the anti‐GM1 antibody activity in 9 of 11 patients. The PEN O:22 inhibited anti‐GM1 antibody activity in only 2 of 11 patients (80 and 86%). Two Guillain‐Barré syndrome patients did not show antibody absorption by any of the Campylobacter serotypes tested, although this does not exclude the involvement of other serotypes. An Escherichia coli control strain did not significantly absorb anti‐GM1 antibodies. The results of this study indicate that anti‐GM1 IgG antibodies in Guillain‐Barré syndrome sera recognize surface epitopes on whole Campylobacter bacteria and that this recognition is strain‐specific. This provides evidence for molecular mimicry in the pathogenesis of Guillain‐Barré syndrome.
The phenotypic spectrum related to the human epilepsy susceptibility gene “EJM1”
Authors: Sander T. , Hildmann T. , Janz D. , Wienker T. F. , Neitzel H. , Bianchi A. , Bauer G. , Sailer U. , Berek K. , Schmitz B. , Beck‐Mannagetta G.
Published: January 2005

Linkage studies of families ascertained through patients with juvenile myoclonic epilepsy (JME) suggest that an HLA‐linked susceptibility gene on chromosome 6, designated “EJM1,” predisposes to a group of idiopathic generalized epilepsies (IGEs) comprising JME, juvenile absence epilepsy (JAE), childhood absence epilepsies (CAE), and epilepsies with generalized tonic–clonic seizures (GTCS). To explore the EJM1‐related phenotypic spectrum, we conducted linkage studies with HLA‐DQα restriction fragment length polymorphisms in 44 families ascertained through patients with CAE or JAE. Our results for the entire group of families provide evidence against a major susceptibility locus for idiopathic absence epilepsies and broader spectra of IGEs in the HLA region. Lod scores less than – 2 were obtained for a region from 10 cM up to 23 cM on either side of the HLA‐DQα locus, depending on the assumed trait model. Suggestive evidence for linkage was found only for a subgroup of families with JME patients assuming an autosomal dominant mode of inheritance with 70% penetrance. A maximum lod score was obtained when family members with JME, JAE, CAE, and idiopathic GTCS were included into the affection status. Our results demonstrate that (1) the genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs is heterogeneous, (2) the gene effect of EJM1 depends on the familial genetic background, and (3) EJM1 confers genetic susceptibility to idiopathic absence epilepsies and broader spectra of IGEs in the presence of family members with JME.
Amyloid β‐proteins 1—40 and 1—42(43) in the soluble fraction of extra‐ and intracranial blood vessels
Authors: Shinkai Yasuhisa , Yoshimura Masahiro , Ito Yuji , Odaka Asano , Suzuki Nobuhiro , Yanagisawa Katsuhiko , Ihara Yasuo
Published: January 2005

To investigate the process of amyloid β‐protein (Aβ) accumulation in cerebral amyloid angiopathy (CAA), the levels of Aβ were determined in the soluble fraction of extra‐ and intracranial blood vessels and leptomeninges obtained at autopsy. Two enzyme immunoassays were employed that are known to sensitively and specifically quantify two Aβ species, Aβ1–40 and 1–42(43). Aβ was detectable in the intracranial blood vessels and leptomeninges with the latter containing the highest levels, while it was undetectable in the extracranial blood vessels. Thus the levels of soluble Aβ correlated well with the prediiection sites for CAA. Among individuals aged 20 to 90, the Aβ levels in the leptomeninges increased sharply in those aged 50 to 70 and thereafter tended to decline. However, only slight degrees of CAA were detected by immunocytochemistry, even when those leptomeninges contained high levels of Aβ comparable with those in Alzheimer's disease. The level of Aβ1–42 was almost always severalfold that of Aβ1–40 in the soluble fraction of leptomeninges. This is in good agreement with the immunocytochemical result showing the presence of Aβ40‐negative, Aβ42(43)‐positive meningeal vessels. These results indicate that Aβ1–42 is the initially deposited species in CAA and that the disruption of Aβ homeostasis precedes Aβ deposition in the meningeal vessels.
Genotype‐phenotype correlation in adult‐onset acid maltase deficiency
Authors: Wokke John H. J. , Ausems Margreet G. E. M. , van den Boogaard Marie‐José H. , Ippel Elly F. , van Diggelen Otto , Kroos Marian A. , Boer Marijke , Jennekens Frans G. I. , Reuser Arnold J. J. , van Amstel Hans Kristian Ploos
Published: January 2005

We performed a clinical, biochemical, and genetic study in 16 patients from 11 families with adult‐onset acid maltase deficiency. All patients were compound heterozygotes and carried the IVS1(– 13T→G) transversion on one allele; the second allele harbored either a deletion of a T at position 525 in exon 2 (7 probands, 64%) or a deletion of exon 18 (1 proband, 9%). Detrioration of handicap was related to age, and decrease in vital capacity to duration of the symptomatic stage. Respiratory insufficiency was never the first manifestation. The levels of activity of serum creatine kinase and of β‐glucosidase in peripheral blood cells or muscle were helpful for the diagnosis, but did not have prognostic value. The adult form of acid maltase deficiency appears to be both clinically and genetically rather homogeneous; decrease of β‐glucosidase activity is the final common pathway leading to destruction of muscle fibers and progression of muscle weakness over a period of years.
A novel mitochondrial ATPase 6 point mutation in familial bilateral striatal necrosis
Authors: Thyagarajan Dominic , Shanske Sara , Vazquez ‐Memije Marta , Devivo Darryl , Dimauro Salvatore
Published: January 2005

A T‐to‐C transition at nucleotide (nt) 9176 in the mitochondrial adenosine triphosphatase 6 (ATPase 6) gene was detected in 2 brothers with a neurological disorder resembling Leigh syndrome. The mutation was also present in the 2 other siblings and in the mother, who were asymptomatic. In the more severely affected boy (the proband), the mutation was homoplasmic in muscle, leucocytes, and fibroblasts. In leucocytes from his affected brother, 98% of mtDNA was mutant. Heteroplasmy of varying degrees was seen in leucocytes from the mother and the 2 unaffected siblings. The mutation changes a highly conserved leucine residue near the carboxyl terminus of the mitochondrial ATPase 6 subunit to proline. It could not be detected in 168 control subjects. Studies of ATP synthesis and hydrolysis in fibroblasts from the proband were normal.
Safety of intravenous valproate
Authors: Devinsky Orrin , Leppik Ilo , James Willmore L. , Pellock John M. , Dean Christine , Gates John , Eugene Ramsay R.
Published: January 2005

This multicenter, open‐label trial was designed to study the safety of intravenous (IV) sodium valproate in patients with epilepsy. All 318 patients (previously treated with antiepileptic drugs) were hospitalized for seizure control or anticipated seizures. The protocol allowed physicians to set the number of infusions and treatment duration. Adverse events, laboratory studies performed, and seizure activity were documented on case report forms. The patients' mean age was 34.4 years (range, 2–87 years). The most common reason for admission was lack of seizure control (235 patients, 185 of whom were admitted for video‐electroencephalographic monitoring). The median dosage of valproate was 375 mg infused over 1 hour. The median number of doses was four, given over 2 days. In 54 patients (17%), transient adverse events were reported. The most frequent were headache, reaction at the injection site, and nausea (2.2% each); somnolence (1.9%); vomiting (1.6%); and dizziness and taste perversion (1.3% each). No persistent or severe hematologic or serum chemistry abnormalities were found. Vital signs were not significantly affected by the IV infusion of valproate. At the dosages and rates of administration studied, intravenous valproate appears to be safe and well tolerated.
Familial hemiplegic migraine and autosomal dominant arteriopathy with leukoencephalopathy (CADASIL)
Authors: Hutchinson Michael , O'Riordan Jonathon , Javed Mohammed , Quin Etain , Macerlaine Donal , Willcox Teresa , Parfrey Nollaig , Nagy Tamas G. , Tournier‐Lasserve Elisabeth
Published: January 2005

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described familial cerebrovascular disorder shown to map to chromosome 19q12. Familial hemiplegic migraine has also been shown in some families to map close to the CADASIL locus. The fully developed CADASIL phenotype consists of recurrent strokes developing in the fourth decade, progressing to a pseudobulbar palsy, spastic quadriparesis, and subcortical dementia. In an Irish family 15 members were fully investigated by magnetic resonance scanning; 10 had typical magnetic resonance features of CADASIL. Five members of this family had familial hemiplegic migraine and 4 of these had magnetic resonance evidence of CADASIL. Two other members had migraine with and without aura as a presenting clinical symptom of CADASIL. This disorder has been shown by linkage analysis to map to the CADASIL locus at chromosome 19. The phenotype at presentation of CADASIL in this family was variable and age related and included familial hemiplegic migraine, migraine with and without aura, transient ischemic attacks, strokes, and spinal cord infarction. This family study increases our understanding of the spectrum of clinical manifestations of this underrecognized familial cerebrovascular disorder.
Chemical pathology of acute demyelinating lesions and its correlation with disability
Authors: De Stefano Nicola , Matthews Paul M. , Antel Jack P. , Preul Mark , Francis Gordon , Arnold Douglas L.
Published: January 2005

We report the chemical pathological changes on magnetic resonance spectroscopic images of 4 patients, each of whom had a single large demyelinating plaque. The patients were followed from soon after the onset of the symptoms for a minimum of 7 months to a maximum of 3 1/2 years. We observed increases in the relative resonance intensities of choline‐containing compounds, lactate, and myo‐inositol inside the lesion acutely. Decreases in relative resonance intensities of N‐acetylaspartate and creatine were seen both in and around the magnetic resonance imaging—detected lesions. In all patients neurological deficits improved and creatine, lactate, and myo‐inositol resonance intensities normalized during the follow‐up. Choline compounds recovered more slowly and were still abnormally high in 1 patient after 7 months. Partial recovery of the N‐acetylaspartate resonance was seen for all patients. Evaluation of the relationships between indices of cerebral chemical pathology, brain lesion volumes, and functional disability showed highly significant negative correlations between N‐acetylaspartate resonance intensities and both brain lesion volumes (r = −0.80, p < 0.0001) and clinical disability (r = −0.73, p < 0.0001). As N‐acetylaspartate is localized solely in neurons in the adult central nervous system, our results suggest that neuronal dysfunction may be a proximate mechanism of disability even in inflammatory disorders primarily affecting myelin and oligodendroglial cells.
Cerebrovascular complications in Ehlers‐Danlos syndrome type IV
Authors: North Kathryn N. , Whiteman David A. H. , Pepin Melanie G. , Byers Peter H.
Published: January 2005

Ehlers‐Danlos syndrome (EDS) type IV is an autosomal dominant disorder that results from mutations in the COL3A 1 gene, which encodes chains of type III procollagen. Individuals with this disorder are predisposed to rupture of arteries, the bowel, and the gravid uterus. To assess the frequency of central nervous system complications, we reviewed clinical data concerning 202 individuals with EDS type IV from 121 families in which the diagnosis was confirmed by biochemical or molecular studies. We identified 19 individuals with cerebrovascular complications, which included intracranial aneurysms with secondary hemorrhage, spontaneous carotidcavernous sinus fistula, and cervical artery dissection. The mean age at presentation with these events was 28.3 years (range, 17–48 years). Although uncommon, EDS type IV is an important potential cause of stroke in young people. The disorder is readily identifiable clinically and the diagnosis has important implications for acute and long‐term management and, potentially, for other family members. Because conventional angiography may exacerbate severe complications, noninvasive procedures such as Doppler and magnetic resonance angiography are the investigations of choice. Anticoagulation therapy may result in increased bruising or bleeding and should be used with caution.
The effect of gabapentin on brain gamma‐aminobutyric acid in patients with epilepsy
Authors: Petroff Ognen A. C. , Rothman Douglas L. , Behar Kevin L. , Lamoureux D. , Mattson Richard H.
Published: January 2005

Gabapentin has come into clinical use as adjunctive therapy in the treatment of epilepsy. Designed to mimic gammaaminobutyric acid (GABA), its mechanism of action remains elusive. In vivo measurements of GABA in human brain were made using 1H magnetic resonance spectroscopy. We used a 2.1‐T magnetic resonance imager‐spectrometer and an 8‐cm surface coil to measure a 13.5‐cm3 volume in the occipital cortex. GABA levels were measured in 14 patients enrolled in an open‐label trial of gabapentin. GABA was elevated in patients taking gabapentin compared with 14 complex partial epilepsy patients, matched for antiepileptic drug treatment. Brain GABA levels appeared to be higher in patients taking high‐dose gabapentin (3,300–3,600 mg/day) than in those taking standard doses (1,200–2,400 mg/ day). Gabapentin appears to increase human brain GABA levels.
Proton magnetic resonance spectroscopy in children with temporal lobe epilepsy
Authors: Cross J. H. , Connelly A. , Jackson G. D. , Johnson C. L. , Neville B. G. R. , Gadian D. G.
Published: January 2005

We performed proton magnetic resonance spectroscopy of the mesial temporal regions in 20 children with intractable temporal lobe epilepsy and compared results with those from 13 normal subjects. Abnormalities of the ratio of N‐acetylaspartate to choline plus creatine (NAAI[Cho+Cr]) were seen in 15 patients (75%). The ratio NAA/(Cho+Cr) was correctly lateralizing in 55% and incorrectly lateralizing in none. Bilateral abnormalities were seen in 45%. Overall there was a unilateral decrease in N‐acetylaspartate on the side ipsilateral to the seizure focus (mean 19% decrease vs normals, with 5% decrease on the contralateral side), suggesting neuronal loss or dysfunction. There was also a bilateral increase in creatine and choline (mean l8%), consistent with reactive astrocytosis. We conclude that proton magnetic resonance spectroscopy can contribute to lateralization of the seizure focus, and by detection of bilateral abnormalities, can contribute to the understanding of the underlying pathophysiology in temporal lobe epilepsy.
Interleukm‐1 receptor antagonist suppresses neurotrophin response in injured rat brain
Authors: Dekosky Steven T. , Styren Scot D. , O'Malley Mark E. , Goss James R. , Kochanek Patrick , Marion Donald , Evans Christopher H. , Robbins Paul D.
Published: January 2005

Traumatic brain injury (TBI) induces astrocytic and microglial activation and proliferation and augmented production of the cytokine interleukin‐lβ (IL‐1β) and nerve growth factor (NGF). The increase in NGF temporally follows the increase in IL‐1β, suggesting that the IL‐1β up‐regulation after trauma directly induces the increase in NGF. We examined the effect of IL‐1 receptor antagonist protein (IL‐1ra) on microglial proliferation and NGF production in rat cortex, following two different models of TBI. Rabbit fibroblasts infected with a retroviral vector containing the human IL‐1ra gene were implanted into the wound cavity immediately following a cortical stab wound or 6 hours after a weight drop‐induced trauma. Both microglial proliferation and NGF up‐regulation were decreased significantly in animals receiving IL‐1ra‐expressing cells compared with animals receiving naive (untransfected) fibroblasts. These data demonstrate that the increase in NGF after central nervous system trauma is directly mediated through IL‐1β and that blocking IL‐1 β following brain injury leads to suppression of an NGF‐mediated reparative response. Such blockade of inflammation, however, may prove to be of significant therapeutic benefit in human brain injury and other inflammatory states.
Brain superoxide dismutase, catalase, and glutathione peroxidase activities in amyotrophic lateral sclerosis
Authors: Przedborski Serge , Donaldson David , Jakowec Michael , Kish Stephen J. , Guttman M. , Rosoklija Gorazd , Hays Arthur P.
Published: January 2005

Amyotrophic lateral sclerosis is a fatal paralytic disorder of unknown cause. Recent evidence implicated the role of free radicals in the death of motor neurons in this disease. To investigate this hypothesis further, we measured the activity of the main free radical scavenging enzymes copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and glutathione peroxidase in postmortem brain samples from 9 patients with sporadic amyotrophic lateral sclerosis and from 9 control subjects. We examined samples from the precentral gyrus of the cerebral cortex, a region affected in amyotrophic lateral sclerosis, and from the cerebellar cortex, a region not affected. The two groups did not differ in age or postmortem delay. In the precentral gyrus from amyotrophic lateral sclerosis samples, glutathione peroxidase activity as measured by spectrophotometric assay (13.8 & 2.6 nmol/min/mg protein [mean & standard error of mean]) was reduced significantly compared to the activity in the precentral gyrus from control samples (22.7 & 0.5 nmol/min/ mg protein). In contrast, glutathione peroxidase activity was not significantly altered in the cerebellar cortex from amyotrophic lateral sclerosis patients compared to controls. Copper/zinc superoxide dismutase, manganese superoxide dismutase (corrected or not corrected for citrate synthase), and catalase were not significantly altered in the precentral gyrus or cerebellar cortex in the patient samples. This study indicated that glutathione peroxidase activity is reduced in a brain region affected in amyotrophic lateral sclerosis, thus suggesting that free radicals may be implicated in the pathogenesis of the disease.
Clinical and genetic analysis of a large pedigree with juvenile myoclonic epilepsy
Authors: Serratosa José M. , Delgado‐Escueta Antonio V. , Medina Marco T. , Zhang Quanwei , Iranmanesh Reza , Sparkes Robert S.
Published: January 2005

Juvenile myoclonic epilepsy is a common type of idiopathic generalized epilepsy characterized by myoclonic, generalized tonic‐clonic, and in 30% of patients, absence seizures. We studied a three‐generation pedigree of 33 members, 10 of whom were clinically affected with juvenile myoclonic epilepsy or presented with subclinical electroencephalographic (EEG) 3.5‐ to 6.0‐Hz diffuse polyspike‐wave or spike‐wave complexes. Juvenile myoclonic epilepsy and the EEG trait segregated as an autosomal dominant trait with 70% penetrance. Linkage analysis using this model showed significant linkage to four microsatellite markers centromeric to human leukocyte antigen (HLA) in chromosome 6p. Maximum lod scores of 3.43 at θm=f = 0.00 for D6S272, D6S466, D6S257, and D6S402 were obtained. Recombinant events in 2 affected members defined the gene region to a 43‐cM interval flanked by D6S258 (HLA region) and D6S313 (centromere). Our results in this large family provide evidence that a gene responsible for juvenile myoclonic epilepsy and the subclinical, 3.5‐ to 6.0‐Hz, polyspike‐wave or spike‐wave EEG pattern is located in chromosome 6p.
Opportunities and challenges in academic neurology: Report of long range planning committee of the american neurological association
Authors: Griffin John W. , Griggs Robert C. , Barchi Robert , Schneck Stuart A. , Moses Hamilton ,   Long Range Planning Committee
Published: January 2005

By most measures, academic neurology is thriving as never before, yet convening forces are changing the face of academic neurology. This report focuses on changes that academic neurology and the American Neurological Association could undertake to seize new opportunities and resist damaging potential changes. These proposals can be categorized in the following four major goals: (1) enhance the quality of a smaller neurology workforce and augment the recruitment gifted young neuroscientists into neurology; (2) foster new diversity in neurological investigation, including clinical research in neurology; (3) document the benefits and relative costs of neurological care, in general, and of academic neurology, in particular; and (4) foster the role of neurologists as teachers to medical caregivers at all levels, including medical students, nonneurological house staff, and primary practitioners.
MELAS‐ and kearns‐sayre‐type with myopathy and autoimmune polyendocrinopahy
Authors: Ohno Kinji , Yamamoto Masahiko , Engel Andrew G. , Michel C. Michel , Roberts Lewis R. , Tan Gerry H. , Fatourechi Vahab
Published: January 2005

A 35‐year‐old woman with features of Kearns‐Sayre syndrome consisting of progressive ptosis, ophthalmoparesis, mitochondrial myopathy, and pigmentary retinopathy also had autoimmune polyglandular syndrome type I1 (Addison's disease, autoimmune insulin‐dependent diabetes meuitus, Hashimoto's thyroiditis, and primary ovarian failure). There was no history of similarly affected relatives. Analysis of muscle mitochondrial DNA (mtDNA) revealed a 2,532‐bp deletion of the type seen in Kearns‐Sayre syndrome as well as a heteroplasmic A3243G mutation in the tRNA‐Leu(UUR) gene of the type seen in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS). The patient's blood and her mother's blood harbored the A3243G mutation but not the deletion, and the maternal grandmother's blood had neither mutation. In muscle, the species of mtDNA harboring the deletion was exclusively associated with the species harboring the A3243G mutation, suggesting that the point mutation predisposed to the large‐scale deletion. The mtDNA species with both mutations accounted for 88% of total muscle mtDNA. Other and as yet unrecognized point mutations in mtDNA might also be associated with, and possible causally related to, largescale mtDNA deletions.
Lack of association of trinucleotide repeat polymorphisms in the very‐low‐density lipoprotein receptor gene with Alzhelner's disease
Authors: Chung Ba Haeyong , Roberts Carol T. , Greenberg Steven , Rebeck G. William , Christie Bs Richard , Wallace Robert , Jacob Howard J. , Hyman Bradley T.
Published: January 2005

Inheritance of the apolipoprotein E ε 4 allele is a risk factor for Alzheimer's disease (AD). A recent report studying Japanese patients suggested that a polymorphism of a trinucleotide repeat in the 5' untranslated region of an apolipoprotein E receptor, the very‐low‐density lipoprotein receptor, is genetically associated with AD, with overrepresentation of the allele containing five copies of the repeat. We determined the allele frequencies of the very‐low‐density lipoprotein receptor in 3 white populations totaling 469 individuals. In contrast to the previous report, we found no differences in allele frequencies between case patients and control subjects. The discrepancy could be due to differences in Japanese and white populations. Nonetheless, these data weaken the likelihood that this polymorphism in the very‐low‐density lipoprotein receptor gene is strongly associated with AD.
Complement activation in the central nervous system following blood–brain barrier damage in man
Authors: Lindsberg Perttu J. , Öhman Juha , Lehto Timo , Wuorimaa Tomi , Meri Seppo , Karjalainen‐Lindsberg Marja‐Liisa , Paetau Anders , Carpén Olli , Kaste Markku
Published: January 2005

The central nervous system (CNS) is virtually isolated from circulating immunological factors such as complment (C), an important mediator of humoral immunity and inflammation. In circulation, C i constantly inhibited to prevent attack on host cells. Since a host of diseases produce an abnormal blood–brain/cerebrospinal fluid (blood–brain/CSF) permeability allowing C protein extravasation, we investigated if C activation occurs in CSF in vitro and in CNS in vivo during subarachnoid hermorrhage (SAH) or brain infrarction. After SAH (n = 15), the terminal complement complex (TCC) concentration on days 0 to 2 was higher in the CSF, 210 ± 61 ng/ml, than in the plasma 63 ± 17 ng/ml, but null in the CSF of controls (n = 8) or patients with an ischemic stroke (n = 7). TCC was eliminated from the CSF after SAH (24 ± 10 ng/ml on days 7 to 10) Incubation of normal human CSF with serum in vitro also activated the terminal C pathway. In 10 fatal ischmemic brain infrarctions, immunohistochemical techniques demonstrated neuronal fragment‐associated deposition of C9 accompanied by neutrophil infiltration. We conclude that the C system becomes activated intrathecally in SAH and focally in the brain parenchyma in ischemic stroke. By promoting chemotaxis and vascular perturbation, C activation may instigate nonimmune inflammation and aggravate CNS damage in diseases associated with plasma extravasation.
Speech‐induced changes in corticospinal excitability
Authors: Tokimura H. , Asakura T. , Tokimura Y. , Oliviero A. , Rothwell J. C.
Published: January 2005

The aim of the experiments was to investigate the effects of speech on the excitability of corticospinal pathways to human hand muscles. Single transcranial magnetic stimuli were given randomly over the hand area of either the left or right motor cortex of 10 right‐handed and 3 left‐handed normal volunteers. Electromyographic responses were recorded in the relaxed first dorsal interosseous muscle while the subjects (a) read aloud a piece of text, (b) read silently, (c) spoke spontaneously, or (d) made sounds without speaking. The only consistent effect across subjects occurred during task a, which significantly increased the size of responses evoked in the dominant hand of all subjects, but had either no effect (8 subjects) or a smaller effect in the nondominant hand. Tasks b and d had no reliabl effects, whereas task c tended to increase response size in both hands. Control measurements suggest that the effects in task a were caused by changes in cortical rather than spinal excitability. This is the first demonstration of lateralized speech effects on the excitability of cortical arm areas. The results provide a useful adjunct to other tests of cerebral dominance, using only single‐ rather than repetitive‐pulse cortical stimulation.
Acute myopathy of intensive care: Clinical, electromyographic, and pathological aspects
Authors: Lacomis David , Giuliani Michael J. , van Cott Anne , Kramer David J.
Published: January 2005

An acute myopathy of intensive care occurs in critically ill patients treated with intravenous corticosteroids and neuromuscular junction‐blocking agents. The full clinicopathological spectrum is uncertain. We evaluated the clinical, electrodiagnostic, and histopathological features of 14 patients who developed acute myopathy of intensive care after organ transplantation or during treatment of severe pulmonary disorders and sepsis. Patients received high‐dose intravenous corticosteroids, usually in conjunction with relatively low to moderate doses of neuromuscular junction‐blocking agents. After discontinuation of the latter drugs, most had diffuse, flaccid weakness with failure to wean frommechanical ventilation. Electrodiagnostic findings were consistent with a necrotizing myopathy. Muscle histopathology revealed myopathy with loss of thick filaments in 79%, mild myopathic changes in 14%, and atrophy of type 1 and type 2 fibers in 7%. Loss of thick filaments was identified in muscle biopsy specimens obtained 30 ± 11 days (mean ± standard deviation) after intravenous corticosteroid treatment but not in those obtained earlier (12 ± 2 days). Critically ill patients, including those receiving organ transplants, may develop acute myopathy of intensive care after exposure to intravenous corticosteroids and neuromuscular junction‐blocking agents, although the exposure to the latter drugs may be minimal. Selective loss of thick filaments is common in acute myopathy of intensive care, especially if the muscle biopsy specimen is obtained 2 weeks or more after intravenous corticosteroid exposure.
A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy
Authors: Dalakas Marinos C. , Quarles Richard H. , Farrer Robert G. , Dambrosia James , Soueidan Shawke , Stein Daniel P. , Cupler Edward , Sekul Elizabeth A. , Otero Carlos
Published: January 2005

Eleven patients with demyelinating polyneuropathy associated with monoclonal IgM antibodies were randomized to receive IVIg or placebo, monthly, for 3 months in a double‐blind study. After a washout period, they crossed over to the alternate therapy. Response was gauged by evaluating muscle strength, sensation, and neuromuscular symptoms at baseline, after 3 months, and at treatment's end. After IVIg therapy, the strenght improved in only 2 of 11 patients, by 28 and 38.5 points from baseline, and declined after placebo. In 1 other patient, the sensory score improved by 13 points. Antibody titers to MAG/SGPG or gangliosides did not appreciably change. We conclude that IVIg has only a modest benefit to not more than 18% of patients with IgM paraproteinemic demyelinating neuropathy.
Confirmation of linkage of oculopharyngel muscular dystrophy to chromosome 14q 11.2‐q13
Authors: Stajich Jeffrey M. , Lennon Felicia , Lee Arnold , Yamaoka Larry , Helms Barbara , Gaskell Perry C. , Roses Allen D. , Vance Jeffrey M. , Pericak‐Vance Margaret A. , Gilchrist James M. , Donald Lauren
Published: January 2005

Oculopharyngeal muscular dystrophy is a late‐onset, autosomally dominant disorder characterized by progressive ptosis, dysphagia, and extremity weakness. Linkage of oculopharyngeal muscular dystrophy to 14q11.2‐q13 has been reported in a series of French Canadian families. Haplotype analysis in these data shows a single segregating disease chromosome, suggesting a founder effect in this population. We ascertained and sampled for linkage studies 5 multigenerational American families with oculopharyngeal muscular dystrophy. Four of the 5 families have known French Canadian ancestry while the fifth is of English/Scottish origin. A peak multipoint lod score of 6.30 was obtained for the marker MYH7.1 in the families, confirming linkage to 14q11.2‐q13. The English/Scottish family exhibited a different chromosomal haplotype for the oculopharyngeal muscular dystrophy alleles than did the families of French Canadian origin. These data suggest that this family may represent a second, possibly independent mutation in this disorder.
Low brain GABA level is associated with poor seizure control
Authors: Petroff Ognen A. C. , Rothman Douglas L. , Behar Kevin L. , Mattson Richard H.
Published: January 2005

Low gamma‐aminobutyric acid (GABA) concentrations in the cerebrospinal fluid are seen in a variety of epileptic syndromes. Low GABA levels outside of the epileptic focus may facilitate spread of discharges beyond the focus. In vivo measurements of GABA were made by 1H spectroscopy using a 2.1‐T magnetic resonance imager‐spectrometer and an 8‐cm surface coil to measure a 14‐cm3 volume in the occipital lobe. Patients with complex partial seizures had lower GABA levels (1.03 mmol/kg of brain; 95% confidence interval [CI], 0.95−1.12; n = 28; p < 0.02) than did subjects without epilepsy (1.18; 95% CI, 1.13−1.24; n = 19). There was a significant association between low GABA levels and recent seizures (correlation coefficient of 0.548, p < 0.01, df of 32). Conversely, patients with well‐controlled seizures had higher brain GABA levels than did patients with recent seizures. Patients with seizures within a day of the measurement had lower GABA levels (0.92 mmol/kg; 95% CI, 0.78−1.06; n = 7) than did patients who were seizure free for 5 years or longer (1.28; 95% CI, 1.09−1.47; n = 4). Poor seizure control is associated with low brain GABA levels.
Horizontal canal benign paroxysmal positioning vertigo (h‐BPPV): Transition of canalolithiasis to cupulolithiasis
Authors: Sven Steddin H. , Brandt Thomas
Published: January 2005

We report on 2 patients with typical features of horizontal canal benign paroxysmal positioning vertigo (h‐BPPV). A vigorous head positioning in these patients from supine to a bending‐over, head‐on‐the‐knees position reversed the direction of nystagmus from geotropic initially to ageotropic when rolling the head from side to side while supine. We explain this by a conversion of canalolithiasis into cupulolithiasis and conclude that (1) canalolithiasis and cupulolithiasis may sequentially occur in the same semicircular canal with subsequent positioning maneuvers and (2) positional nystagmus beating toward the uppermost ear is not a pathognomonic sign of central vestibular disturbance but can indicate occasional cupulolithiasis.
Bilateral brachial plexus neuritis following parvovirus B19 and cytomegalovirus infection
Authors: Maas J. J. , Beersma M. F. C. , Haan J. , Jonkers G. J. P. M. , Kroes A. C. M.
Published: January 2005

A man, 23 years of age, had a typical erythema infectiosum, complicated by a severe bilateral brachial plexus neuritis. Motor function recovered slowly and only partially after 6 months. An infection by human parvovirus B19 was demonstrated, with strongly positive and gradually declining IgM antibodies and viral DNA detectable in serum for more than 3 months. There was also clear evidence of a recent infection by cytomegalovirus. The interaction between these two viruses could be responsible for this rare and severe complication of common infections in this patient.