Showing papers in "Annals of Neurology in 2001"

Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the Diagnosis of Multiple Sclerosis

Abstract: The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions.

Abstract: Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.

Primary progressive aphasia

Abstract: Primary progressive aphasia (PPA) is a focal dementia characterized by an isolated and gradual dissolution of language function. The disease starts with word-finding disturbances (anomia) and frequently proceeds to impair the grammatical structure (syntax) and comprehension (semantics) of language. The speech output in PPA can be fluent or nonfluent. Memory, visual processing, and personality remain relatively well-preserved until the advanced stages and help to distiguish PPA from frontal lobe dementia and the typical forms of Alzheimer's disease. The term "semantic dementia" was originally introduced to designate a different group of patients with a combination of verbal and visual processing deficits. In practice, however, this diagnosis is also being used in a variant sense to denote a subtype of PPA with fluent speech and impaired comprehension, even in the absence of visual processing deficits. Insofar as the diagnosis of semantic dementia can have these two different meanings, it is important to specify whether it is being used in the original sense or to denote a subtype of PPA. Structural and physiological neuroimaging confirms the selective predilection of PPA for the left hemisphere, especially for its language-related cortices. A few patients with PPA display the neuropathological markers of Alzheimer's disease, but in an unusual distribution. The majority of the autopsies in PPA have shown either Pick's disease or lobar atrophy without distinctive histopathology. The suggestion has been made that PPA and frontal lobe dementia constitute phenotypical variations of a unitary disease process within the "Pick-lobar atrophy" spectrum. Recent advances in chromosome 17-linked dementias justify a rigorous search for tau polymorphisms and tauopathy in sporadic PPA. An informed approach to this syndrome will increase the effectiveness with which clinicians can address the unique challenges associated with the diagnosis and care of PPA.

European/Canadian multicenter, double‐blind, randomized, placebo‐controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis

Abstract: Two prior double-blind, placebo-controlled, randomized trials demonstrated that glatiramer acetate (GA) reduces relapse rates in patients with relapsing remitting multiple sclerosis (RRMS). This study was designed to determine the effect, onset, and durability of any effect of GA on disease activity monitored with magnetic resonance imaging (MRI) in patients with RRMS. Two hundred thirty-nine eligible patients were randomized to receive either 20 mg GA (n = 119) or placebo (n = 120) by daily subcutaneous injection. Eligibility required one or more relapses in the 2 years before entry and at least one enhancing lesion on a screening MRI. The study was a randomized, double-blind, placebo-controlled phase during which all patients studied underwent monthly MRI scans and clinical assessments over 9 months. The primary outcome measure was the total number of enhancing lesions on T1-weighted images. Secondary outcome measures included the proportion of patients with enhancing lesions, the number of new enhancing lesions and change in their volume; the number of new lesions detected on T2-weighted images and change in their volume, and the change in volume of hypointense lesions seen on unenhanced T1-weighted images. Clinical measures of disease activity were also evaluated. The active treatment and placebo groups were comparable at entry for all demographic, clinical, and MRI variables. Treatment with GA showed a significant reduction in the total number of enhancing lesions compared with placebo (-10.8, 95% confidence interval -18.0 to -3.7; p = 0.003). Consistent differences favoring treatment with GA were seen for almost all secondary end points examined: number of new enhancing lesions (p < 0.003), monthly change in the volume of enhancing lesions (p = 0.01), and change in volume (p = 0.006) and number of new lesions seen on T2-weighted images (p < 0.003). The relapse rate was also significantly reduced by 33% for GA-treated patients (p = 0.012). All effects increased over time. Glatiramer acetate significantly reduced MRI-measured disease activity and burden.

Prospective study of caffeine consumption and risk of Parkinson's disease in men and women

Abstract: Results of case-control studies and of a prospective investigation in men suggest that consumption of coffee could protect against the risk of Parkinson's disease, but the active constituent is not clear. To address the hypothesis that caffeine is protective against Parkinson's disease, we examined the relationship of coffee and caffeine consumption to the risk of this disease among participants in two ongoing cohorts, the Health Professionals' Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). The study population comprised 47,351 men and 88,565 women who were free of Parkinson's disease, stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every two to four years. During the follow-up (10 years in men, 16 years in women), we documented a total of 288 incident cases of Parkinson's disease. Among men, after adjustment for age and smoking, the relative risk of Parkinson's disease was 0.42 (95% CI: 0.23-0.78; p for trend < 0.001) for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee (p for trend = 0.004), caffeine from noncoffee sources (p for trend < 0.001), and tea (p for trend = 0.02) but not decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson's disease was U-shaped, with the lowest risk observed at moderate intakes (1-3 cups of coffee/day, or the third quintile of caffeine consumption). These results support a possible protective effect of moderate doses of caffeine on risk of Parkinson's disease.

Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease

Abstract: Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimer's disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimer's disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimer's disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left-sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimer's disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimer's disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role.

Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy

Abstract: This multicenter, randomized, double-blind, crossover trial compared a six week course of oral prednisolone tapering from 60 mg to 10 mg daily with intravenous immunoglobulin (IVIg) 2.0 g/kg given over one to two days for treating chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Twenty-four of the thirty-two randomized patients completed both treatment periods. Both treatments produced significant improvements in the primary outcome measure, change in an 11-point disability scale two weeks after randomization. There was slightly, but not significantly, more improvement after IVIg than with prednisolone, the mean difference between the groups in change in disability grade being 0.16 (95% CI = -0.35 to 0.66). There were also slightly, but not significantly, greater improvements favoring IVIg in the secondary outcome measures: time to walk 10 meters after two weeks and improvement in disability grade after six weeks. Results may have been biased against IVIg by the eight patients who did not complete the second arm of the trial. A serious adverse event (psychosis) attributable to treatment occurred in one patient while on prednisolone and in none with IVIg.

Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy.

Abstract: Several mutations in the amyloid precursor protein (APP) gene have been found to associate with pathologic deposition of the beta-amyloid peptide (Abeta) in neuritic plaques or in the walls of cerebral vessels. We report a mutation at a novel site in APP in a three-generation Iowa family with autosomal dominant dementia beginning in the sixth or seventh decade of life. The proband and an affected brother had progressive aphasic dementia, leukoencephalopathy, and occipital calcifications. Neuropathological examination of the proband revealed severe cerebral amyloid angiopathy, widespread neurofibrillary tangles, and unusually extensive distribution of Abeta40 in plaques. The affected brothers shared a missense mutation in APP, resulting in substitution of asparagine for aspartic acid at position 694. This site corresponds to residue 23 of Abeta, thus differing from familial Alzheimer's disease mutations, which occur outside the Abeta sequence. Restriction enzyme analysis of DNA from 94 unrelated patients with sporadic cerebral amyloid angiopathy-related hemorrhage found no other instances of this mutation. These results suggest a novel site within Abeta that may promote its deposition and toxicity.

Lewy bodies and parkinsonism in families with parkin mutations.

Abstract: Previous work has established that compound mutations and homozygous loss of function of the parkin gene cause early-onset, autosomal recessive parkinsonism. Classically, this disease has been associated with loss of dopaminergic neurons in the substantia nigra pars compacta and locus ceruleus, without Lewy body pathology. We have sequenced the parkin gene of 38 patients with early-onset Parkinson's disease (<41 years). Two probands with mutations were followed up. Clinical evaluation of their families was performed, blinded to both genetic and pathological findings. Chromosome 6q25.2-27 haplotype analysis was carried out independently of the trait; parkin gene expression was examined at both the RNA and protein levels. Haplotype analysis of these families revealed a common chromosome 6, with a novel 40 bp exon 3 deletion that cosegregated with disease. In the proband of the smaller kindred, an exon 7 R275W substitution was identified in addition to the exon 3 deletion; RNA analysis demonstrated that the mutations were on alternate transcripts. However, Lewy body pathology typical of idiopathic Parkinson's disease was found at autopsy in the proband from the smaller kindred. These data suggest that compound heterozygous parkin mutations and loss of parkin protein may lead to early-onset parkinsonism with Lewy body pathology, while a hemizygous mutation may confer increased susceptibility to typical Parkinson's disease.

CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity.

Abstract: We have defined a new paraneoplastic immunoglobulin G (IgG) autoantibody specific for CRMP-5, a previously unknown 62-kd neuronal cytoplasmic protein of the collapsin response-mediator family. CRMP-5 is in adult central and peripheral neurons, including synapses, and in small-cell lung carcinomas. Since 1993, our Clinical Neuroimmunology Laboratory has detected CRMP-5-IgG in 121 patients among approximately 68,000 whose sera were submitted for standardized immunofluorescence screening because a subacute neurological presentation was suspected to be paraneoplastic. This makes CRMP-5 autoantibody as frequent as PCA-1 (anti-Yo) autoantibody, second only to ANNA-1 (anti-Hu). Clinical information, obtained for 116 patients, revealed multifocal neurological signs. Most remarkable were the high frequencies of chorea (11%) and cranial neuropathy (17%, including 10% loss of olfaction/taste, 7% optic neuropathy). Other common signs were peripheral neuropathy (47%), autonomic neuropathy (31%), cerebellar ataxia (26%), subacute dementia (25%), and neuromuscular junction disorders (12%). Spinal fluid was inflammatory in 86%, and CRMP-5-IgG in 37% equaled or significantly exceeded serum titers. Lung carcinoma (mostly limited small-cell) was found in 77% of patients; thymoma was in 6%. Half of those remaining had miscellaneous neoplasms; all but two were smokers. Serum IgG in all cases bound to recombinant CRMP-5 (predominantly N-terminal epitopes), but not to human CRMP-2 or CRMP-3.

Alzheimer's disease versus Dementia with Lewy bodies : Cerebral metabolic distinction with autopsy confirmation

Abstract: Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later clinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.

Multiple sclerosis: Altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage

Abstract: Glutamate excitotoxicity, recently demonstrated in an animal model of multiple sclerosis (MS), is evoked by altered glutamate homeostasis. In the present study, we investigated the major regulating factors in glutamate excitotoxicity by immunohistochemistry in MS and control white matter with markers for glutamate production (glutaminase), glutamate transport (GLAST, GLT-1 and EAAT-1), glutamate metabolism (glutamate dehydrogenase [GDH] and glutamine synthetase [GS]), axonal damage (SMI 32) and CNS cell types. Active MS lesions showed high-level glutaminase expression in macrophages and microglia in close proximity to dystrophic axons. Correlation between glutaminase expression and axonal damage was confirmed experimentally in animals. White matter from other inflammatory neurologic diseases displayed glutaminase reactivity, whereas normals and noninflammatory conditions showed none. All three glutamate transporters were expressed robustly, mainly on oligodendrocytes, in normal, control and MS white matter, except for GLT-1, which showed low-level expression around active MS lesions. GS and GDH were present in oligodendrocytes in normal and non-MS white matter but were absent from both active and chronic silent MS lesions, suggesting lasting metabolic impediments. Thus, imbalanced glutamate homeostasis contributes to axonal and oligodendroglial pathology in MS. Manipulation of this imbalance may have therapeutic import.

Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment.

Abstract: Layer II of the entorhinal cortex contains the cells of origin for the perforant path, plays a critical role in memory processing, and consistently degenerates in end-stage Alzheimer's disease. The extent to which neuron loss in layer II of entorhinal cortex is related to mild cognitive impairment without dementia has not been extensively investigated. We analyzed 29 participants who came to autopsy from our ongoing longitudinal study of aging and dementia composed of religious clergy (Religious Orders Study). All individuals underwent detailed clinical evaluation within 12 months of death and were categorized as having no cognitive impairment (n = 8), mild cognitive impairment (n = 10), or mild or moderate Alzheimer's disease (n = 11). Sections through the entorhinal cortex were immunoreacted with an antibody directed against a neuron-specific nuclear protein (NeuN). Stereological counts of NeuN-immunoreactive stellate cells, their volume, and the volume of layer II entorhinal cortex were estimated. Cases exhibiting no cognitive impairment averaged 639,625 +/- 184,600 layer II stellate neurons in the right entorhinal cortex. Individuals with mild cognitive impairment (63.5%; p 0.33). There was also significant atrophy of layer II entorhinal cortex neurons in individuals with mild cognitive impairment (24.1%) and Alzheimer's disease (25.1%). The volume of layer II was also reduced in individuals with mild cognitive impairment (26.5%), with a further reduction in those with Alzheimer's disease (46.4%). The loss and atrophy of layer II entorhinal cortex neurons significantly correlated with performance on clinical tests of declarative memory. Atrophy of layer II entorhinal cortex and the neurons within this layer significantly correlated with performance on the Mini Mental Status Examination. These data indicate that atrophy and loss of layer II entorhinal cortex neurons occur in elderly subjects with mild cognitive impairment prior to the onset of dementia and suggests that these changes are not exacerbated in early Alzheimer's disease.

Neuropeptides and neurotrophins in neonatal blood of children with autism or mental retardation.

Abstract: There has been little exploration of major biologic regulators of cerebral development in autism. In archived neonatal blood of children with autistic spectrum disorders (n = 69), mental retardation without autism (n = 60), or cerebral palsy (CP, n = 63) and of control children (n = 54), we used recycling immunoaffinity chromatography to measure the neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), calcitonin gene-related peptide (CGRP), and the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4/5 (NT4/5), Neonatal concentrations of VIP, CGRP, BDNF, and NT4/5 were higher (ANOVA, all p values < 0.0001 by Scheffe test for pairwise differences) in children in the autistic spectrum and in those with mental retardation without autism than in control children. In 99% of children with autism and 97% with mental retardation, levels of at least one of these substances exceeded those of all control children. Concentrations were similar in subgroups of the autistic spectrum (core syndrome with or without mental retardation, other autistic spectrum disorders with or without mental retardation) and in the presence or absence of a history of regression. Among children with mental retardation, concentrations did not differ by severity or known cause (n = 11, including 4 with Down syndrome). Concentrations of measured substances were similar in children with CP as compared with control subjects. SP, PACAP, NGF, and NT3 were not different by diagnostic group. No measured analyte distinguished children with autism from children with mental retardation alone. In autism and in a heterogeneous group of disorders of cognitive function, overexpression of certain neuropeptides and neurotrophins was observed in peripheral blood drawn in the first days of life.

Potassium channel antibodies in two patients with reversible limbic encephalitis.

Abstract: Limbic encephalitis (LE) is often associated with lung, thymic, or testicular tumours and antibodies to Hu, CV2, or Ma2 (Ta) antigens. In these cases, it generally has a poor prognosis. Here we describe two patients with symptoms of LE, negative for typical paraneoplastic antibodies, in whom antibodies to voltage-gated potassium channels (VGKC) were detected retrospectively in serial serum samples. Patient 1 had a thymoma recurrence, but in patient 2 no tumour has been detected in the years following presentation. Plasma exchange was effective in reducing VGKC antibody levels, with substantial improvement in mental symptoms in patient 1. In patient 2, the VGKC antibodies fell spontaneously over two years, with almost complete recovery of mental function. Although neither patient had obvious neuromyotonia at presentation, both showed excessive secretions. We suggest that patients with limbic symptoms and excessive secretions should be tested for VGKC antibodies, and, if they are present, prompt and effective immunosuppressive treatment should be considered.

Low cerebrospinal fluid hypocretin (orexin) and altered energy homeostasis in human narcolepsy

Abstract: Hypocretins (orexins) are hypothalamic neuropeptides involved in sleep and energy homeostasis. Hypocretin mutations produce narcolepsy in animal models. In humans, narcolepsy is rarely due to hypocretin mutations, but this system is deficient in the cerebrospinal fluid (CSF) and brain of a small number of patients. A recent study also indicates increased body mass index (BMI) in narcolepsy. The sensitivity of low CSF hypocretin was examined in 38 successive narcolepsy-cataplexy cases [36 human leukocyte antigen (HLA)-DQB1*0602-positive] and 34 matched controls (15 controls and 19 neurological patients). BMI and CSF leptin levels were also measured. Hypocretin-1 was measurable (169 to 376 pg/ml) in all controls. Levels were unaffected by freezing/thawing or prolonged storage and did not display any concentration gradient. Hypocretin-1 was dramatically decreased (<100 pg/ml) in 32 of 38 patients (all HLA-positive). Four patients had normal levels (2 HLA-negative). Two HLA-positive patients had high levels (609 and 637 pg/ml). CSF leptin and adjusted BMI were significantly higher in patients versus controls. We conclude that the hypocretin ligand is deficient in most cases of human narcolepsy, providing possible diagnostic applications. Increased BMI and leptin indicate altered energy homeostasis. Sleep and energy metabolism are likely to be functionally connected through the hypocretin system.

Immunopathology of secondary‐progressive multiple sclerosis

Abstract: Twenty-three plaques obtained at early autopsy from 2 patients with secondary-progressive multiple sclerosis were examined immunohistochemically for microglia/macrophages, and for immunoglobulins and components of activated complement. Most of the lesions examined in both cases exhibited evidence of low-grade active demyelination of an unusual type (frustrated phagocytosis) in periplaque white matter. This included linear groups of microglia engaging short segments of disrupted myelin that were associated with deposits of C3d, an opsonin formed during complement activation. Similar microglia/C3d/myelin profiles were not observed in newly forming lesions in cases of acute multiple sclerosis or other central white matter diseases. As C3d coupling is known to increase the immunogenicity of potential antigens enormously, present findings point to disrupted myelin close to plaques as a possible source of the putative multiple sclerosis antigen. Ongoing myelin destruction found in a high proportion of old, established plaques was surprising. It suggests that slowly expanding lesions (progressive plaques), in which ongoing myelin breakdown occurs in the absence of florid perivascular cell cuffing or other histological signs of acute inflammation, contribute to disease progression in cases of secondary-progressive multiple sclerosis.

Fluoxetine modulates motor performance and cerebral activation of patients recovering from stroke.

Abstract: In order to determine the influence of a single dose of fluoxetine on the cerebral motor activation of lacunar stroke patients in the early phase of recovery, we conducted a prospective, double-blind, crossover, placebo-controlled study on 8 patients with pure motor hemiparesia. Each patient underwent two functional magnetic resonance imaging (fMRI) examinations: one under fluoxetine and one under placebo. The first was performed 2 weeks after stroke onset and the second a week later. During the two fMRI examinations, patients performed an active controlled motor task with the affected hand and a passive one conducted by the examiner with the same hand. Motor performance was evaluated by motor tests under placebo and under fluoxetine immediately before the examinations to investigate the effect of fluoxetine on motor function. Under fluoxetine, during the active motor task, hyperactivation in the ipsilesional primary motor cortex was found. Moreover, fluoxetine significantly improved motor skills of the affected side. We found that a single dose of fluoxetine was enough to modulate cerebral sensory-motor activation in patients. This redistribution of activation toward the motor cortex output activation was associated with an enhancement of motor performance.

Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr α-synuclein mutation

Abstract: We describe an Australian family of Greek origin with a parkinsonian syndrome and an Ala53Thr alpha-synuclein gene mutation. Five of 9 siblings were affected, the average age of onset was 45 years, and the initial symptoms were variable, including resting tremor, bradykinesia, and gait disturbance, as previously described in families with the same point mutation. Affected family members responded well to levodopa, developed progressive cognitive impairment, and had a disease duration of 5 to 16 years. Pathologic features typical of idiopathic Parkinson's disease were found at autopsy. However, there were several additional features not previously reported in families with this gene mutation. These features included severe central hypoventilation, orthostatic hypotension, prominent myoclonus, and urinary incontinence. An abundance of alpha-synuclein-immunoreactive Lewy neurites were found in the brainstem pigmented nuclei, hippocampus, and temporal neocortex. The Lewy neurites were associated with temporal lobe vacuolation. Subcortical basal ganglia cell loss and gliosis were seen. These additional clinical and pathological features suggest that the Ala53Thr alpha-synuclein mutation can produce a more widespread disorder than found in typical idiopathic Parkinson's disease.

Delayed cerebral edema and fatal coma after minor head trauma : role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine

Abstract: Trivial head trauma may be complicated by severe, sometimes even fatal, cerebral edema and coma occurring after a lucid interval ("delayed cerebral edema"). Attacks of familial hemiplegic migraine (FHM) can be triggered by minor head trauma and are sometimes accompanied by coma. Mutations in the CACNA1A calcium channel subunit gene on chromosome 19 are associated with a wide spectrum of mutation-specific episodic and chronic neurological disorders, including FHM with or without coma. We investigated the role of the CACNA1A gene in three subjects with delayed cerebral edema. Two subjects originated from a family with extreme FHM, and one subject was the previously asymptomatic daughter of a sporadic patient with hemiplegic migraine attacks. In all three subjects with delayed severe edema, we found a C-to-T substitution resulting in the substitution of serine for lysine at codon 218 (S218L) in the CACNA1A gene. The mutation was absent in nonaffected family members and 152 control individuals. Haplotype analysis excluded a common founder for both families. Neuropathological examination in one subject showed Purkinje cell loss with relative preservation of granule cells and sparing of the dentate and inferior olivary nuclei. We conclude that the novel S218L mutation in the CACNA1A calcium channel subunit gene is involved in FHM and delayed fatal cerebral edema and coma after minor head trauma. This finding may have important implications for the understanding and treatment of this dramatic syndrome.

The incidence of mitochondrial encephalomyopathies in childhood: clinical features and morphological, biochemical, and DNA abnormalities.

Abstract: In this study we present incidence, point prevalence, and mortality figures of mitochondrial encephalomyopathies in a population-based study of children from western Sweden. Through the screening of registers and review of medical records, we identified 32 patients under 16 years of age from the study population who were diagnosed between January 1, 1984, and December 31, 1998. The incidence of mitochondrial encephalomyopathies in preschool children (<6 years of age) was 1 out of 11,000. The preschool incidence of Leigh's syndrome was 1 out of 32,000, and the preschool incidences of both Alper's syndrome and infantile mitochondrial myopathy with cytochrome C oxidase deficiency were 1 out of 51,000. The point prevalence January 1, 1999) of mitochondrial encephalomyopathies in children under 16 years of age was 1 out of 21,000. The median survival for patients with infantile onset was until 12 years of age. We identified 4 cases with mitochondrial DNA point mutations, 2 cases with mitochondrial DNA deletions, and 2 cases with nuclear mutations in the SURF1 gene. We conclude that mitochondrial encephalomyopathies are relatively common neurometabolic disorders in childhood.

Mortality in epilepsy in the first 11 to 14 years after diagnosis: multivariate analysis of a long-term, prospective, population-based cohort

Abstract: The United Kingdom National General Practice Study of Epilepsy is a prospective, population-based study of newly diagnosed epilepsy. A cohort of 792 patients has now been followed for up to 14 years (median follow-up [25th, 75th percentiles] 11.8 years, range 10.6-11.7 years), a total of 11,400 person-years. These data are sufficient for a detailed analysis of mortality in this early phase of epilepsy. Over 70% of patients in this cohort have developed lasting remission from seizures, although the mortality rate in the long term was still twice that of the general population. The standardized mortality ratio (SMR), the number of observed deaths per number of expected deaths, was 2.1 (95% confidence interval [CI] = 1.8, 2.4). Patients with acute symptomatic epilepsy (SMR 3.0; 95% CI = 2.0, 4.3), remote symptomatic epilepsy (SMR 3.7; 95% CI = 2.9, 4.6), and epilepsy due to congenital neurological deficits (SMR 25; 95% CI = 5.1, 73.1) had significantly increased long-term mortality rates, whereas patients with idiopathic epilepsy did not (SMR 1.3; 95% CI = 0.9, 1.9). This increase in mortality rate was noted particularly in the first few years after diagnosis. Multivariate Cox regression and time-dependent co-variate analyses were utilized for the first time in a prospective study of mortality in epilepsy. The former showed that patients with generalized tonic-clonic seizures had an increased risk of mortality. The hazard ratio (HR), or risk of mortality in a particular group with a particular risk factor compared to another group without that particular risk factor, was 6.2 (95% CI = 1.4, 27.7; p = 0.049). Cerebrovascular disease (HR 2.4; 95% CI = 1.7, 3.4; p < 0.0001), central nervous system tumor (HR 12.0; 95% CI = 7.9, 18.2; p < 0.0001), alcohol (HR 2.9; 95% CI = 1.5, 5.7; p = 0.004), and congenital neurological deficits (HR 10.9; 95% CI = 3.2, 36.1; p = 0.003) as causes for epilepsy and older age at index seizure (HR 1.9; 95% CI = 1.7,2.0; p < 0.0001) were also associated with significantly increased mortality rates. These hazard ratios suggest that epilepsy due to congenital neurological deficits may carry almost the same risk of mortality as epilepsy due to central nervous system tumors and that epileptic seizures subsequent to alcohol abuse may carry almost the same risk of mortality as epilepsy due to cerebrovascular disease. The occurrence of one or more seizures before the index seizure (the seizure that led to the diagnosis of epilepsy and enrolment in the study) was associated with a significantly reduced mortality rate (HR 0.57; 95% CI = 0.42, 0.76; p = 0.00001). Time-dependent co-variate analysis was used to examine the influence of ongoing factors, such as seizure recurrence, remission, and antiepileptic drug use, on mortality rates in the cohort. Seizure recurrence (HR 1.30; 95% CI = 0.84, 2.01) and antiepileptic drug treatment (HR 0.97; 95% CI = 0.67, 1.38) did not influence mortality rate. There were only 5 epilepsy-related deaths (1 each of sudden unexpected death in epilepsy, status epilepticus, burns, drowning, and cervical fracture), suggesting that death directly due to epileptic seizures is uncommon in a population-based cohort with epilepsy.

Electrically active axons degenerate when exposed to nitric oxide.

Abstract: Axonal degeneration is a major cause of permanent deficit in inflammatory neurological diseases such as multiple sclerosis. Axons undergo degeneration specifically at the site of the inflammatory lesions, suggesting that locally produced inflammatory factors mediate the phenomenon. One such factor is nitric oxide (NO), which we have previously reported can cause reversible conduction block in axons. Here we confirm these observations and extend them to show that axons exhibit the early stages of wallerian degeneration if they are conducting impulses at physiological frequencies while they are exposed to the low micromolar concentrations of NO that are likely to occur at sites of inflammation. Rat dorsal roots were concurrently exposed in vivo to both NO and sustained impulse activity at 1, 50, or 100 Hz. Although our in vivo observations necessarily focused on the more acute responses, morphological examination of exposed roots at the end of the recording period revealed nodal and paranodal changes consistent with acute wallerian degeneration in roots stimulated at 50 or 100 Hz. This interpretation was confirmed in a few experiments that were prolonged to permit more obvious indicators of degeneration to develop. In these experiments the formation of myelin ovoids and frank axonolysis occurred in more than 95% of fibers. Roots stimulated at only 1 Hz appeared normal. We propose that the combination of normal impulse traffic and NO at sites of inflammation may cause axonal degeneration and that electrical activity may therefore be an important factor in causing permanent disability in patients with neuroinflammatory disorders.

Animal model of axonal Guillain-Barré syndrome induced by sensitization with GM1 ganglioside.

Abstract: Some humans develop the axonal form of Guillain-Barre syndrome after receiving bovine brain ganglioside. On sensitization with the ganglioside mixture, all of a group of rabbits injected developed high anti-GM1 IgG antibody titers, flaccid limb weakness of acute onset, and a monophasic illness course. Pathological findings for the peripheral nerves showed predominant Wallerian-like degeneration, with neither lymphocytic infiltration nor demyelination. IgG was deposited on the axons of the anterior roots, and GM1 was proved to be present on the axons of peripheral nerves. Sensitization with purified GM1 also induced axonal neuropathy, indicating that GM1 was the immunogen in the mixture. A model of human axonal Guillain-Barre syndrome has been established that uses inoculation with a bovine brain ganglioside mixture or isolated GM1. This model may help to clarify the molecular pathogenesis of the syndrome and to develop new treatments for it.

Adrenoleukodystrophy: Incidence, new mutation rate, and results of extended family screening

Abstract: Utilizing the plasma very long chain fatty acid assay, supplemented by mutation analysis and immunofluorescence assay, we determined the number of X-linked adrenoleukodystrophy (X-ALD) hemizygotes from the United States identified each year in the two laboratories that perform most of the assays in this country: the Kennedy Krieger Institute between 1981 and 1998 and the Mayo Clinic Rochester from 1996 to 1998 The minimum frequency of hemizygotes identified in the United States is estimated to be 1:42,000 and that of hemizygotes plus heterozygotes 1:16,800 Our studies involved 616 pedigrees with a total of 12,787 identified at-risk members Diagnostic assays were performed in 4,169 at-risk persons (33%) and included members of the extended family Only 5% of male probands and 17% of X-ALD hemizygotes were found to have new mutations The extended family testing led to the identification of 594 hemizygotes and 1,270 heterozygotes Two hundred fifty of the newly identified hemizygotes were asymptomatic and represent the group in which therapy has the greatest chance of success Identification of heterozygotes provides the opportunity for disease prevention through genetic counseling Diagnostic tests should be offered to all at-risk relatives of X-ALD patients and should include members of the extended family

Increased expression of the pro-inflammatory enzyme cyclooxygenase-2 in amyotrophic lateral sclerosis.

Abstract: Mutations in the copper/zinc superoxide dismutase (mSOD1) gene are associated with a familial form of amyotrophic lateral sclerosis (ALS), and their expression in transgenic mice produces an ALS-like syndrome Recent observations suggest a role for inflammatory-related events in the progression and propagation of the neurodegenerative process in ALS Consistent with this view, the present study demonstrates that, during the course of the disease, the expression of cyclooxygenase type 2 (Cox-2), a key enzyme in the synthesis of prostanoids, which are potent mediators of inflammation, is dramatically increased In both early symptomatic and end-stage transgenic mSOD1 mice, neurons and, to a lesser extent, glial cells in the anterior horn of the spinal cord exhibit robust Cox-2 immunoreactivity Cox-2 mRNA and protein levels and catalytic activity are also significantly increased in the spinal cord of the transgenic mSOD1 mice The time course of the spinal cord Cox-2 upregulation parallels that of motor neuronal loss in transgenic mSOD1 mice We also show that Cox-2 activity is dramatically increased in postmortem spinal cord samples from sporadic ALS patients We speculate that Cox-2 upregulation, through its pivotal role in inflammation, is instrumental in the ALS neurodegenerative process and that Cox-2 inhibition may be a valuable therapeutic avenue for the treatment of ALS

Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell

Abstract: By the time a clinical diagnosis of Parkinson's disease (PD) is made, a significant loss of dopaminergic neurons has already occurred. Identifying patients in the period between the presumed onset of dopaminergic cell loss and the appearance of clinical parkinsonism may be of major importance in the development of effective neuroprotective treatment strategies. In an effort to develop a feasible strategy to detect preclinical PD, a combination of olfactory processing tasks, including odor detection, odor identification, and odor discrimination was used to select groups of hyposmic and normosmic individuals from a total of 250 relatives (parents, siblings, or children) of subjects with PD. Single photon emission computed tomography (SPECT) with [123I]beta-CIT as a dopamine transporter ligand was used to assess nigrostriatal dopaminergic function in 25 hyposmic and 23 normosmic relatives of PD patients. An abnormal reduction in striatal dopamine transporter binding was found in 4 out of 25 hyposmic relatives of PD patients, two of whom subsequently developed clinical parkinsonism, and in none of the 23 normosmic relatives. These observations demonstrate that subclinical reductions in dopamine transporter binding can be detected in asymptomatic relatives of sporadic PD patients by means of [123I]beta-CIT and SPECT. The results further indicate that olfactory deficits may precede clinical motor signs in PD.

A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats.

Abstract: The adult rodent brain is capable of generating neuronal progenitor cells in the subventricular zone, and in the dentate gyrus of the hippocampus, throughout the life of the animal. Signals that regulate progenitor cell proliferation, differentiation, and migration are not well known. We report that administration of a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio]diazen-1-ium-1,2-diolate (DETA/NONOate), to young adult rats significantly increases cell proliferation and migration in the subventricular zone and the dentate gyrus. Treatment with DETA/ NONOate also increases neurogenesis in the dentate gyrus. Furthermore, administration of DETA/NONOate to rats subjected to embolic middle cerebral artery occlusion significantly increases cell proliferation and migration in the subventricular zone and the dentate gyrus, and these rats exhibit significant improvements of neurological outcome during recovery from ischemic stroke. Administration of DETA/NONOate significantly increases cortical levels of guanosine monophosphate both in ischemic and nonischemic rats, supporting the role of nitric oxide in promoting cell proliferation and neurogenesis. Thus, our data indicate that nitric oxide is involved in the regulation of progenitor cells and neurogenesis in the adult brain. This suggests that nitric oxide delivered to the brain well after stroke may have therapeutic benefits.

Orbitofrontal and anterior cingulate cortex neurofibrillary tangle burden is associated with agitation in Alzheimer disease.

Abstract: Few studies evaluate neuropathological correlates of behavioral changes in Alzheimer disease (AD). We identified 31 autopsy patients with a diagnosis of definite AD. Behavioral changes were assessed with the Neuropsychiatric Inventory. Brain sections were collected from bilateral orbitofrontal and left anterior cingulate, superior temporal, inferior parietal, occipital, and hippocampal cortices for quantification of neurofibrillary tangles (NFTs) and diffuse and neuritic plaques. Sections from frontal, cingulate, and hippocampal cortices were reviewed for the presence of Lewy bodies (LBs). Hypothesis-driven correlational analyses were performed by the bootstrap method. Subgroup analyses contrasted a group with high scores of one specific behavior to a group with low scores after equating groups for other behaviors. NFT burden in the left orbitofrontal cortex across all 31 patients significantly correlated with agitation scores (r = 0.41, p < 0.015) and NFTs correlated significantly (r = 0.66, p = 0.004) with higher agitation scores in the subgroup analysis. Left anterior cingulate NFTs, although not within our hypotheses, also showed a significant relationship to agitation within the subgroups (r = 0.76, p = 0.0003; Bonferroni p = 0.02). Seven patients, including three in the agitation subgroup, had cortical LBs. Aberrant motor behavior and NFT density in the left orbitofrontal cortex showed a significant relationship for the entire group (r = 0.38, p < 0.03) and for subgroups (r = 0.49, p = 0.04), whereas apathy and left anterior cingulate NFTs showed a significant relationship only for the entire group (r = 0.25, p < or = 0.01). These observations suggest that agitation and aberrant motor behavior are correlates of greater NFT pathology in the orbitofrontal cortex in AD, whereas increasing apathy may relate to greater NFT burden in the anterior cingulate.

How long do new-onset seizures in children last?

Abstract: Although there are data on the duration of seizures in patients with refractory epilepsy, little is known about the duration of seizures in nonrefractory epilepsy populations. In a prospective study, seizure duration was determined in 407 children with a first unprovoked seizure using a structured interview and review of medical and ambulance records. Analysis focused on the distribution of seizure duration and on the conditional probability that a seizure would stop once it had already lasted for a specified time. Seizures lasted > or = 5 minutes in 50% of cases, > or = 10 minutes in 29%, > or = 20 minutes in 16%, and > or = 30 minutes in 12%. Seizure duration data were best fit as the sum of two exponential distributions, one with a mean of 3.6 minutes accounting for 76% of cases and the other with a mean of 31 minutes accounting for 24% of cases. The longer a seizure lasted, the less likely it was to stop within the next few minutes. In the 182 children with 2 or more seizures, the durations of the first and second seizures were highly correlated (r = 0.395, p < 0.0001). We conclude that the distribution of seizure duration in children with a first unprovoked seizure differs markedly from that observed in patients with refractory epilepsy. A subgroup of patients are predisposed to prolonged seizures. The data suggest that, once a seizure lasts for more than 5-10 minutes, it is unlikely to stop spontaneously within the next few minutes, and intervention is therefore indicated. These findings also support the continued use of the current definition of status epilepticus as a seizure lasting for 30 minutes or longer for epidemiologic studies.