bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of single brain metastasis: Radiotherapy alone or combined with neurosurgery
Authors: Vecht Charles J. , Haaxma‐Reiche Hanny , Noordijk Evert M. , Padberg George W. , Voormolen Joan H. C. , Hoekstra Foppe H. , Tans Joseph Th. J. , Lambooij Nanno , Metsaars Jan A. L. , Wattendorff A. Rolf , Brand Ronald , Hermans Jo
Published: January 2005

Most patients treated for single or multiple brain metastases die from progression of extracranial tumor activity. This makes it uncertain whether the combination of neurosurgery and radiontherapy for treatment of single brain metastasis will lead to better results than less invasive treatment with radiotherapy alone. The effect of neurosurgical excision plus radiotherapy was compared with radiotherapy alone in a prospectively randomized trial with 63 evaluable patients with systemic cancer and a radiological diagnosis of single brain metastasis. Radiotherapy was given to the whole brain by a novel scheme of 2 faractions per day of each 2 Gy for a total of 40 Gy. Before randomization, patients were stratified by site (lung cancer vs nonlung cancer) and status of extracranial disease (progressive vs. stable). Survival as such and functionally independent survival (FIS; defined as world Health Organization performance status ≤ 1 and neurological funcition ≤ 1) were compared between both treatment arms. The combined treatment compared with radiotherapy alone led to a longer survival (p =0.04) and a longer FIS (p=0.06). This was most pronounced in patients with stable extracranial disease (median survival, 12vs 7 mo; median FIS 9 vs 4 Mo). Patients with progressive extracranial cancer had a median overall survival of 5 months and a FIS of 2.5 months irrespective of given treatment. Improvement in functional status occurred more rapidly and for longer periods of time after neurosurgial excision and radiotherapy than after radiotherpy alone. Patients older than 60 years had a hazard ratio of dying of 2.74(p=0.001) compared with younger patients, but in both age groups the combined treatment did better then radiotherapy alone. We coclude that patients with single brain metastasis and stable extracranial tumor activity should be treated with surgical excision and radiotherapy. For patients with progressive extracranial disease during the previous 3 months, radiotherapy alone appears to be sufficient. After treatment of single brain metastasis, parients remain functionally independent until a few months before death.
Evidence for mitochondrial dysfunction in patients with alternating hemiplegia of childhood
Authors: Arnold Douglas L. , Silver Kenneth , Andermann Frederick
Published: January 2005

Phosphorus magnetic resonance spectra of resting muscle were obtained from 4 patients with alternating hemiplegia of childhood. All patients had abnormally high resonance intensities from inorganic phosphate and an abnormally law calculared cytosolic phosphorylation potential. Tow of the 4 patients had abnormally law resonance intensities from phosphocreatine and an abnormally high calculated cytosolic free adenosine diphosphare conecntration. These abnormalities are indicative of mitochondrial dysfunction. The combination of a central nervous system disorder and evidence of mitochondrial dysfunction in muscle suggests that alternating hemiplegia of childhood may represent a previously unrecognized phenotype of mitochondrial disease.
Human leukocyte antigens in Fisher's syundrome
Authors: Yuki Nobuhiro , Sato Shuzo , Tsuji Shoji , Ogawa Kimiaki , Miyatake Tadashi
Published: January 2005

We performed human leukocyte antigens(HLA)typing for class I antigens on 19 Japanese patients with Fisher's syndrome. We demonstrated a statistically significant association between the disease and the HLA‐B39 antigen.
Myoblast transfer in duchenne muscular dystrophy
Authors: Karpati George , Ajdukovic Djordje , Arnold Douglas , Gledhill Robert B. , Guttmann Ronald , Holland Paul , Koch Penelope A. , Shoubridge Eric , Spence Desmond , Vanasse Michel , Watters Gordon V. , Abrahamowicz Michael , Duff Catherine , Worton Ronald G.
Published: January 2005

One biceps muscle of 8 patients with Duchenne muscular dystrophy was injected at 55 sites with a total of 55 million viable, purified, and contamination‐free normal myoblasts (myoblast transfer). The other biceps of each patient was injected with a placebo to serve as a control. The procedure was blinded to the patients, parents, and investigators. Myoblasts derived from a biopsy specimen of the fathers were cultured and purified under strict conditions and carefully screened for microbial contamination. All patients received cyclophosphamide for immunosuppression for 6 or 12 months. No serious complications were observed after myoblast transfer, indicating that the procedure is safe. The overall therapeutic efficiency of myoblast transfer was poor as judged by the results in maximal voluntary force generation, dystrophin content of the muscle, magnetic resonance imaging of the muscle, and the lack of donor‐derived DNA and dystrophin messenger RNA in the injected muscle. An improved efficiency of the take of myoblasts might be achieved by using younger cells and injecting the myoblasts with a myonecrotic agent (to increase the prevalence of regeneration) and a basal laminal fenestrating agent.
Modulation of motor cortical outputs to the reading hand of braille readers
Authors: Pascual‐Leone Alvaro , Cammarota Angel , Wassermann Eric M. , Brasil‐Neto Joaquim P. , Cohen Leonardo G. , Hallett Mark
Published: January 2005

We used focal transcranial magnetic stimulation to map the motor cortical areas targeting the first dorsal interosseous and the abductor digiti minimi muscles bilaterally in 10 proficient braille readers and 10 blind controls who were matched for age (mean, 50.6 yr) and age at time of blindness (mean, 7.5 yr). The proficient braille readers had learned braille at age 8 to 14 years and used it daily for 5 to 10 hours. Controls had not learned braille until age 17 to 21 years and used it daily for <1 hour. In the controls, motor representations of the right and left first dorsal interosseous and abductor digiti minimi muscles were not significantly different. However, in the proficient braille readers, the representation of the first dorsal interosseous muscle in the reading hand was significantly larger than that in the nonreading hand or in either hand of the controls. Conversely, the representation of the abductor digiti minimi muscle in the reading hand was significantly smaller than that in the nonreading hand or in either hand of the controls. These differences were not due to differences in motor thresholds. Our results suggest that the cortical representation of the reading finger in proficient braille readers is enlarged at the expense of the representation of other fingers.
Heterogeneity of autoantibodies in stiff‐man syndrome
Authors: Grimaldi Luigi M. E. , Martino Gianvito , Braghi Simona , Quattrini Angelo , Furlan Roberto , Bosi Emanuele , Comi Giancarlo
Published: January 2005

Stiff‐man syndrome is a rare neurological disorder characterized by skeletal muscle rigidity and spasms in which detection of circulating anti–glutamic acid decarboxylase antibodies has suggested an autoimmune pathogenesis. To further define the role of autoimmunity in the pathogenesis, we studied anti–glutamic acid decarboxylase antibodies, as well as organ‐ and non–organ‐specific autoantibodies in 13 patients with stiff‐man syndrome and 127 patients with other neurological disorders. Thyrogastric antibodies were more frequent in patients with stiff‐man syndrome (46%) than in those with other neurological disorders (12%) (p < 0.05). Non–organ‐specific antibodies were found at a similar frequency in the patients with stiff‐man syndrome (61%) and those with other neurological disorders (65%). Islet‐cell autoantibodies and anti–glutamic acid decarboxylase antibodies were more common in stiff‐man syndrome patients (38% and 31%) compared to the patients with other neurological disorders (6% and 3%, respectively; p < 0.001). With the exception of 1 patient in the other neurological disorders group, anti–glutamic acid decarboxylase antibodies were always associated with islet‐cell autoantibodies. Four patients with stiff‐man syndrome had an associated solid tumor: 3 of them had antibodies recognizing a 125/130‐kd protein and not glutamic acid decarboxylase. Our study indicates that with immunological markers, patients with stiff‐man syndrome can be subdivided into three groups: (1) patients with circulating islet‐cell autoantibodies, anti–glutamic acid decarboxylase as well as other organ‐specific autoantibodies, and the frequent association with an autoimmune disease (autoimmune variant); (2) patients with associated neoplasms and circulating non‐organ‐specific autoantibodies but neither islet‐cell nor anti–glutamic acid decarboxylase autoantibodies (paraneoplastic variant); and (3) patients with no evidence of any known autoantibody or association with other clinically evident diseases (idiopathic variant). We conclude that the presence of anti–glutamic acid decarboxylase antibodies is restricted to a subgroup of stiff‐man syndrome patients with associated autoimmune diseases. The absence of these antibodies does not exclude a diagnosis of stiff‐man syndrome, which is still based on clinical and neurophysiological evidence.
Positron emission tomography measures of benzodiazepine receptors in Huntington's disease
Authors: Holthoff Vjera A. , Koeppe Robert A. , Frey Kirk A. , Penney John B. , Markel Dorene S. , Kuhl David E. , Young Anne B.
Published: January 2005

We performed positron emission tomographic (PET) measurements of the regional distribution volume of benzodiazepine receptors and regional glucose metabolism in 6 drug‐free patients with early Huntington's disease following injection of [11C] flumazenil, a nonsubtype selective central benzodiazepine receptor antagonist, and 18F‐2‐fluoro‐2‐deoxy‐D‐glucose, respectively. Flumazenil data were analyzed with a recently developed two‐compartment, two‐parameter tracer kinetic model. Benzodiazepine receptor density is related to distribution volume for flumazenil. In comparison with a group of healthy volunteers, benzodiazepine receptor density was significantly decreased in the caudate nucleus. Glucose metabolism was significantly reduced not only in the caudate nucleus but also in the putamen and thalamus. The changes in benzodiazepine receptor density observed in the caudate nucleus are commensurate with data obtained in postmortem autoradiographic studies of receptor density. Based on such postmortem studies we also anticipated changes in putamen and thalamic benzodiazepine receptor density. However, relatively little is known on receptor changes in early Huntington's disease, because the autoradiographic data available were obtained mostly in patients with advanced disease. The decreased glucose metabolism in the caudate and putamen agrees well with previously published results of PET studies, whereas metabolic impairment of the thalamus has not yet been described in Huntington's disease. The present study suggests that regional metabolism and γ‐aminobutyric acid (GABA)‐benzodiazepine receptor changes in subcortical structures of patients with early Huntington's disease do not occur with the same time course: Caudate benzodiazepine receptor density is already severely impaired when other subcortical structures reveal only minor abnormalities. Impairment of neuronal metabolism seems to predate GABA/benzodiazepine receptor changes since the putamen and thalamus demonstrate metabolic impairment without detectable loss of benzodiazepine receptor density.
Devic's neuromyelitis optica: A clinicopathological study of 8 patients
Authors: Mandler Raül N. , Davis Larry E. , Jeffery Douglas R. , Kornfeld Mario
Published: January 2005

We report the clinical, imaging, and laboratory features of 8 patients with Devic's neuromyelitis optica. All patients had severe myelopathy and optic neuritis. In no patient was the brain, the brainstem, or the cerebellum affected, even after several years of disease. Various immunosuppressive treatments failed to benefit the patients, 5 of whom died. Autopsies of these 5 patients demonstrated a severe necrotizing myelopathy with thickening of blood vessel walls and no lymphocyte infiltrates. In the appropriate clinical setting, the lack of white matter abnormalities demonstrated by magnetic resonance imaging of the head facilitates the recognition of Devic's syndrome during life. Inasmuch as Devic's myelopathy is necrotizing, rather thatn demyelinating, the prognosis of this syndrome is poor.
Neuroanatomy of Rett syndrome: A volumetric imaging study
Authors: Reiss Allan L. , Faruque Faisal , Naidu Sakkubai , Abrams Michael , Beaty Terri , Bryan R. Nick , Moser Hugo
Published: January 2005

Rett syndrome is a pediatric neurological disorder of unknown etiology defined by the presence of severe neurodevelopment decline, acquired microcephaly, dementia, abnormalities of movement, autistic behavior, and seizures in young female children. In this study, the neuroanatomy of 11 females with Rett syndrome and 15 age‐ and gender‐matched control subjects ws investigated in vivo with quantitative neuroimaging techniques. Compared to control subjects, the patients with Rett syndrome were found to have significantly reduced cerebral volume; evidence of greater loss of gray matter in comparison to white matter; regional variation in cortical gray matter, with the frontal regions showing the largest decrease; and reduced volume of the caudate nucleus and midbrain, even when taking into account general reduction in the size of the brain. In addition, there was no evidence of an ongoing degenerative process in this sample of girls with Rett syndrome. The consistency of these data with results from neuropathological investigations points to the need for continued quantitative neuroimaging studies of children with this condition. In particular, research employing serial longitudinal scans of very young children manifesting early signs of the clinical syndrome holds promise for helping to elucidate the neuropathological pathways leading to the debilitating clinical manifestations of Rett syndrome.
Decreased hippocampal muscarinic cholinergic receptor binding measured by 123I‐iododexetimide and single‐photon emission computed tomography in epilepsy
Authors: Müller‐Gärtner Hans W. , Mayberg Helen S. , Fisher Robert S. , Lesser Ronald P. , Wilson Alan A. , Ravert Hayden T. , Dannals Robert F. , Wagner Henry N. , Uematsu Sumio , Frost J. James
Published: January 2005

Regional binding of 123I‐iododexetimide, a muscarinic acetylchline receptor antagonist, was measured in vivo in the temporal lobes of 4 patients with complex partial seizures using single‐photon emissions computed tomography. In the anterior hippocampus ipsilateral to the electrical focus, 123I‐iododexetimide binding was decreased by 40 ± 9% (mean 7plusmn; SD, p <0.01) compared with the contralateral hippocampus; 123I‐iododexetimide binding in other temporal lobe regions was symmetrical. The data indicate a regionally specific change of muscarinic acetylcholine receptor in anterior hippocampus in complex partial seizures of temporal lobe origin.
Correlation of striatal fluorodopa uptake in the MPTP Monkey with dopaminergic indices
Authors: Pate Brian D. , Kawamata T. , Yamada T. , McGeer E. G. , Hewitt K. A. , Snow B. J. , Ruth T. J. , Calne D. B.
Published: January 2005

Striatal 18F‐6‐fluorodopa (FD) uptake constants were measured by positron emission tomography in (1) normal cynomolgus monkeys and (2) a series of cynomolgus and rhesus monkeys that had received intracarotid infusions of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). After the animals were killed, the number and average size of dopaminergic neurons in the substantia nigra pars compacta were measured. Striatal levels of dopamine and its metabolites, and the striatal activities of the dopaminergic synthetic enzymes, were also determined. The striatal FD uptake constants showed highly significant positive correlations with both number and size of dopaminergic neurons, indicating atrophy of surviving neurons in MPTP‐treated animals. The uptake constants also showed significant positive correlations with striatal levels of dopamine, total catecholamines, and the activities of the synthetic enzymes. Both histochemical and biochemical data on tyrosine hydroxylase suggested some contralateral enzyme loss in these MPTP‐treated monkeys, as well as decreased enzyme activity in surviving neurons on the lesioned side. However, residual enzyme activities were apparently not rate limiting to striatal FD uptake. It is concluded that PET‐FD measurements by positron emission tomography provide a good index of the integrity of the nigrostriatal pathway.
Magnetic stimulation of the brain in generalized epilepsy: Reversal of cortical hyperexcitability by anticonvulsants
Authors: Reutens David C. , Berkovic Samuel F. , Macdonell Richard A. L. , Bladin Peter F.
Published: January 2005

Observations on experimental models suggest that diffuse cortical hyperexcitability is an important abnormality in the generalized epilepsies. We used the threshold for transcranial magnetic stimulation as an index of motor cortical excitability in 89 neurologically normal control subjects and 56 patients with idiopathic generalized epilepsy (20 untreated and 36 chronically treated with anticonvulsants). Magnetic stimulation was repeated in 10 patients after valproate monotherapy had been commenced and in 23 control subjects. The threshold intensity was significantly lower in the untreated patients (46 ± 5% [mean ± 95% confidence interval]) than in the control subjects (56 ± 2%). Treated patients had significantly higher thresholds (64 ± 4%) than did untreated patients and control subjects. A significant increase in threshold intensity (8 ± 2%) occurred in patients retested after starting valproate; there was no significant change in retested control subjects (−1 ± 2%). Threshold intensity was positively correlated with plasma valproate levels (rs = 0.37). The findings suggest that cortical excitability is increased in idiopathic generalized epilepsy and is reduced following anticonvulsant treatment. Transcranial magnetic stimulation is of use in examining the pathophysiology of generalized epilepsy. Furthermore, changes in threshold intensity in response to anticonvulsant treatment may prove useful in guiding therapy.
Neuroglial cholinesterases in the normal brain and in Alzheimer's disease: Relationship to plaques, tangles, and patterns of selective vulnerability
Authors: Wright Christopher I. , Geula Changiz , Mesulam M.‐Marsel
Published: January 2005

Butyrylcholinesterase (BChE) and an altered form of acetylcholinesterase (AChE) accumulate in the plaques and tangles of Alzheimer's disease (AD). The sources for these plaque‐ and tangle‐bound cholinesterases have not been identified. We now report that AChE and BChE activities with pH preferences and inhibitor selectivities identical to those of plaque‐ and tangle‐bound cholinesterases are found in the astrocytes and oligodendrocytes of control and AD brains. These glial‐type cholinesterases are selectively inhibited by indolamines and protease inhibitors. In control brains glial‐type cholinesterases appear confined to the intracellular space, whereas in patients with AD they decorate plaques and tangles as well. In control and AD brains AChE‐positive glia are distributed throughout the cortical layers and subcortical white matter, whereas BChE‐positive glia reach high densities only in the deep cortical layers and white matter. In non‐AD control brains, the ratio of BChE to AChE glia was higher in entorhinal and inferotemporal cortex, two regions with a high susceptibility to the pathology of AD, than in primary somatosensory and visual cortex, two areas with a relatively lower susceptibility to the disease process. There were no age‐related differences in the density or distribution of cholinesterase‐positive glia. In comparison with age‐matched control specimens, AD brains had a significantly higher density of BChE glia and a lower density of AChE glia in entorhinal and inferotemporal regions but not in the primary somatosensory or visual areas. These results suggest that glia constitute a likely source for the cholinesterase activity of plaques and tangles and that a high ratio of BChE‐ to AChE‐positive glia may play a permissive or causative role in the neuropathology of AD.
Delayed apperance of anti–myelin‐associated glycoprotein antibodies in a patient with chronic demyelinating polyneuropathy
Authors: Valldeoriola F. , Graus F. , Steck A. J. , Muñoz E. , de la Fuente M. , Gallart T. , Ribalta T. , Bombí J. A. , Tolosa E.
Published: January 2005

A patient who had a polyneuropathy compatible with a chronic inflammatory demyelinating polyneuropathy and was initially negative for anti‐myelin‐associated glycoprotein (MAG) antibodies developed a double monoclonal gammopathy, IgM kappa and IgM lambda, two years after the diagnosis. The IgM kappa, but not the IgM lambda, exhibited strong anti‐MAG antibody activity. The late appearance of the anti‐MAG immunoreactivity suggests that in patients with an initial diagnosis of chronic inflammatory demyelinating polyneuropathy, the search for anti‐MAG antibodies should be repeated during the course of the neuropathy.
Myelin basic protein‐specific T‐cell responses in identical twins discordant or concordant for multiple sclerosis
Authors: Martin Roland , Voskuhl Rhonda , Flerlage Marjorie , McFarlin Dale E. , McFarland Henry F.
Published: January 2005

Although multiple sclerosis (MS) is thought to be an autoimmune disease, the target antigen of the immune response is unknown. Both myelin basic protein (MBP) and proteolipid protein (PLP) have been considered candidate autoantigens. Because the immune response to either foreign or self antigens is influenced by the genetic background of the host, the importance of these candidate antigens has been difficult to establish in humans because of genetic diversity. To eliminate genetic differences in MS patients and healthy controls, we have studied the MBP‐specific T‐cell response in 6 sets of identical twins, 3 of which were concordant and 3 discordant for MS. A total of 638 short‐term T‐cell lines were established and characterized for MBP‐specific proliferative and cytotoxic activity, fine specificity, and human leukocyte antigen (HLA) restriction. Similar frequencies of MBP‐specific T cells were observed in affected and unaffected individuals. A slightly higher percentage of cytotoxic T‐cell lines was found in affected individuals. For most of the cell lines, the restriction elements were the HLA class II antigens that have been reported previously to be associated with MS; no important differences with respect to HLA restriction were found between the patients and healthy individuals. The peptide epitopes of MBP that were recognized most frequently by the T‐cell lines were those previously shown to be immunodominant. Differences in specificity were seen in some discordant twins indicating that, despite genetic identity, the MBP‐specific T‐cell repertoire may be shaped differently. These findings indicate that differences in frequency, peptide specificity, or HLA restriction are not sufficient to implicate MBP‐specific T cells in the pathogenesis of MS. However, the T‐cell response to MBP may still represent one necessary component with disease occurring when this response is combined with other host characteristics such as regulation of cytokine‐, adhesion molecule‐, or HLA‐antigen expression in the nervous system or immunoregulatory mechanisms.
Pathological markers associated with normal aging and dementia in the elderly
Authors: Crystal Howard A. , Dickson Dennis W. , Sliwinski Martin J. , Lipton Richard B. , Grober Ellen , Marks‐Nelson Harriet , Antis Phyllis
Published: January 2005

We investigated the associations of pathological markers of Alzheimer's disease (AD) and diffuse Lewy body disease as well as possible markers of vascular dementia with cognitive function in a sample of 20 nondemented and 35 demented subjects (median age of both groups, 88 years) who had been studied prospectively for 4.0 ± 2.1 years. Very old demented subjects almost always had nonneuritic senile plaques, but over half had no neuritic senile plaques and little other AD pathology. Five subjects had cortical Lewy bodies; all were demented. We propose that hippocampal sclerosis, leukoencephalopathy, and multiple lacunae are possible markers of vascular dementia. When grouped together, these markers were significantly associated with dementia and occurred in 40% of demented subjects. As the relative frequency of neuritic markers of AD (and possibly AD itself) declines in the tenth decade, vascular dementia may become an increasingly important type of dementia.
Carbamazepine‐induced heart block in a child with tuberous sclerosis and cardiac rhabdomyoma: Implications for evaluation and follow‐up
Authors: Weig Spencer G. , Pollack Phyllis
Published: January 2005

We describe a young child with tuberous sclerosis and cardiac rhabdomyoma who developed reversible heart block after being placed on carbamazepine treatment for seizures. Patients of any age with known or suspected intrinsic cardiac disease should be monitored for conduction disturbance if they are treated with carbamazepine.
The pathogenesis of superficial siderosis of the central nervous system
Authors: Koeppen Arnulf H. , Dickson Andrew C. , Chu Richard C. , Thach Robert E.
Published: January 2005

In advanced cases of superficial siderosis of the human central nervous system, the clinical triad of hearing loss, cerebellar ataxia, and myelopathy permits the diagnosis at the bedside, and magnetic resonance imaging readily confirms the hemosiderin deposits in brainstem, cerebellum, and spinal cord. To study the pathogenesis of this condition and explain the selective vulnerability of the cerebellum, experimental siderosis was induced in rabbits by the repeated intracisternal injection of autologous red blood cells. The earliest cellular response in the cerebellar molecular layer was hyperplasia and hypertrophy of microglia as displayed by immunocytochemistry for ferritin. Microglia also contained iron, but ferritin biosynthesis appeared to proceed without commensurate iron accumulation. This early apoferritin response probably occurred due to the presence of heme, rather than iron, in the cerebrospinal fluid and subpial tissue. Ferritin biosynthesis is accelerated when the ferritin repressor protein is dissociated from ferritin messenger ribonucleic acid. A specific antiserum localized ferritin repressor protein predominantly to astrocytes including Bergmann glia. It is proposed that abundance and proximity of ferritin repressor protein–immunoreactive Bergmann glia and ferritin‐containing microglia in the cerebellar molecular layer permit prompt cellular interaction in the conversion of heme to ferritin and ultimately hemosiderin.
Spastic paraparesis associated with human T‐lymphotropic virus type I: A clinical, serological, and genomic study in Iranian‐born Mashhadi Jews
Authors: Achiron A. , Pinhas‐Hamiel O. , Doll L. , Djaldetti R. , Chen A. , Ziv I. , Avni A. , Frankel G. , Melamed E. , Shohat B.
Published: January 2005

The Mashhadi‐Jewish community originating in Iran is a closed and ethnically segregated population with a unique history and a high rate of intrafamilial marriage among its members. A high risk of infection by human T‐lymphotropic virus type I (HTLV‐I) and of adult T‐cell leukemia associated with such infection was found in this population. HTLV‐I is also associated with a syndrome of progressive spastic paraparesis. We therefore evaluated the occurrence of HTLV‐I infection and spastic paraparesis in Mashhadi‐born Iranian Jews who immigrated to Israel. We examined 83 Mashhadi‐born subjects (52 women, 31 men; mean age, 61 ± 15.5 years) and 73 age‐matched non‐Mashhadi Iranian‐born Jews. Blood samples were tested for HTLV‐I antibodies by particle agglutination test. The polymerase chain reaction (PCR) was used to detect HTLV‐I proviral DNA sequences from peripheral blood mononuclear cells. Fifteen Mashhadi‐born Jews (18%) were both seropositive and PCR‐positive for HTLV‐I. Four HTLV‐I‐seronegative subjects were found to be positive for HTLV‐I proviral DNA by PCR. Of the 19 HTLV‐I–infected subjects (11 women, 8 men; mean age, 59 ± 16 years), 13 (68%) had spastic paraparesis of varying severity. There were no signs of myelopathy in the Mashhadi‐born subjects who were negative for HTLV‐I proviral DNA by PCR. None of the non‐Mashhadi Iranian Jews was seropositive or PCR‐positive for HTLV‐I proviral DNA, or had clinical signs of spastic paraparesis. Our study indicates a high incidence of HTLV‐I infection and spastic paraparesis in Mashhadi‐born Iranian Jews. Possible transmission mechanisms may be related to a high rate of infection in this closed community, or to a genetically transmitted virus in a susceptible high‐inbred population.
The apolipoprotein ε4 allele in patients with Alzheimer's disease
Authors: Mayeux Richard , Stern Yaakov , Ottman Ruth , Tatemichi Thomas K. , Tang Ming‐Xin , Maestre Gladys , Ngai Colleen , Tycko Benjamin , Ginsberg Henry
Published: January 2005

Apolipoproein E (APO‐E) binds to the β‐amyloid peptide and is present in senile neuritic plaques in Alzheimer's disease (AD). The ε4 isoform of APO‐E has been associated with both sporadic and familial late‐onset AD, implying a causal role. Among patients and control subjects similar in age, gender, and ethnic group from the New York City community of Washington Heights‐Inwood, we found that the odds ratio (OR) for AD associated with homozygosity for APO‐ε4 was 17.9 (95% confidence interval [CI], 4.6–69.8) and that associated with heterozygosity for APO‐ε4 was 4.2 (95% CI, 1.8–9.5), compared with persons with other APO‐E genotypes. The association was stronger among patients with sporadic disease (OR = 10.3; 95% CI, 3.4–31.1) than among those with a family history of dementia in a first‐degree relative (OR = 0.9; 95% CI, 0.1–13.5). The association between APO‐ε4 and AD did not differ according to age at onset (<65 vs ≥65), but appeared to vary across the 3 ethnic groups investigated (black, Hispanic, and white). Our data confirm the association between AD and APO‐ε4 and support the hypothesis that the APO‐ε4 allele either confers genetic susceptibility to AD or may be in linkage disequilibrium with another susceptibility locus. Ethnic variability in the allelic frequency of APO‐ε4 in the elderly warrants further investigation.
Characteristics of medial temporal lobe epilepsy: II. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology
Authors: Williamson P. D. , French J. A. , Thadani V. M. , Kim J. H. , Novelly R. A. , Spencer S. S. , Spencer D. D. , Mattson R. H.
Published: January 2005

Sixty‐seven patients with temporal lobe epilepsy without circumscribed, potentially epileptogenic lesions, who were studied with intracranial electrodes and who became seizure free following temporal lobectomy were retrospectively evaluated with regard to preoperative scalp electroencephalographic (EEG) findings, neuropsychological test results, neuroimaging findings, results of surgery, and pathology of resected tissue. Interictal scalp EEG showed paroxysmal abnormalities during prolonged monitoring in 64 patients (96%). These were localized in the anterior temporal region in 60 (94%) of these 64 patients. Bilateral independent paroxysmal activity occurred in 42% of the patients and was preponderant over the side of seizure origin in half. Ictal EEG changes were rarely detected at the time of clinical seizure onset, but lateralized buildup of rhythmic seizure activity during the seizure occurred in 80% of patients. In 13%, the scalp EEG seizure buildup was, however, contralateral to the side of seizure origin as subsequently determined by depth EEG and curative surgery. Lateralized postictal showing, when present, was a very reliable lateralizing finding. Neuropsychological testing provided lateralizing findings concordant with the side of seizure origin in 73% of patients. When neuropsychological testing produced discordant results or nonlateralizing findings, those patients were usually found to have right temporal seizure origin. Intracarotid amobarbital (Amytal) testing demonstrated absent or marginal memory functions on the side of seizure onset in 63% of patients, but 26 patients (37%) had bilaterally intact memory. In those patients who had magnetic resonance imaging, it was very sensitive in detecting subtle medial temporal abnormalities. These abnormalities were present in 23 of 28 magnetic resonance images, and corresponded with mesial temporal sclerosis on pathological examination in all but 2 patients. Eighty‐one percent of the 51 patients who had adequate pathological examination of tissue had mesial temporal sclerosis. Forty‐one patients with adequate pathological examination had histories of febrile seizures and of these 38 (93%) had mesial temporal sclerosis.
A new point mutation of the prion protein gene in Creutzfeldt‐Jakob disease
Authors: Pocchiari Maurizio , Salvatore Mirella , Cutruzzolá Francesca , Genuardi Maurizio , Allocatelli Carlo Travaglini , Masullo Carlo , Macchi Giorgio , Alemá Giovanni , Galgani Simona , Xi You Geng , Petraroli Rosella , Silvestrini Maria Chiara , Brunori Maurizio
Published: January 2005

Complete sequencing of the prion protein open reading frame of a 68‐year‐old woman affected by a familial form of Creutzfeldt‐Jakob disease (CJD) revealed a new mutation at codon 210 resulting in the substitution of isoleucine for valine. Moreover, a new 24‐bp deletion encompassing codons 54 to 61 or 62 to 69 was found in the other allele. Four of the 17 asymptomatic relatives tested carry the 210 mutation. Two of them were 81 and 82 years old. Four of 22 patients with CJD whose recorded familial history was negative for demented illnesses, but none of 103 healthy control subjects, tested positive for the 210 mutation. These data suggest that the 210 mutation is associated with CJD, but that environmental factors or incomplete penetrance may contribute to the development of the disease. This finding also suggests that in Italy, familial CJD is more common than previously reported.
A 10‐year experience with postpump chorea
Authors: Medlock Michael D. , Cruse Robert S. , Winek Sally Jo , Geiss Dale M. , Horndasch Richard L. , Schultz Debra L. , Aldag Jean C.
Published: January 2005

Postpump chorea (PPC) is the development of choreoathetoid movements within 2 weeks following cardiopulmonary bypass. Over a 10‐year period, 668 children underwent open cardiac surgery, of whom 8 (1.2%) developed PPC. Age at surgery ranged from 8 to 34 months. The onset of chorea was 3 to 12 days following surgery. Computed tomography and magnetic resonance imaging showed atrophy but no focal lesions. Cerebral positron emission tomography using [18F]fluorodeoxyglucose in a patient following 12 months of chorea showed patchy areas of decreased glucose metabolism. None of the patients were developmentally normal 22 to 130 months following surgery. Three patients have had transient and 5 have persistent chorea. Neurological deficits ranged from a mild learning disability to progressive hypotonia and obtundation ending in death. One of 4 patients who received haloperidol had a decrease in the severity of chorea. We compared PPC patients with 39 randomly selected controls. During surgery, affected patients spent significantly more time on pump and at temperatures under 36°C, were cooled to lower temperatures than controls, and were more likely to have had a circulatory arrest. One patient developed chorea without a history of circulatory arrest. We conclude that (1) there is a strong association between PPC, deep hypothermia, and circulatory arrest, (2) absence of characteristic macroscopic changes suggests a biochemical or microembolic etiology in some cases, (3) chorea is frequently associated with developmental delay, and (4) the prognosis for complete resolution of chorea is guarded.
Cerebellar hypermetria is larger when the inertial load is artificially increased
Authors: Manto M. , Godaux E. , Jacquy J.
Published: January 2005

Hypermetria is a classical cerebellar symptom designating the overshoot observed when a patient is asked to make a very fast and accurate movement. The movement studied here was wrist flexion. Hypermetria was found to be increased by artificially increasing the inertia of the moving hand. A normal subject adapted himself to increasing inertia by increasing both his agonist activity (the launching force) and its antagonist activity (the braking force). In the same circumstances, a patient with symptoms of cerebellar system dysfunction was found to be able to increase his agonist activity but not his antagonist activity.
Synaptotagmin can cause an immune‐mediated model of Lambert‐Eaton myasthenic syndrome in rats
Authors: Takamori Masaharu , Hamada Toshio , Komai Kiyonobu , Takahashi Masami , Yoshida Akira
Published: January 2005

The possible antigenicity of synaptotagmin, a synaptic vesicle protein acting as a cooperative calcium (Ca2+) receptor in exocytosis, was tested to determine whether it is involved in the induction of Lambert‐Eaton myasthenic syndrome in which antibodies against voltage‐dependent Ca2+ channels or related molecules play a pathogenic role. Repeated injections to Lewis rats with peptides of synaptotagmin residues 20 through 53 or 1 through 30 that are presumably exposed at the nerve terminal surface during exocytosis induced corresponding antipeptide antibodies; on immunoblots, antibodies recognized synaptotagmin that was expressed in the clonal cells. Electrophysiologically, the peptide (residues 20–53)‐immunized rats showed (1) reduced acetylcholine quantal content of end‐plate potential, (2) an increase in quantal content at high extracellular Ca2+ concentration, and (3) early facilitation followed by less marked depression of end‐plate potential amplitude at a tetanic rate of repetitive nerve stimulation. Findings are similar to those in human Lambert‐Eaton myasthenic syndrome and passively transferred Lambert‐Eaton myasthenic syndrome in mice, and thus suggest that antibody to a synaptotagmin–voltage‐dependent Ca2+ channel complex may be involved in the pathogenesis of Lambert‐Eaton myasthenic syndrome. The peptide (residues 1–30)‐immunized rats showed no electrophysiological abnormality.
Amyotrophic lateral sclerosis patient antibodies label Ca2+ channel α1 subunit
Authors: Kimura Fumiharu , Smith R. Glenn , Delbono Osvaldo , Nyormoi Okot , Schneider Toni , Nastainczyk Wolfgang , Hofmann Franz , Stefani Enrico , Appel Stanley H.
Published: January 2005

Sporadic amyotrophic lateral sclerosis is an idiopathic human degenerative disease of spinal cord and brain motor neurons. Prior studies demonstrated that most patients with amyotrophic lateral sclerosis posses immunoglobulins that bind to purified L‐type voltage‐gated calcium channels, that titers of anti–voltage‐gated calcium channel antibodies correlate with disease progression rates, and that amyotrophic lateral sclerosis patient‐derived antibodies (ALS IgG) produce electrophysiological changes in the function of voltage‐gated calcium channels. Using Western transfer immunoblots and enzyme‐linked immunosorbent assays, the calcium ionophore–forming α1 subunig of the voltage‐gated calcium channel is now identified as the major voltage‐gated calcium channel antigen to which ALS IgG binds. Additionally, the binding of an L‐type voltage‐gated calcium channel α1 subunit–directed monoclonal antibody, which itself mimics the effects of ALS IgG on skeletal muscle voltage‐gated calcium channel currents, is selectively prevented by preaddition of ALS IgG. Voltage‐gated calcium channel–binding IgG from patients with Lambert‐Eaton myasthenic syndrome appears to be differentiated from ALS IgG by the reactivity of the former to both α1 and β subunits of the calcium channel. These assays provide further evidence linking amyotrophic lateral sclerosis to an autoimmune process, and suggest one means to differentiate immunoglobulins from patients with amyotrophic lateral sclerosis from those of patients with another autoimmune disease expressing calcium channel antibodies.
Plasma exchange and intravenous immunoglobulin treatment of neuromuscular disease
Authors: Thornton Charles A. , Griggs Robert C.
Published: January 2005

Removal of immunoglobulin by plasma exchange and administration of immunoglobulin by intravenous infusion each improve selected neuromuscular diseases. Both treatments are expensive and relatively brief in their duration of action, but they benefit both self‐limited neuromuscular diseases such as the Guillain‐Barré syndrome and acute exacerbations of more chronic neuromuscular diseases including myasthenia gravis and chronic inflammatory demyelinating polyneuropathy. It is likely that plasma exchange acts by removing pathogenic antibodies. The mechanism by which intravenous immunoglobulin acts is less clear. Possibilities include (1) antiidiotypic antibody effect, (2) complement absorption, (3) downregulation of immunoglobulin production, (4) receptor blockade, (5) virus neutralization, (6) enhancement of suppressor cells, and (7) inhibition of lymphocyte proliferation. Although plasma exchange and intravenous immunoglobulin have major side effects, severe reactions are uncommon with plasma exchange and rare with intravenous immunoglobulin. Because of their low incidence of life‐threatening complications, both treatments have major appeal to clinicians. Because of their brief action and high cost as well as the uncertainty as to whether either or both should be employed, their role in the therapeutic armamentarium of the neurologist requires further study.
Nigrostriatal function in vitamin E deficiency: Clinical, experimental, and positron emission tomographic studies
Authors: Dexter David T. , Brooks David J. , Harding A. E. , Burn David J. , Muller David P. R. , Goss‐Sampson M. A. , Jenner P. G. , Marsden C. David
Published: January 2005

Four patients with vitamin E deficiency and sensory ataxia were studied using [18F]dopa positron emission tomography. The 2 most disabled patients, who had severe and prolonged vitamin E deficiency due to abetalipoproteinemia, showed reduced [18F]dopa uptake in both putamen and caudate. Putaminal uptake was in a similar range to that seen in Parkinson's disease. Studies of [3H]mazindol binding in the striatum of vitamin E–deficient rats indicated a reduced number of dopamine terminals, which was most severe in ventrolateral striatum. These observations suggest that severe and prolonged vitamin E deficiency results in loss of nigrostriatal nerve terminals, and support the hypothesis that oxidative stress may contribute to the etiology of Parkinson's disease.
Oligodendrocyte lysis by CD4+ T cells independent of tumor necrosis factor
Authors: Antel Jack P. , Williams Kenneth , Blain Manon , McRea Ellie , McLaurin JoAnne
Published: January 2005

The capacity of human CD4+ T cells to lyse heterologous human oligodendrocytes in an 18‐hour chromium 51–release assay was compared to that of systemic blood‐derived macrophages and central nervous system–derived microglia. CD4+ T cells, activated with either phytohemagglutinin, anti‐CD3 antibody, or antigen (myelin basic protein), could induce lysis of the oligodendrocytes whereas macrophages and microglia, activated with interferon‐γ and lipopolysaccharide, could not. The CD4+ T‐cell effect was not inhibited with an anti–tumor necrosis factor‐α–neutralizing antibody. Both the CD4+ T cells and the macrophages could induce lysis of tumor necrosis factor–sensitive rodent cell lines, Wehi 164, and L929; these effects were inhibited with anti–tumor necrosis factor antibody. Pretreatment of the CD4+ T cells with cyclosporine or mitomycin C did not inhibit oligodendrocyte lysis. These results indicate that at least in vitro, CD4+ T cells can induce a form of oligodendrocyte injury that is not reproduced by macrophages or microglia or by tumor necrosis factor. The non–major histocompatibility complex (MHC)–restricted injury of oligodendrocytes induced by both myelin antigen–reactive and mitogen‐stimulated T cells may provide a basis whereby cytotoxic CD4+ T cells could interact with a target cell that does not express MHC class II molecules. Our results suggest that immune‐mediated oligodendrocyte/myelin injury, as is postulated to occur in the disease multiple sclerosis, may involve multiple effector mechanisms.
Autosomal‐dominant cerebellar ataxia with retinal degeneration (ADCA type II) is genetically different from ADCA type I
Authors: Benomar A. , Le Guern E. , Dürr A. , Ouhabi H. , Stevanin G. , Yahyaoui M. , Chkili T. , Agid Y. , Brice A.
Published: January 2005

Autosomal‐dominant cerebellar ataxia (ADCA) type II is a neurodegenerative disorder presenting with cerebellar ataxia and retinal degeneration. We analyzed the clinical features of 21 patients with ADCA type II from 3 Moroccan and 2 French families. Mean age at onset was 17 years earlier in offspring than in their parents, compatible with anticipation. There was a suggestion of imprinting, with predominantly paternal transmission of early onset and severe forms of the affection. Candidate genes were tested in the family with the largest pedigree. The two known loci for ADCA type I (spinal cerebellar ataxia 1 and 2) were excluded, as were candidate loci, retinitis pigmentosa 1 locus (RP1) and the genes for rhodopsine and peripherin‐rds, responsible for autosomal dominant retinitis pigmentosa. ADCA type II does not therefore result from an allelic mutation of the tested genes for ADCA type I or autosomal dominant retinitis pigmentosa.
Rett syndrome: Controlled study of an oral opiate antagonist, naltrexone
Authors: Percy Alan K. , Glaze Daniel G. , Schultz Rebecca J. , Zoghbi Huda Y. , Williamson Daniel , Frost James D. , Jankovic Joseph J. , del Junco Deborah , Skender Martha , Waring Steve , Myer Edwin C.
Published: January 2005

Hypothesis: The opiate antagonist, naltrexone, will be beneficial in Rett syndrome. Subjects: Twenty‐five individuals fulfilling the criteria for Rett syndrome. Method: Randomized, double‐blind, placebo‐controlled crossover trial with two treatment periods, 4 months each, and an intervening 1‐month washout period. Clinical stage, motor and cognitive development, motor–behavioral analysis, neurophysiological parameters (computerized electroencephalographic analysis, breathing characteristics, quantification of stereotyped hand movements, and sleep characteristics), and cerebrospinal fluid β‐endorphin measurements were evaluated at baseline and at the end of each treatment period. Results: Only data from the first period of this study were analyzed due to significant sequence effects in the crossover design. This analysis indicated positive effects on certain respiratory characteristics including decreased disorganized breathing during wakefulness. Four (40%) of the individuals receiving naltrexone progressed one or more clinical stages versus none of the individuals receiving placebo. The adjusted (for baseline value and Rett stage) end of treatment psychomotor test age (Bayley Scales) was significantly higher for the placebo group. There was no significant change for the other parameters. Conclusion: Naltrexone may modify some of the respiratory disturbance in Rett syndrome. Declines in motor function and more rapid progression of the disorder suggest a deleterious effect.