Archives of Neurology

Published by American Medical Association
Print ISSN: 0003-9942
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The Archives of Neurology celebrates 50 years of existence. In 1919, it started as part of the Archives of General Psychiatry and Neurology. The journals split in 1959; both have flourished, becoming premier journals in their respective areas. Why did they split, and what has been the relationship between the two disciplines since then?Both journals had lead editorials1,2 by their respective editors in the first issues, Harold G. Wolff, MD, for Neurology and Roy R. Grinker Sr, MD, for General Psychiatry. Wolff served as Chief Editor from 1959 until 1963; subsequent Chief Editors were H. Houston Merritt, MD, New York, 1963-1972; Fred Plum, MD, New York, 1972-1976; Maurice W. Van Allen, MD, Iowa, 1976-1981; Robert J. Joynt, MD, PhD, Rochester, New York, 1982-1997; and Roger N. Rosenberg, MD, Dallas, Texas, 1997-present. Both of the original editors reviewed the reasons for the division, suggested which articles would be appropriate for their journal, and both (along with every editor I’ve ever known) exulted in the fact that they now had more space, which would allow more articles to be published, with shortening of the publication time. The old dictum that you had to practice some psychiatry to make a living as a neurologist had disappeared by the time of the division of the journals. The specialty of neurology had strengthened considerably in the late 1940s and 1950s. The American Academy of Neurology had been founded in 1948, and they had produced their own journal. The academy had established a forum in which younger and nonacademic neurologists could come together. A large number of Veterans Administration hospitals had been built, and neurology was established as a necessary specialty to treat veterans with trauma to the nervous system and with other neurological diseases. These hospitals supplied opportunities to establish or expand existing programs in neurology. The National Institute of Neurological Diseases and Stroke was founded to further research and expand training in neurology. The training grants they provided help found and expand many neurology programs. As part of these factors, many medical schools that have incorporated neurology into medical or psychiatric programs established independent departments. Now, only schools with antediluvian thinking have not done so. Both specialties benefited from the growth of a restricted pharmacotherapy, neurology with new antiepileptic drugs, steroids, and antibiotics, and psychiatry with tranquilizers and antipsychotic drugs.
 
Interferon beta is 1 of 2 first-line treatments for relapsing-remitting multiple sclerosis (MS). However, not all patients respond to interferon beta therapy, and to date there is a lack of surrogate markers that reliably correlate with responsiveness to interferon beta therapy in MS. To identify allelic variants that influence response to interferon beta therapy in patients with MS. Genome-wide scan. Academic research. Patients Two hundred patients having relapsing-remitting MS treated with interferon beta and having a follow-up period of at least 2 years were classified as responders or nonresponders to treatment based on stringent clinical criteria. In the first phase of the study, a pooling-based genome-wide association study of 428 867 single-nucleotide polymorphisms (SNPs) was performed in 53 responders and 53 nonresponders to interferon beta therapy. After applying several selection criteria, 383 SNPs were individually genotyped in an independent validation cohort of 49 responders and 45 nonresponders to interferon beta therapy using a different genotyping platform. Eighteen SNPs had uncorrected P < .05 associated with interferon beta responder status in the validation cohort. Of these, 7 SNPs were located in genes that code for alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid-type glutamate receptor GRIA3, type 1 interferon-related proteins ADAR and IFNAR2, cell cycle-dependent protein CIT, zinc finger proteins ZFAT and ZFHX4, and guanosine triphosphatase-activating protein STARD13. This study supports an underlying polygenic response to interferon beta treatment in MS and highlights the importance of the glutamatergic system in patient response to interferon beta therapy.
 
Ischemic stroke is thought to have a polygenic basis, but identification of stroke susceptibility genes and quantification of associated risks have been hampered by conflicting results from underpowered case-control studies. We performed a meta-analysis of all candidate gene association studies in ischemic stroke. Electronic databases were searched up until January 2003 for all case-control and nested case-control studies in English-language journals relating to the investigation of any candidate gene for ischemic stroke in humans. Cases were required to have neuroimaging evidence of the diagnosis. To maintain genetic homogeneity, only studies in white adults were included. Studies that evaluated quantitative traits or intermediate phenotypes were excluded. Data from 120 case-control studies were included. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) from random- and fixed-effects models were calculated. Of 32 genes studied, 15 polymorphisms were identified for which at least 3 studies had been conducted. Statistically significant associations with ischemic stroke were identified for factor V Leiden Arg506Gln (OR, 1.33; 95% CI, 1.12-1.58), methylenetetrahydrofolate reductase C677T (OR, 1.24; 95% CI, 1.08-1.42), prothrombin G20210A (OR, 1.44; 95% CI, 1.11-1.86), and angiotensin-converting enzyme insertion/deletion (OR, 1.21; 95% CI, 1.08-1.35). These were also the most investigated candidate genes, including 4588, 3387, 3028, and 2990 cases, respectively. No statistically significant association with ischemic stroke was detected for the 3 next most investigated genes (factor XIII, apolipoprotein E, and human platelet antigen type 1). There is a genetic component to common stroke. No single gene with major effect was identified; rather, common variants in several genes, each exerting a modest effect, contribute to the risk of stroke. These findings have important implications for the design of future genetic studies and for predictive genetic testing for stroke and other multifactorial diseases.
 
The M1 isoform of human aquaporin 4 (hAQP4). hAQP4 consists of 6 transmembrane -helices. There are 2 isoforms of hAQP4, M1 and M23, which differ in their N terminus start site. Three immunogenic linear determinants in the context of HLA-DRB1*03:01 are described in this study.  
Aquaporin 4 281-300 is the immunodominant linear determinant of human aquaporin 4 (hAQP4). HLA-DRB1*03:01 transgenic mice were immunized with a full-length hAQP4 complete Freund adjuvant emulsion, resulting in each mouse receiving 100 µg of antigen. On day 10, cells taken from the lymph nodes (A) and spleens (B) were collected from mice to generate single-cell suspensions. Thereafter, cells (0.5 10 6 cells) were incubated for 48 hours in 96-well enzyme-linked immunosorbent spot assay plates coated with anti–interferon-(IFN-) or anti–interleukin-17 (IL-17) with single overlapping hAQP4 peptides (50 µg/mL) (Table 1), media only, full-length hAQP4 (50 µg/mL), or concanavalin A (ConA) (1 µg/mL). Spot-forming units represent the absolute number of cells that are secreting a specific cytokine in response to antigen in the well (*P .001). Error bars indicate SE.  
Aquaporin 4284-298 (AQP4284-298) and AQP4285-299 are the immunogenic regions of AQP4281-300. HLA-DRB1*03:01 transgenic mice were immunized with AQP4281-300. On day 10, cells (2.5 × 105 cells) taken from the lymph nodes (A) and spleens (B) were incubated for 48 hours in enzyme-linked immunosorbent spot assay plates coated with anti–interferon-γ (IFN-γ) or anti–interleukin-17 (IL-17) with a single overlapping peptide of AQP4 (50 μg/mL) (Table 2), human AQP4281-300 (50 μg/mL), media only, or concanavalin A (ConA) (1 μg/mL). Spot-forming units represent the absolute number of cells that are secreting a specific cytokine in response to antigen in the well (* P < .05 and † P < .01). Error bars indicate SE.
Aquaporin 4 281-300 (AQP 281-300 ) does not inhibit AQP4 antibody binding. AQP4-specific and isotype control recombinant antibodies (rAbs) were incubated with a U87MG glial cell line stably transfected with the M23 isoform of human AQP4 in the presence or absence of AQP4 peptide. A, Fluorescence micrographs demonstrate robust binding of AQP4-specific rAbs 53 and 58 (green) to the transfected cell line. No staining was observed in the absence of rAb (secondary control) or when using an isotype control rAb (ON7-5 No. 51). A rabbit polyclonal anti-AQP4 antibody against the intracellular C-terminal portion of AQP4 was used as an internal control for AQP4 expression. B, Percentage binding of AQP4-specific rAbs 53 and 58 in the presence and absence of AQP4 peptides. NMO indicates neuromyelitis optica. Error bars indicate SE.  
Objective To identify linear determinants of human aquaporin 4 (hAQP4) in the context of HLA-DRB1*03:01. Design In this controlled study with humanized experimental animals, HLA-DRB1*03:01 transgenic mice were immunized with whole-protein hAQP4 emulsified in complete Freund adjuvant. To test T-cell responses, lymph node cells and splenocytes were cultured in vitro with synthetic peptides 20 amino acids long that overlap by 10 amino acids across the entirety of hAQP4. The frequency of interferon γ, interleukin (IL) 17, granulocyte-macrophage colony-stimulating factor, and IL-5–secreting CD4+ T cells was determined by the enzyme-linked immunosorbent sport assay. Quantitative immunofluorescence microscopy was performed to determine whether hAQP4281-300 inhibits the binding of anti-hAQP4 recombinant antibody to surface full-length hAQP4. Setting Academic neuroimmunology laboratories. Subjects Humanized HLA-DRB1*03:01+/+ H-2b−/− transgenic mice on a B10 background. Results Peptide hAQP4281-300 generated a significantly (P <.01) greater TH1 and TH17 immune response than any of the other linear peptides screened. This 20mer peptide contains 2 dominant immunogenic 15mer peptides. hAQP4284-298 induced predominantly an IL-17 and granulocyte-macrophage colony-stimulating factor TH cell phenotype, whereas hAQP4285-299 resulted in a higher frequency of TH1 cells. hAQP4281-300 did not interfere with recombinant AQP4 autoantibody binding. Conclusions hAQP4281-330 is the dominant linear immunogenic determinant of hAQP4 in the context of HLA-DRB1*03:01. Within hAQP4281-330 are 2 dominant immunogenic determinants that induce differential TH phenotypes. hAQP4 determinants identified in this study can serve as diagnostic biomarkers in patients with neuromyelitis optica and may facilitate the monitoring of treatment responses to pharmacotherapies.
 
Survival and factors affecting survival were studied in 1,484 new cases of acute definite stroke occurring between Jan 1, 1970, and June 30, 1971, in Manitoba. The 962 infarctions, 279 hemorrhages, and 243 unidentified strokes were ascertained from hospital claim reports. Personal, clinical, and laboratory data were collected from hospital medical records, death certificates, and autopsy reports. Cases were followed up until Dec 31, 1973, to determine survival. Survival was significantly better in infarction than in hemorrhage, in subarachnoid hemorrhage than in intracerebral hemorrhage, in men than in women, in the young than in the old, in the married than in the single, in hemorrhage cases from rural areas than from urban areas, and in those discharged home than in those transferred to long-term care hospitals. These data may help in predicting the outcome of stroke and in planning for more efficient care.
 
Using the life table method, 962 cases of infarction, 279 cases of hemorrhage, and 243 cases of undetermined type of stroke, occurring in Manitoba between Jan 1, 1970, and June 30, 1971, were analyzed for factors affecting survival. Survival until Dec 31, 1973, was found to be adversely affected by the presence of coma or unconsciousness and the absence of localizing signs and symptoms. Also, the prognosis was poor if the heart was enlarged on the x-ray film or the ECG was abnormal. On the other hand, the presence of individual clinical entities such as hypertension, hypertensive heart disease, myocardial infarction, atrial fibrillation, or diabetes did not affect the survival significantly. These findings will help in predicting the prognosis and in planning for management of stroke cases.
 
Premature infants have been frequently observed to manifest hydrocephalus after intraventricular hemorrhage (IVH). For the complete newborn population of Nova Scotia in 1976 to 1978, we found a very low incidence of hydrocephalus in children whose birth weight was less than 1,500 g. Eighty-two percent of these babies were born in a perinatal center; 18% were transported. Chart review of survivors (58%) and autopsy review of deaths (autopsy rate, 86%) showed that in the province's three neonatal intensive care units, only four of 314 such babies manifested progressive hydrocephalus. Only one of four infants was examined after IVH. An IVH was noted at autopsy in 42% of cases. No survivor manifested hydrocephalus one to three years later as judged by head circumference and neurosurgical records. Our results may reflect the impact of regionalized perinatal care, or that post-IVH hydrocephalus is rare in an unselected population.
 
Magnetic resonance (MR) (1.5 tesla) studies were performed in ten patients with temporal lobe epilepsy and two with temporofrontal epilepsy. Two patients with temporal lobe epilepsy and one with temporofrontal epilepsy exhibited areas of increased signal intensity on T2-weighted images in the mesiobasal portion of the temporal lobe shown by electroencephalography to be the epileptogenic focus; no analogous abnormalities had been found in these patients on computed tomographic scans. Pathologic studies have not revealed a specific ultrastructural correlate for the MR findings in this group of patients. We found MR to be a useful, noninvasive diagnostic adjunct in the presurgical assessment of some patients with temporal lobe epilepsy. Where abnormalities were found, they corresponded with the epileptogenic focus as defined by electroencephalography.
 
Simultaneous steady-state serum total and free (non-protein-bound) concentrations of carbamazepine and carbamazepine-10,11-epoxide were measured in 68 patients under the age of 21 years with epilepsy (44 males, 24 females; mean age, 11.8 +/- 4.5 years). Thirty patients were maintained on monotherapy with carbamazepine. Mean serum total carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 7.0 +/- 2.4 mg/L (29.5 +/- 10.0 mumol/L) and 1.5 +/- 0.6 mg/L (5.9 +/- 2.6 mumol/L), respectively. Mean serum-free carbamazepine and carbamazepine-10,11-epoxide concentrations obtained were 1.3 +/- 0.5 mg/L (5.7 +/- 2.1 mumol/L) and 0.5 +/- 0.3 mg/L (2.2 +/- 1.1 mumol/L), respectively. Binding of carbamazepine and carbamazepine-10,11-epoxide was 81% +/- 3% and 62% +/- 10%, respectively. There was no significant difference in binding between male and female patients or those maintained on monotherapy and polytherapy. Age correlated significantly with carbamazepine binding but not with carbamazepine-10,11-epoxide binding. Free concentrations of carbamazepine and carbamazepine-10,11-epoxide correlated significantly with total carbamazepine and total carbamazepine-10,11-epoxide concentrations, respectively, indicating that the binding capacities of both carbamazepine and carbamazepine-10,11-epoxide are constant at serum total carbamazepine concentrations within the quoted therapeutic range.
 
The effects of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine, were evaluated in seven outpatients with frequent epileptic seizures. The study included an initial 4-week period with the carbamazepine dose optimized for each patient. Patients were then crossed over, dose by dose, to carbamazepine-10,11-epoxide and followed up for another 4 weeks. Dosing was single blind. The evaluation of the anticonvulsant effect was hampered by marked fluctuations in plasma levels during treatment with carbamazepine-10,11-epoxide. There was, however, no significant change in seizure control. During epoxide treatment, no subjective side effects were reported despite epoxide plasma concentrations up to 57 mumol/L. Neuropsychological assessment revealed a significant improvement in finger motor speed and logical reasoning during the carbamazepine-10,11-epoxide period. Subnormal serum sodium levels in two patients were normalized after switching from carbamazepine to the epoxide. Continued investigations with this active metabolite of carbamazepine in epilepsy are therefore justified.
 
The clinical effects of carbamazepine-10,11-epoxide were assessed in six patients with trigeminal neuralgia. The patients were first given an optimal therapeutic dose of carbamazepine. Part of or the entire carbamazepine dose was then exchanged for the metabolite carbamazepine-10,11-epoxide for three to six days. The patients were unaware of changes in the therapeutic regimen (single-blind). Carbamazepine dosages ranged from 400 to 1,400 mg/day and carbamazepine-10,11-epoxide dosages ranged from 300 to 1,000 mg/day. The clinical effects were assessed by the patients' recordings of pain attacks. When carbamazepine-10,11-epoxide and carbamazepine were given in similar doses, the pain control was comparable. On a plasma concentration basis, carbamazepine-10,11-epoxide had a considerably higher pain-relieving potency than carbamazepine. During carbamazepine treatment, the epoxide metabolite contributes to the antineuralgic effect to an extent that might be comparable to that of the parent drug. No side effects were seen during carbamazepine-10,11-epoxide therapy.
 
To study the results of intralumbar administration of chemotherapeutic agents for the treatment of neoplastic meningitis and to determine how these results relate to the variable and often subtherapeutic drug concentrations in the ventricular cerebrospinal fluid (CSF) compartment. Ventricular and lumbar pharmacokinetic studies were done following intralumbar administration of DTC-101, an extended-release formulation of cytarabine. Nine patients (age range, 23 to 67 years; median age, 42 years) with leptomeningeal metastases were treated with 18 courses of intralumbar DTC-101. Eight patients who were treated with 14 courses underwent pharmacokinetic CSF sampling from the lumbar sac and lateral ventricle. Cytarabine concentrations were determined by using high-pressure liquid chromatography. Following intralumbar administration of DTC-101, therapeutic free cytarabine concentrations were achieved rapidly in both of the ventricular and lumbar CSF compartments and maintained for 2 weeks. The mean pharmacokinetic parameters of free cytarabine in the lumbar and ventricular CSF compartments were as follows: maximum concentration, 226 and 6.06 mg/L; half-life, 277 and 130 hours; and area under the concentration vs time curve, 4120 and 598 micrograms/h per milliliter, respectively. Intralumbar administration of DTC-101 results in extended cytotoxic free cytarabine concentrations in both of the lumbar and ventricular regions of CSF and allows an every-other-week drug-dosing schedule.
 
Depo cytarabine (DTC 101 [formerly identified as Depo/Ara-C]) is a slow-releasing, depot formulation in which cytarabine is encapsulated within the aqueous compartments of microscopic (DepoFoam) particles. A phase I trial of DTC 101, given intraventricularly, was conducted in patients with leptomeningeal metastasis. Nine patients were given 1 to 7 cycles of DTC 101 in doses ranging from 25 to 125 mg that were administered via an Ommaya reservoir into the lateral ventricle. The dose-limiting toxic reaction was encephalopathy that occurred at the 125-mg dose level. All toxic episodes but one were transient and reversible, with the total duration of toxicity lasting from 1 to 7 days. The ventricular concentration of free cytarabine released from DTC 101 into cerebrospinal fluid decreased biexponentially with an initial half-life of 7.2 +/- 1.7 (+/- SEM) hours and a terminal half-life of 140 +/- 49 hours. The cerebrospinal fluid was cleared of malignant cells within 3 weeks of initial therapy in five of six cytologically evaluable patients. The duration of response ranged from 2 to more than 14 weeks, with a median of over 11 weeks. In conclusion, DTC 101 appears to be a pharmacologically attractive agent for use against leptomeningeal metastasis. The toxic episodes that occur with this therapy are well tolerated by patients.
 
In 101 eyes with either anterior or retrobulbar optic neuropathy of ischemic or inflammatory origin, ocular pain occurred significantly more often with retrobulbar optic neuropathy. The association of pain with posterior optic nerve lesions supports Whitnall's hypothesis that the pain of optic nerve inflammation is caused by traction of the origins of the superior and medial recti on the optic nerve sheath at the orbital apex. Eye pain reflected neither severity nor origin of optic neuropathy.
 
In humans and monkeys, the intraparietal sulcus separates the superior parietal lobule from the inferior parietal lobule (IPL). Whereas in humans Brodmann's area 7 is above this sulcus, in monkeys it is below and therefore part of the IPL. In humans, the IPL consists of Brodmann's areas 39 and 40. Some investigators contend that the monkey homologue of the human IPL (areas 39 and 40) is the monkey's IPL (area 7). Others contend that it is, at least in part, in the monkey's superior temporal sulcus (STS). In humans, IPL lesions induce neglect. Although IPL lesions in monkeys also have been reported to induce neglect, the STS was involved in these lesions. We sought to learn which of these two areas, when ablated, produces neglect. Study of five adult stump-tailed macaque monkeys by making five isolated STS and six IPL lesions. Inferior parietal lobule lesions were associated with misreaching but not with unilateral neglect. Neglect was observed in association with five of the six STS lesions. With regard to neglect, STS may be the monkey homologue of the human IPL. Animals with STS lesions and humans with IPL lesions may manifest unilateral neglect because these areas are necessary for normal awareness of external stimuli. This awareness may result from the integration of the areas important in stimulus localization (the "where is it?" system) and stimulus identification (the "what is it?" system), as well as the areas important in defining the biologic importance of stimuli, such as the frontal lobes and limbic areas.
 
Friedreich ataxia (FA) is the most frequent autosomal recessive cerebellar ataxia. Although the phenotype is well known, disease progression has not been evaluated in a prospective manner. To perform a long-term prospective follow-up of neurological, cardiological, and oculomotor function in patients with FA (FA patients). In this open-labeled prospective survey, we examined 104 FA patients every 6 months during a median period of 5 years (range, 6 months to 7 years), with a systematic standardized protocol. Data are reported as mean +/- SD. Neurological examinations were performed at the Federation of Neurology and the Department of Genetics of the Salpêtrière Hospital, Paris, France. Cardiological follow-up was performed at the Department of Cardiology; oculomotor examinations were performed at the Institut National de la Santé et de la Récherche Médicale Unit 679, at the same hospital. Patients We studied 104 FA patients with a confirmed molecular diagnosis. None were receiving antioxidant therapy at baseline; 88 accepted treatment with the coenzyme Q(10) analogue idebenone (5 mg/kg per day). Sixteen preferred not to be treated. Neurological status was evaluated with the International Cooperative Ataxia Rating Scale (ICARS) and a quantitative writing test. Cardiological evaluations included echocardiography, electrocardiography, and Holter monitoring. Oculomotor function was evaluated by electro-oculography to determine the frequency of square wave jerks. The total ICARS score worsened during follow-up, whether or not the patients were treated with idebenone (1.93 +/- 0.25 and 4.43 +/- 1.56 points per year, respectively). The total ICARS score increased faster in patients with onset before age 15 years compared with the others (2.6 +/- 0.4 [n = 51] vs 1.1 +/- 0.3 [n = 37]; P = .05). The posture subscore increased faster in patients able to stand at baseline, who also had shorter disease durations than patients unable to stand (1.25 +/- 0.12 vs 0.47 +/- 0.22 point per year; P<.001). Neurological progression was underestimated, however, by the ICARS scores, which reached a plateau in patients with long disease durations. Oculomotor function slightly deteriorated (0.09 +/- 0.02 Hz per year; P<.001). Left ventricular mass index decreased (-4.1 +/- 1.5 g/m(2) per year; P = .008), as did ejection fraction (-1.32% +/- 0.29% per year; P<.001). The neurological condition of FA patients deteriorated slowly over time, even with idebenone treatment. Although cardiac hypertrophy decreased under treatment, cardiac function did not improve. The ICARS scale is not appropriate to evaluate the progression of FA in patients with long disease durations. Additional quantitative measures may improve the reliability of this scale.
 
We interviewed and neurologically reexamined 94 patients who had previous pneumococcal meningitis. The findings were allocated into groups with and without a causal relationship to the meningitis. The main sequelae after meningitis were dizziness (23%), tiredness (22%), mild memory deficits (21%), and gait ataxia (18%), whereas other focal neurologic signs were rare. By a rating (0 to 5) of the presence and severity of sequelae after meningitis, 54% of the patients were found to have sequelae. The clinical condition at the time of acute illness was studied in subgroups of patients who had different neurologic sequelae or high sequelae ratings. Gait ataxia was associated with a state of agitation and confusion when the patient was admitted for meningitis. High sequelae ratings on reexamination were associated with an affected consciousness at the acute stage of the disease and with high numbers of WBCs in the CSF at the time of hospitalization.
 
Botulinum toxin A (BTX) is the currently preferred symptomatic treatment for primary hemifacial spasm (HFS), but its long-term efficacy and safety are not known. To assess the long-term effectiveness and safety of BTX in the treatment of primary HFS. Retrospective review of medical records of the 1st and 10th years of treatment. Outpatient clinics of 4 Italian university centers in the Italian Movement Disorders Study Group. A series of 65 patients with primary HFS who had received BTX injections regularly for at least 10 years. Mean duration of improvement and quality of the effect induced by the preceding treatment (measured using a patient self-evaluation scale) and occurrence and duration of adverse effects in the 1st and 10th years of treatment. Using a mean BTX dose per treatment session similar to that used by others, we obtained a 95% response rate and an overall mean duration of improvement of 12.6 weeks during year 1. The effectiveness of BTX in relieving the symptoms of primary HFS, as measured by the response rate and average duration of improvement, remained unchanged in the 1st and 10th years. Patients needed statistically similar BTX doses in the 1st and 10th years. The rate of local adverse effects (including upper lid ptosis, facial weakness, and diplopia) diminished significantly in the 10th year of treatment. Treatment with BTX effectively induces sustained relief from symptoms of HFS in the long term, with only minimal and transient adverse reactions.
 
Alzheimer disease (AD) is defined neuropathologically by the presence of neurofibrillary tangles and plaques associated with tau and beta-amyloid protein deposition. The colocalization of microglia and beta-amyloid plaques has been widely reported in pathological examination of AD and suggests that neuroinflammation may play a role in pathogenesis and/or progression. Because postmortem histopathological analyses are limited to single end-stage assessment, the time course and nature of this relationship are not well understood. To image microglial activation and beta-amyloid deposition in the brains of subjects with and without AD. Using two carbon 11 ([11C])-labeled positron emission tomographic imaging agents, Pittsburgh Compound B (PiB) and (R)-PK11195, we examined the relationship between amyloid deposition and microglial activation in different stages of AD using 5 control subjects, 6 subjects diagnosed with mild cognitive impairment, and 6 patients with mild to moderate AD. Consistent with prior reports, subjects with a clinical diagnosis of probable AD showed significantly greater levels of [11C]PiB retention than control subjects, whereas patients with mild cognitive impairment spanned a range from control-like to AD-like levels of [11C]PiB retention. Additionally, 2 asymptomatic control subjects also exhibited evidence of elevated PiB retention in regions associated with the early emergence of plaques in AD and may represent prodromal cases of AD. We observed no differences in brain [11C](R)-PK11195 retention when subjects were grouped by clinical diagnosis or the presence or absence of beta-amyloid pathological findings as indicated by analyses of [11C]PiB retention. These findings suggest that either microglial activation is limited to later stages of severe AD or [11C](R)-PK11195 is too insensitive to detect the level of microglial activation associated with mild to moderate AD.
 
To investigate amyloid accumulation by carbon 11-labeled Pittsburgh Compound B (11C-PiB) in hereditary cerebral amyloid angiopathy and APP locus duplication. Positron emission tomography with 11C-PiB and magnetic resonance imaging were performed for 2 patients, 49-year-old and 60-year-old siblings with APP locus duplication, with hereditary Alzheimer disease and cerebral amyloid angiopathy. Change in 11C-PiB uptake. Uptake of 11C-PiB was increased especially in the striatum (caudate nucleus to 225% and 280% of the control mean and putamen to 166% and 185% of the control mean) and in the posterior cingulate (to 168% and 198% of the control mean), and it was marginally increased in other cortical brain areas. The pattern of increased 11C-PiB uptake was different from that seen in sporadic Alzheimer disease. Amyloid imaging with 11C-PiB positron emission tomography is a useful tool for detecting in vivo amyloid accumulation in patients with hereditary cerebral amyloid angiopathy. However, the pattern of 11C-PiB accumulation differs between patients with typical AD and patients with APP locus duplication.
 
To evaluate the cognitive reserve hypothesis by examining whether individuals of greater educational attainment have better cognitive function than individuals with less education in the presence of elevated fibrillar brain amyloid levels. Design, Setting, and Uptake of carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) was measured for participants assessed between August 15, 2003, and January 8, 2008, at the Washington University Alzheimer's Disease Research Center and diagnosed either as nondemented (n = 161) or with dementia of the Alzheimer type (n = 37). Multiple regression was used to determine whether [(11)C]PiB uptake interacted with level of educational attainment to predict cognitive function. Scores on the Clinical Dementia Rating sum of boxes, Mini-Mental State Examination, and Short Blessed Test and individual measures from a psychometric battery. Uptake of [(11)C]PiB interacted with years of education in predicting scores on the Clinical Dementia Rating sum of boxes (P = .003), the Mini-Mental State Examination (P < .001), the Short Blessed Test (P = .03), and a measure of verbal abstract reasoning and conceptualization (P = .02) such that performance on these measures increased with increasing education for participants with elevated PiB uptake. Education was unrelated to global cognitive functioning scores among those with lower PiB uptake. The results support the hypothesis that cognitive reserve influences the association between Alzheimer disease pathological burden and cognition.
 
The clinical and radiologic findings in 11 patients with brain-stem tuberculoma were reviewed. Clinical manifestations included various combinations of focal signs and symptoms of subacute onset, similar to those produced by other space-occupying lesions of the brain stem. Evidence of systemic tuberculosis was found in six cases (55%). Computed tomography (CT) usually showed an isodense or hyperdense brain-stem mass with abnormal contrast enhancement; associated supratentorial granulomas were found in four cases, and hydrocephalus was found in two cases. Magnetic resonance imaging showed irregular brain-stem lesions with long T1 and short T2 relaxation times. Cerebrospinal fluid findings were also nonspecific, as smears for acid-fast bacilli were most often negative. An incorrect diagnosis of pontine glioma was made in one patient. In contrast, proper integration of data from CT and magnetic resonance imaging findings, cerebrospinal fluid analysis, and x-ray films of the chest permitted an accurate diagnosis in ten cases. Prompt therapy with antituberculous drugs resulted in clinical improvement, documented by CT, in most patients. Brain-stem tuberculoma should be suspected in patients with space-occupying lesions of the brain stem who live in geographic areas where tuberculosis is endemic. Early diagnosis and prompt medical therapy are important in preventing mortality and reducing morbidity.
 
Case Characteristics and IHC Findings of Frontal Cortical Biopsy Specimens 
Immunohistochemical examination of protein aggregates in the frontal cortex biopsy specimens using-amyloid antibody (clone 4G8). Inserts show cytoplasmic labeling with hyperphosphorylated tau antibody (clone AT8). Large panels, original magnification 100, scale bar, 200 µm; inserts, original magnification 400, scale bar, 10 µm. In case 5, there is pale staining of fleecy aggregates, and in cases 6 and 8, predominantly dense plaques are seen. In the remaining cases, all types (ie, fleecy, diffuse, and dense plaques) were noted. Cytoplasmic hyperphosphorylated tau labeling was seen in 3 cases (8, 9, and 10) and even then only in occasional neurons. 
Visualization of the results of statistical parametric mapping analysis. The regions with statistically significant increases (corrected P value at cluster level .01) in carbon 11-labeled Pittsburgh Compound B uptake in patients with-amyloid aggregates (n = 5, cases 6-10) compared with patients without any-amyloid aggregates (n = 4, cases 1-4) in the cortical biopsy specimen are indicated with colors. 
Scatterplot of carbon 11-labeled Pittsburgh Compound B ([ 11 C]PiB) uptake (region of interest) in the right frontal cortex. A indicates the number of-amyloid (clone 4G8) aggregates in the right frontal cortical biopsy specimen (count of diffuse and dense aggregates independent of size in a visual field). The diamonds are labeled by case numbers indicated in Figure 1 and Figure 3 and Table 1. 
To compare carbon 11-labeled Pittsburgh Compound B ([11C]PiB) positron emission tomography (PET) findings in patients with and without Alzheimer disease lesions in frontal cortical biopsy specimens. Cross-sectional study of [11C]PiB PET findings in patients with or without beta-amyloid (Abeta) aggregates in frontal cortical biopsy specimens. Two university hospitals in Finland. Patients Ten patients who had undergone intraventricular pressure monitoring with a frontal cortical biopsy (evaluated for Abeta aggregates and hyperphosphorylated tau) for suspected normal-pressure hydrocephalus. [11C]PiB PET and evaluation for cognitive impairment using a battery of neuropsychological tests. Immunohistochemical evaluation for Abeta aggregates and hyperphosphorylated tau in the frontal cortical biopsy specimen and [11C]PiB PET. In patients with Abeta aggregates in the frontal cortical biopsy specimen, PET imaging revealed higher [11C]PiB uptake (P < .05) in the frontal, parietal, and lateral temporal cortices and in the striatum as compared with the patients without frontal Abeta deposits. Our study supports the use of noninvasive [11C]PiB PET in the assessment of Abeta deposition in the brain. Large prospective studies are required to verify whether [11C]PiB PET will be a diagnostic aid, particularly in early Alzheimer disease.
 
Mucormycosis is fulminant fungal infection that usually occurs in debilitated patients with an underlying pathologic condition. The common clinical types include rhinocerebral, pulmonary, disseminated, and intestinal forms. This report describes 11 cases seen in our institution since 1970. Of nine patients with underlying diabetes mellitus, eight developed rhinocerebral mucormycosis and one had the cutaneous form. Two additional patients with acute leukemia showed the disseminated and pulmonary forms of mucormycosis. In nine patients, the diagnosis was established by histologic appearance and by culture of infected tissue obtained by biopsy. In two patients the diagnosis was made during postmortem examination. Five patients survived. We have emphasized the importance of early diagnosis and prompt, appropriate medical and surgical therapy to obtain a significant survival rate in patients with this frequently fatal disease.
 
Rapid eye movement sleep behavior disorder (RBD) is a parasomnia that is manifested by dream enactment behavior. The electrophysiologic substrate for RBD on polysomnography is rapid eye movement sleep without atonia. Rapid eye movement sleep behavior disorder likely stems from neuronal network dysfunction in the brainstem, although it is not yet clear which specific networks are involved. Rapid eye movement sleep behavior disorder is often associated with the sporadic synucleinopathies but rarely associated with the sporadic tauopathies. There are no reports on the possible association of rapid eye movement sleep without atonia and RBD with any familial tauopathy. To characterize the clinical sleep and polysomnography features in a kindred with a familial tauopathy. We performed standard polysomnography in 11 members of the pallidopontonigral degeneration kindred irrespective of any sleep-related complaints. Neuropathologic findings were analyzed in those who subsequently underwent autopsy. Six affected and 5 genealogically at-risk family members were studied. None of the 11 had a history of dream enactment behavior. Nine of the 11 members attained sufficient rapid eye movement sleep on polysomnography, and the electrophysiologic features of rapid eye movement sleep without atonia and behavioral manifestations of RBD were absent in all subjects. Neuropathologic examination of 4 affected individuals revealed marked nigral degeneration in 3 along with mild degenerative changes in the locus coeruleus, pontine nuclei and tegmentum, and medullary tegmentum. These findings argue against nigral degeneration being the primary cause of RBD. The absence of the historical, electrophysiologic, and behavioral manifestations of RBD in this kindred provides further evidence that RBD is rare in the sporadic and familial tauopathies. The difference in frequencies of RBD associated with the synucleinopathies compared with the tauopathies suggests differences in the selective vulnerability of brainstem circuits between the synucleinopathies and tauopathies.
 
To update some of the clinical features of St Louis encephalitis (SLE), a common arboviral infection that occurs in epidemic patterns in the south-central and midwestern United States. Eleven patients with SLE from a 1995 epidemic in Dallas, Tex, were studied clinically, radiologically, neurophysiologically, and neuropathologically (in 1 case). The electroencephalograms and magnetic resonance imaging (MRI) scans of our patients revealed features that have received little attention in previous studies. Of the 9 patients who were examined with electroencephalography, all 9 had seizures or other abnormalities, and 1 had nonconvulsive status epilepticus. Two of 6 patients who had MRIs showed substantia nigra edema. Finally, 2 (18%) of our patients had coinfection with the human immunodeficiency virus. The MRI findings of substantia nigra edema in patients with SLE have not been previously reported. Nonconvulsive status epilepticus can occur in patients with SLE and should be considered in patients with prolonged encephalopathy. Finally, human immunodeficiency virus coinfection may be a risk factor for symptomatic SLE infection.
 
Magnetic resonance images of the brain. A, A T2-weighted fluid-attenuated inversion recovery axial image showing hyperintensity and swelling of both hippocampi (white arrows) and a small cortical lesion (black arrow) in the left occipital lobe. B, A diffusion-weighted axial image showing restricted diffusion at both hippocampi (white arrows). The cortical lesion (black arrow) is also visible in this image. C, A susceptibility-weighted axial image with small hypointense foci suggestive of hemorrhage (arrows). D, A T1-weighted gadolinium-enhanced coronal image shows a normal basilar artery (black arrow) and normal posterior cerebral arteries (white arrows). 
A 78-year-old man presented in a confused state with short-term and autobiographical memory impairment and visuospatial disorientation. The neurological examination revealed right temporal superior quadrantanopia. Magnetic resonance imaging (MRI) performed 48 hours after symptom onset (Figure 1) showed hyperintensity and diffuse swelling of both hippocampi on T2-weighted fluid-attenuated inversion recovery sequences, restricted free-water diffusion on diffusion-weighted images, and small hemorrhages on susceptibility-weighted images. These findings suggested a vascular ischemic process and, less probably, paraneoplastic syndrome, infectious encephalitis, or space-occupying lesions. Cerebrospinal fluid analysis showed normal biochemical and cytological measures. Images from positron emission tomography (PET) with fludeoxyglucose F 18 (FDG) and with carbon 11–tagged methionine (Met) were coregistered to the original MRI using a 3-dimensional advanced image fusion tool (Syngo 3D, eSoft; Siemens Medical Solutions) that is based on multimodal volume registration by maximization of mutual information.1 The FDG-PET image showed hypometabolism, whereas the Met-PET image exhibited low to moderate uptake in the corresponding MRI hyperintense areas, suggesting the presence of neuronal damage with mild inflammatory activity (Figure 2). The acute clinical presentation allowed us to establish a stroke of cardioembolic origin as the most likely cause, supported by the presence of paroxysmal atrial fibrillation. The patient's condition remains stable with anticoagulant treatment.
 
Hereditary spastic paraplegia (HSP) with thin corpus callosum (CC) is a rare neurodegenerative disorder classified as a complicated form of spastic paraplegia. Some patients with HSP with thin CC have previously been described in Japanese families, and the genetic locus was linked to chromosome 15q13-15. Our objective was to further clinically and genetically characterize HSP with thin CC. We describe the clinical, structural, and functional follow-up and the genetic characterization of 2 sisters aged 26 and 31 years who had severe spastic paraplegia and cognitive impairment. Magnetic resonance imaging revealed a thin CC with progressing frontoparietal cortical atrophy paralleled by cognitive decline. Using transcranial magnetic stimulation, we delineated a lack of transcallosal inhibition. Images obtained with(18)fluorodeoxyglucose positron emission tomography showed reduced cortical and thalamic hypometabolism that decreased further within 4 years. Additionally, combined axonal loss and demyelinating sensorimotor polyneuropathy were present. Because other family members were not affected, autosomal recessive inheritance was considered likely. Genetic analysis of this autosomal recessive HSP was consistent with the linkage to 15q13-15 (markers D15S971, D15S118, D15S994, and D15S659). No mutation was found within the SLC12A6 gene. Progressive axonal degeneration occurs in the corticocortical projections, corticospinal tract, and peripheral nerves in HSP with thin CC linking to chromosome 15q13-15 in a German pedigree.
 
A progressive decline in episodic memory affecting activities of daily living is the usual clinical presentation of Alzheimer disease. However, patients presenting with atypical or focal clinical symptoms such as language or visuospatial dysfunction often pose a diagnostic challenge. To explore the presence and topography of beta amyloid (Abeta) as measured by carbon 11-labeled Pittsburgh Compound B ((11)C-PiB) in patients with atypical presentations of dementia. At a tertiary referral center for memory disorders, 15 healthy controls, 10 patients with Alzheimer disease, a patient with primary progressive aphasia (PPA), and a patient with posterior cortical atrophy (PCA) underwent (11)C-PiB positron emission tomographic studies. Retention of (11)C-PiB was compared between different groups using statistical parametric mapping. The topography of cortical (11)C-PiB binding in atypical vs typical Alzheimer disease. Cortical (11)C-PiB binding was higher in the group with Alzheimer disease and in the patients with PPA and PCA than the controls (P < .001). Both patients with atypical dementia had a similar (11)C-PiB binding pattern to Alzheimer disease although (11)C-PiB retention was higher on the left cerebral hemisphere in the patient with PPA (P < .01) and higher in the occipital cortex in the patient with PCA (P < .01). The presence of distinctive focal (11)C-PiB retention patterns was demonstrated in 2 patients with atypical onset of dementia. Pittsburgh Compound B has the potential to facilitate differential diagnosis of dementia and identify patients who could benefit from specific therapeutic strategies aimed at beta amyloid reduction.
 
Fused carbon 11-labeled Pittsburgh Compound B nondisplaceable binding potential and magnetic resonance images for a subject with Down syndrome and Alzheimer disease (top) and a control without Down syndrome (bottom). 
To investigate the safety, acceptability, and feasibility of positron emission tomography (PET) using carbon 11-labeled Pittsburgh Compound B ([(11)C]PiB) to measure cerebral β-amyloid in adults with Down syndrome (DS) and to explore if the technique differentiates between participants with and without Alzheimer disease (AD). Proof-of-principle case-controlled study of a nonrandomly selected cohort of participants with DS (with or without AD) compared within group and with healthy controls without DS. All had dynamic [(11)C]PiB PET and magnetic resonance imaging. Carbon 11-labeled PiB binding in the regions of interest associated with AD was quantitatively analyzed. Wolfson Brain Imaging Centre, Cambridge, England. Nine with DS (aged 25-64 years), of whom 5 had a diagnosis of AD, and 14 healthy controls without DS (aged 33-69 years). Positive [(11)C]PiB binding in regions of interest. The scanning process was feasible and acceptable with no adverse events or safety concerns. Maps and regional values of nondisplaceable binding potential were produced using the reference tissue-input Logan plot, with the cerebellum used as the reference tissue. When compared with the healthy control group without DS, only participants with DS older than 45 years had significant [(11)C]PiB binding in regions of interest usually associated with AD, whether or not they had clinical evidence of dementia. Dynamic [(11)C]PiB PET can be used successfully to measure cerebral β-amyloid deposition in DS. A clinical diagnosis of AD and age appear to be predictors of [(11)C]PiB binding in regions of interest, but given the small numbers, we cannot generalize the results.
 
Hypertensive putaminal hemorrhage remains a major cause of hemorrhagic stroke carrying extremely high morbidity. Considerable controversy remains regarding the optimal form of therapy. Between 1983 and 1989 we conducted a prospective randomized trial with three treatment strategies: best medical management, best medical management plus intracranial pressure monitoring, and surgical evacuation. Only patients with significant deficit harboring a putaminal hematoma at least 3.0 cm in diameter were entered. The study was interrupted after 21 patients had been studied (9, best medical management; 4, intracranial pressure monitoring; and 8, surgical evacuation). No differences were found among groups for age, admission blood pressure, and time interval between onset of symptoms and arrival at hospital. None of the subjects were capable of returning to prestroke activity. Fifteen (71%) died or remained vegetative at 6 months, and only 4 (19%) were capable of independent life at home. Of the 9 patients in the best medical management arm, 7 were dead or vegetative. In the surgical group, 4 patients died and only 2 were capable of independent life. These results suggest that current medical and neurosurgical therapies remain ineffective in preventing the devastating neurologic consequences of hypertensive putaminal hemorrhage.
 
Superior sagittal sinus thrombosis, documented by cerebral angiography, was demonstrated by indium-111 platelet scintigraphy in a 40-year-old man presenting with seizures and intracerebral hematoma. Early scintigraphy demonstrated focal increased indium-111 activity at the two ends of the thrombus, while later scintigraphy showed diffuse increased activity in the area of the sinus. This initial experience suggests that platelet scintigraphy may provide unique information regarding the natural history of intracranial venous thrombosis.
 
Unconcentrated cerebrospinal fluid (CSF) and serum samples from 1114 consecutive patients were examined for presence of oligoclonal IgG bands (OB) by agarose isoelectric focusing (AIF) followed by protein transfer to nitrocellulose membrane, immunolabeling, and avidinbiotin-peroxidase staining (avidin-biotin AIF). Oligoclonal bands were demonstrated in CSF from all 58 patients with multiple sclerosis (MS), eight of 29 with aseptic nervous system infections, and 9% of 1014 with other neurological disorders (OND) considered as noninflammatory at primary clinical evaluation. Comparative examination of all specimens in another laboratory by conventional AIF after concentration of CSF revealed lower frequencies of OB in all diagnostic groups. In addition to the high sensitivity of avidinbiotin AIF, which enables detection of OB by separation of 5 microL of unconcentrated CSF even when the CSF IgG level is around the lower normal range, the procedure also has optimal specificity since IgG exclusively is detected. Avidin-biotin AIF may be the method preferred for routine examination of CSF for OB. Demonstration of OB in CSF is valuable especially in MS, where, in contrast to diagnostic aids such as evoked potentials and neuro-imaging, it establishes inflammatory type of nervous system involvements. Oligoclonal IgG bands in CSF from patients with OND reflect intrathecal immune response and should lead to investigations of infectious etiology.
 
The cerebrospinal fluid flow pattern in seven patients with leukemia or lymphoma, but without prior meningeal or cerebral disease, was studied following introduction of indium-diethylenetriamine pentaacetic acid In-DTPA 111 in a lateral ventricle through an Ommaya reservoir. The time to egress from the ventricular system into the basal cisterns was variable but generally short. One hour after administration, the basal cisterns were clearly visible in all patients. Thereafter, kinetics throughout the cranial and spinal subarachnoid space were consistent. The flow patterns of three patients cured of meningeal dissemination and one patient with mild meningeal leukemia were similar to the normal pattern.
 
To determine the association between admission blood glucose and outcome in ischemic stroke patients treated with thrombolysis. A prospective, open, multinational, observational study. An ongoing Internet-based, academic-driven, interactive thrombolysis register. Between 2002 and 2007, 16 049 patients were recorded in the SITS-ISTR. Blood glucose was recorded at admission. Blood glucose was divided into the following categories: less than 80, 80-120 (reference range), 121-140, 141-160, 161-180, 181-200, and greater than 200 mg/dL. Outcomes were mortality and independence (modified Rankin Scale score of 0-2) at 3 months and symptomatic intracerebral hemorrhage (SICH) (National Institutes of Health Stroke Scale deterioration ≥4 points within 24 hours and type 2 parenchymal hemorrhage). In multivariable analysis, blood glucose as a continuous variable was independently associated with a higher mortality (P < .001), lower independence (P < .001), and an increased risk of SICH (P = .005). Blood glucose greater than 120 mg/dL as a categorical variable was associated with a significantly higher odds for mortality (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.07-1.44; P = .004) and a lower odds for independence (OR, 0.58; 95% CI, 0.48-0.70; P < .001), and blood glucose from 181 to 200 mg/dL was associated with an increased risk of SICH (OR, 2.86; 95% CI, 1.69-4.83; P < .001) compared with the reference level. The trends of associations between blood glucose and outcomes were similar in patients with diabetes (17%) or without such history, except for mortality (P = .23) and SICH (P = .06) in which the association was not statistically significant in patients with diabetes. Admission hyperglycemia was an independent predictor for poor outcome after stroke/thrombolysis, though SICH rates did not increase significantly until reaching 180 mg/dL. These results suggest that tight control of blood glucose may be indicated in the hyperacute phase following thrombolysis. Randomized trial data are needed.
 
We performed electrodiagnostic tests on 113 consecutive patients with acute Guillain-Barré syndrome (103 within 3 weeks of onset). The most common motor conduction abnormalities were proximal conduction block alone (27%), proximal block associated with a distal lesion (27%), and generalized slowing (22%). Other combinations of abnormalities each occurred in fewer than 10% of patients. Thirty-seven percent of patients initially had normal sensory nerve conduction study results, most often in association with proximal conduction block. The characteristic early electrodiagnostic changes in Guillain-Barré syndrome were often present when cerebrospinal fluid protein concentration was still normal. Extensive early fibrillations occurred in 10 patients, 6 of whom recovered well. Patients with early generalized slowing of motor nerve conduction velocity, combined abnormalities, or low muscle action potential amplitudes in ulnar, median, and peroneal nerves generally, but not always, had poorer outcomes than patients with conduction block in one nerve segment. There was no consistent relationship between results of electrophysiologic studies and overall clinical grade or limb power, except that none of the patients with an isolated proximal block had virtual or complete paralysis in the same limb.
 
Internuclear ophthalmoplegia (INO) is a sign of exquisite localizing value, often due to either multiple sclerosis or infarction. To demonstrate that unusual causes of INO are more common than the 11% reported in previous series, this review considers a case series of 410 inpatients whom I personally examined during a 33-year period. In this series, the cause of INO was infarction in 157 patients (38%), multiple sclerosis in 139 (34%), and unusual causes in 114 (28%). Unusual causes included trauma (20 cases), tentorial herniation (20 cases), infection (17 cases), tumor (17 cases), iatrogenic injury (12 cases), hemorrhage (13 cases), vasculitis (7 cases), and miscellaneous (8 cases). Internuclear ophthalmoplegia was unilateral in 136 of the infarct cases (87%), 38 of those with multiple sclerosis (27%), and 48 of the unusual cases (42%). Because unusual causes compose more than one quarter of the cases, the differential diagnosis of INO should be tripartite: multiple sclerosis, stroke, and other causes.
 
The world is facing a looming epidemic of stroke.1 Although the incidence of stroke in high-income countries declined by about 42% (1%/y) between 1970 and 2008, concurrent with a reduction in the prevalence and level of causal risk factors in the population, the incidence of stroke in low-income countries increased by about 225% (5.6%/y) in the same period, concurrent with increasing exposure of the population to raised blood pressure, smoking, physical inactivity, and Westernized diets that are low in fruit and vegetables but high in salt and fat, as well as an increasing average age of the population.1,2
 
A variable natural history was found in a standardized follow-up study of 118 patients with subacute sclerosing panencephalitis (SSPE). Only 20% followed the sequence:behavior change, mental deterioration, periodic attacks, severe debility, and death within a year. Six stages were identified: 0, subtle psychointellectual symptoms; 1, obvious psychointellectual and neurological changes; 2, stereotyped attacks; 3, vegetative psychomotor condition; 4, improvement; 5, relapse. Illness began in stage 0 for 32%; 1, 36%; 2, 19%; 1 and 2 simultaneously, 13%. In early development, 77% were hyperactive, and 27% had psychointellectual difficulties one to five years prior to obvious illness. The average duration of each stage was as follows: stage 0, two years; 1, 2.5 months; 2, 7.5 months; 3, 5.5 months; 4, 3.5 years; 5, 1.5 years. Noteworthy improvements and plateaus occurred in more than half of the patients. In stage 4, improvement was long-term and substantial for 5% and modest for 18%. Survival followed an exponential curve with an average half-life of 1.8 years; 41% of the patients survived beyond two years. Half of the patients passed through neither stage 0 nor stage 4; their half-life was 0.7 years. The remainder had a half-life of 3.0 years.
 
Regional metabolic and perfusion deficits in 50 subjects with dementia or mild cognitive impairment. Magnitudes of the deficits observed by either fludeoxyglucose F18 (FDG) regional cerebral glucose uptake (CMRglc) or [11C]dihydrotetrabenazine (DTBZ) blood-to-brain transport rate (K1) vary similarly across regions. Error bars represent 1 SD of the percent of normal mean for all subjects with mild dementia and mild cognitive impairment. SMC indicates sensorimotor cortex.
To compare assessment of regional cerebral metabolic changes with [(11)C]dihydrotetrabenazine (DTBZ)-positron emission tomography (PET) measurement of regional cerebral blood flow (K(1)) and fludeoxyglucose F18 (FDG)-PET measurement of regional cerebral glucose uptake (CMR(glc)) in a clinically representative sample of subjects with mild dementia and mild cognitive impairment (MCI). [(11)C]Dihydrotetrabenazine-PET K(1) and FDG-PET CMR(glc) measurements were performed. University-based cognitive disorders clinic. Fifty subjects with either mild dementia (Mini-Mental State Examination score > or = 18) or MCI. Their results were compared with those of 80 normal control subjects. The DTBZ-PET regional K(1) and FDG-PET CMR(glc) measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K(1) and FDG-PET CMR(glc) deficits were assessed with stereotaxic surface projections (SSPs) of parametric images. The DTBZ-PET regional K(1) and FDG-PET CMR(glc) measurements were highly correlated, both within and between subjects. The SSP maps of deficits in DTBZ-PET regional K(1) and FDG-PET CMR(glc) measurements were markedly similar. The DTBZ-PET K(1) SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMR(glc) maps. Both DTBZ-PET K(1) and FDG-PET CMR(glc) measurements provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. Blood flow measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. Blood flow assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve utility of PET imaging in mild dementia and MCI.
 
In vivo carbon 11–labeled Pittsburgh Compound B imaging and Consortium to Establish a Registry for AD (CERAD) assessment of neuritic plaques (NPs). Participant E, with fibrillar β-amyloid (Aβ) primarily in diffuse plaques, is identified by circles. Participant A has a low distribution volume ratio (DVR) and no NPs. Three participants with moderate NPs have a DVR greater than 1.2 in at least 1 of the CERAD regions. Participants are marked A to F to correspond to the data in the tables, text, and other figures.
Potential factors limiting agreement between in vivo β-amyloid imaging and diagnostic neuropathologic assessment, illustrated for participant E. A, β-Amyloid (Aβ) load in the neuritic plaque (black arrow) in the superior and middle temporal gyri (SMTG) (Hirano, original magnification ×100). B, Fibrillar Aβ in diffuse plaques (white arrow) and blood vessel wall (arrowhead) in the SMTG (thioflavin S, original magnification ×100). C, The Aβ load by immunohistochemical analysis in the SMTG (6E10 antibody, original magnification ×100). D, Sagittal parametric carbon 11–labeled Pittsburgh Compound B image overlaid on a magnetic resonance image shows a high Aβ load in the precuneus. E, Fibrillar Aβ load in diffuse plaques (white arrow) in the precuneus (PRC) not routinely evaluated by Consortium to Establish a Registry for AD assessment (thioflavin S, original magnification ×100). F, Cerebral amyloid angiopathy in the occipital gyrus (OCG) (hematoxylin-eosin, original magnification ×100) (inset: original magnification ×200).
In vivo carbon 11–labeled Pittsburgh Compound B and β-amyloid (Aβ) levels by immunohistochemical analysis in the precuneus. Aβ reflects percentage area in which Aβ is detected by 6E10 antibody. A detectable level of Aβ is observed at a distribution volume ratio (DVR) greater than 1.2. Participants are marked A to F to correspond to the data in the tables, text, and other figures.
In demented older adults, in vivo amyloid imaging shows agreement with diagnostic neuropathologic assessment of β-amyloid (Aβ). However, the extent of agreement in nondemented older adults remains unclear. To compare Aβ quantified using in vivo carbon 11-labeled Pittsburgh Compound B positron emission tomography and postmortem neuropathologic assessment of Aβ in older adults. Case series. Community-dwelling older adults who came to autopsy. Five nondemented and 1 demented participant from the Baltimore Longitudinal Study of Aging. Agreement between the mean cortical distribution volume ratio and the Consortium to Establish a Registry for AD (CERAD) neuritic plaque (NP) score used for pathologic diagnosis of Alzheimer disease. Of the 6 participants, 4 had moderate NPs, 2 had sparse or no detectable NPs, and 3 had microscopic findings of cerebral amyloid angiopathy at autopsy. On in vivo imaging, the mean cortical distribution volume ratio ranged from 0.96 to 1.59. Although there was agreement between in vivo amyloid imaging and CERAD NP scores in participants with either high or negligible Aβ levels in vivo, only limited agreement was observed among those with intermediate levels of Aβ. The best overall agreement was achieved at a distribution volume ratio of 1.2. In older adults, variable agreement between in vivo imaging and CERAD NP score was observed. The limited agreement may, in part, reflect differences in typical measurements of Aβ using imaging compared with the CERAD neuropathologic protocol. Direct quantification of regional Aβ in relation to in vivo imaging is necessary to further enhance our understanding of the imaging-pathologic assessment correlation.
 
Human postmortem and animal experimental results suggest a decline of the cerebral dopaminergic neuronal system with age. In this study, the radiotracer carbon 11-labeled-raclopride and positron emission tomography were applied to determine the effect of age on striatal D2 dopamine receptors in 32 healthy volunteer subjects (age range, 21 to 68 years; median, 31 years). An index of specific 11C-raclopride binding was calculated for putamen, caudate nucleus, and other brain regions in each subject. A significant decrease with age of the index for specific tracer uptake was found in putamen and caudate nucleus. The decrease was steep until 30 years, but slower afterward. After approximately 30 years of age, the decline of specific 11C-raclopride binding in putamen was found to be 0.6% per year. Our results suggest that D2 dopamine receptor binding sites (mainly postsynaptically located) decrease as a consequence of normal aging in parallel with the decline of the presynaptic nigrostriatal dopaminergic neuronal system.
 
To assess the frequency and type of neurologic involvement in a cohort of patients with generalized Wegener granulomatosis (WG). In a prospective analysis the clinical, electrophysiologic, radiological, and serologic data of 128 patients have been studied over a median observation period of 19 months (range, 1-60 months). Sixty-four patients (50%) revealed central or peripheral nervous system involvement. Peripheral neuropathy (PN) affected 56 patients, in 9 cases the central nervous system was involved, and in 6 cases the cranial nerves were involved. Thirty-one patients showed a distal symmetrical polyneuropathy, 25 a mononeuritis multiplex. Within the first 2 years of the disease course 47 of the 56 patients had developed their PN, sometimes as the initial symptom of WG. Patients with PN were significantly more often male (34 of 65 patients) than female (22 of 63 patients, P =.04), were significantly older at the onset of WG (median age, 53 vs 44 years; P =.001), had a significantly larger disease extent (P =.001), and had higher classic antineutrophil cytoplasmic antibody titers (P =.002) than neurologically unaffected patients. Response to immunosuppression was moderate concerning peripheral nervous system manifestations. Peripheral neuropathy is frequent in generalized WG, occurring early in the disease course. As PN can be the first and sole symptom of a beginning systemic vasculitis, it is important that in cases of PN of an unclear origin, interdisciplinary investigations are initiated to detect, treat, and closely follow-up a possible underlying WG, especially as these patients seem to have a more severe disease course.
 
To determine whether abnormalities in regional cerebral functional activity estimated by iofetamine hydrochloride I 123 and single photon emission computed tomography can be detected in mild or moderate as well as severe cases of Alzheimer's disease (AD), we performed iofetamine I 123-single photon emission computed tomography in 37 patients with probable AD (nine patients with mild, 18 patients with moderate, and ten patients with severe dementia) and nine age-matched control subjects. Iofetamine I 123 uptake was measured in right and left frontal, temporal, parietal, and occipital cortices. Mean (right and left) iofetamine I 123 activity was lowest in the parietal region of patients with AD and was significantly reduced in the other three regions compared with control subjects. Only in the parietal region was lower relative iofetamine I 123 activity associated with an impaired level of patient function and with cognitive deficit.
 
Specific binding to dopamine transporters may serve as a tool to detect early loss of nigrostriatal dopaminergic neurons in patients with Parkinson's disease. To determine striatal dopamine transporter binding using the cocaine analogue [I-123]N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chl orophenyl) tropane ([I-123]IPT) and single photon emission computed tomography. We studied 9 control subjects (mean age, 58 years; range, 41-69 years) and 28 patients with early Parkinson's disease (Hoehn and Yahr stages I [n = 14] and II [n = 14] [symptom duration, <5 years]; mean age, 55.5 years; range, 36-71 years). Single photon emission computed tomography was performed 90 minutes after injection of 120 to 150 MBq of radioactive [I-123]IPT. Specific striatal [I-123] IPT binding (mean +/- SD) was significantly reduced in patients with early Parkinson's disease (ipsilateral striatum: 4.09+/-0.97; range, 2.46-6.40; contralateral striatum: 3.32+/-0.76; range, 1.80-5.13) compared with controls (left striatum: 7.28+/-0.94; range, 5.78-8.81; right striatum: 7.41+/-1.28; range, 5.58-9.44). IPT binding ratios (mean +/- SD) were significantly lower in patients with Hoehn and Yahr stage II (ipsilateral striatum: 3.47+/-0.75; contralateral striatum: 2.96+/-0.73) compared with those with Hoehn and Yahr stage I (ipsilateral striatum: 4.72+/-0.75; contralateral striatum: 3.69+/-0.61) (P<.001). The ipsilateral striatum of patients with Hoehn and Yahr stage I showed a significant mean+/-SD reduction of IPT binding (ipsilateral striatum: 4.72+/-0.75) compared with either right or left striatum of controls (P<.001). Only in 1 patient was IPT binding to the ipsilateral striatum (ratio, 6.40) higher than the lowest value observed in the striatum of a control subject (ratio, 5.58). Use of [I-123] IPT and single photon emission computed tomography demonstrates a reduction of dopamine transporter binding in patients with early Parkinson's disease. Significantly reduced IPT binding already observed in the ipsilateral striatum of patients with Hoehn and Yahr stage I demonstrates the potential of this method to detect preclinical disease.
 
Two amines, N-isopropyl p-iodoamphetamine and N,N,N'-trimethyl-N'-[2-hydroxyl-3-methyl-5-iodobenzyl]-1,3-prop anediamine, have been labeled with iodine 123. The brain uptake of these radioactive tracers is proportional to cerebral blood flow. These tracers are retained in the brain for a sufficiently long time so that imaging can be performed with standard, readily available instrumentation. Transaxial tomography with amines is useful in acute cerebral infarction, in which the x-ray computed tomographic scan may be normal for several days after onset of symptoms while the uptake of radioisotope-labeled amines will be altered immediately after the onset of the stroke. It is also useful in examining patients with cerebral vascular disease and in the preoperative examination of patients with partial epilepsy.
 
To test the usefulness of single photon emission computed tomography (SPECT) with iodobenzamide in imaging basal ganglia and to elucidate the postulated upward regulation of the striatal D2 dopamine receptors in patients with early Parkinson's disease. Fourteen patients with Parkinson's disease and eight control subjects were investigated with SPECT using iodobenzamide labeled with iodine 123 as dopamine receptor ligand. Neurological outpatient service at a university hospital in Kuopio, Finland. Fourteen patients with recently diagnosed unilateral, unmedicated Parkinson's disease and eight healthy control subjects. The SPECT images revealed high uptake of iodobenzamide in the basal ganglia. In the patient group, the accumulation was more intense and the iodobenzamide affinity rate was significantly higher in the striatum contralateral to the parkinsonian symptoms. Also, the basal ganglia-cerebellum ratio was higher in the contralateral hemisphere. In the control group, no significant side-to-side differences were observed. Iodobenzamide with SPECT imaging is useful in evaluating patients with Parkinson's disease. The results also suggest compensatory D2 dopamine receptor upward regulation in the striatum of patients with early unmedicated Parkinson's disease.
 
Fourteen patients (10 with left-sided and 4 with right-sided cerebral infarction) were prospectively studied with single-photon emission computed tomography (SPECT) using N-isopropyl-p-(I 123) iodoamphetamine (IMP, SPECTamine) to determine its usefulness in predicting neurologic/language recovery after cerebral infarction. All neuro-SPECT imaging was performed within 30 days after infarction. Detailed assessment of neurologic and/or language recovery (after 3 months) was carried out prospectively in each patient. Patients with smaller volume IMP defects in the region of infarction demonstrated significantly better neurologic and language recovery than patients with large IMP defects. Analysis of the IMP "redistribution" phenomenon failed to demonstrate definitively a relationship with clinical recovery. It was concluded that the volume of the IMP defect can aid in predicting recovery potential after cerebral infarction.
 
Top-cited authors
Ronald C Petersen
  • Mayo Foundation for Medical Education and Research
Glenn E Smith
  • University of Florida
Steve Waring
  • Essentia Institute of Rural Health
Bengt Winblad
  • Karolinska Institutet
David Bennett
  • Rush University Medical Center