The neural cell adhesion molecule (NCAM) present in the cerebrospinal fluid of multiple sclerosis patients is unsialylated.

The neural cell adhesion molecule (NCAM) is a glycoprotein localised in the plasma membrane of neural and glial cells, which plays a role in myelination and remyelination. It increases in the cerebrospinal fluid (CSF) of acute multiple sclerosis (MS) patients treated with corticosteroids who are improving after an attack, but it has not been shown if it appears in its sialylated (PSA) or unsialylated form. We studied the NCAM and the PSA-NCAM in serum and CSF samples of 16 acute and non-acute MS patients and in the sera of 10 non-neurological controls. The NCAM and the PSA-NCAM were dosed by two different ELISA previously set-up. The NCAM in the serum and in the CSF of the control group presented mean levels similar to those shown in previous papers: 1620 +/- 216 and 970 +/- 210 ng/ml. In the MS patient group the means were 1700 +/- 546 in the sera and 926 +/- 285 in the CSFs. All the sera were PSA-NCAM-positive: the mean PSA-NCAM concentration in the control group was 3150 +/- 950 ng/ml, while in the MS patient group it was 3570 +/- 905 ng/ml. The correlation between serum levels of NCAM and PSA-NCAM was highly significant (p < 0.001). Student's "t" test did not show any significant difference between serum levels of the two groups, both for the NCAM and for the PSA-NCAM. CSF samples did not show any positive results for the PSA-NCAM, in either controls or in MS patients. These results demonstrate that the high levels of NCAM we previously found in the CSF of improving MS patients treated with steroids did not contain a quota of PSA-NCAM, but only the unsialylated soluble form of the molecule.

Transcranial Doppler ultrasonography in adults with sickle cell disease.

BACKGROUND: Transcranial Doppler (TCD) is used to select children with sickle cell disease (SCD) for primary stroke prevention using regular blood transfusion. Whether it can also identify high stroke risk in adults with SCD is not known. METHODS: The authors examined 112 adult patients from two convenience population samples with SCD and 53 healthy control subjects to compare velocities in adults to those reported in children with SCD and to evaluate the influence of age and hematocrit on TCD. RESULTS: Adults with SCD had a higher mean time-averaged maximum mean velocity (110.9 +/- 25.7 cm/s) compared with healthy controls (71.1 +/- 12.0 cm/s), and the difference is approximately proportional to their anemia. No cases with velocities >/=200 cm/s (the threshold used in children for prophylactic treatment) were found in this sample. CONCLUSIONS: Transcranial Doppler velocities in adults with sickle cell disease (SCD) are lower than those in children with SCD. Velocity criteria used in children cannot be used to stratify risk of stroke in adults.

Migraine-mimicking headache and sickle cell disease: a transcranial Doppler study.

Headache occurs in sickle cell disease (SCD), but its characteristics and frequency have not previously been studied. Our aim was to study patterns of headache in adults with SCD and to correlate its presence with blood flow velocities measured by transcranial Doppler (TCD) and with brain magnetic resonance imaging (MRI) abnormalities. We studied 56 adults with SCD. Twenty-eight patients (50%) had severe and frequent headaches. In 20 patients (35.7%) the headache met the International Headache Society criteria for migraine without aura. Patients with frequent and severe headache presented TCD velocities significantly higher than those without headache, or with milder headache. No correlation was found between headache and abnormalities in brain MRI. A migraine-mimicking headache occurs in SCD but we should not understand it as a primary headache because the blood flow abnormalities secondary to SCD detected by TCD seem to play an important role in these patients.

Transcranial Doppler assessment of cerebral blood flow: effect of cardiac transplantation.

The authors prospectively studied transcranial Doppler changes in patients with refractory congestive heart failure before and after cardiac transplantation. They evaluated 22 patients preoperatively and 14 patients after transplantation. Mean postoperative flow velocity increased by 53.3% (p < 0.0001). Preoperative waveform changes became normal after transplantation.

The role of NCAM in remyelination.

The neural cell adhesion molecule (NCAM) is expressed by myelinating precursor cells in neonatal mouse spinal cord and by remyelinating cells after chemically induced demyelination in adult mouse. It shows tempting suggestions about its possible involvement in the reparative mechanisms and the remyelination processes that take place in multiple sclerosis (MS). In fact, its levels progressively increase in the cerebrospinal fluid (CSF) of acute MS patients subjected to steroid treatment, paralleling the progressive clinical improvement after the attack. Such an increase is not found in acute MS patients not treated with steroids nor in non-acute patients subjected to the same steroid treatment.

Interferon-beta (INF-beta) antibodies in interferon-beta1a- and interferon-beta1b-treated multiple sclerosis patients. Prevalence, kinetics, cross-reactivity, and factors enhancing interferon-beta immunogenicity in vivo.

We analysed the role of dosage, route and frequency of administration of clinical grade interferon-beta (IFN-beta) preparations in inducing anti-IFN-beta antibodies (IFN-beta-Abs) in 5 groups of relapsing-remitting multiple sclerosis (RRMS) patients who were respectively treated as follows: 1) weekly intramuscular (i.m.) injections of 30 mg of recombinant IFN-beta1a (Avonex), 2) subcutis (s.c.) injections of 250 mg IFN-beta1b (Betaferon) every other day, 3) weekly i.m. injections of 250 mg IFN-beta1b (Betaferon), 4) s.c. injections of 22 mg of IFN-beta1a (Rebif) three times a week, and 5) i.m. injections of 22 mg of IFN-beta1a (Rebif) twice a week. IFN-beta-Abs were determined by ELISA. IFN-beta1b was more immunogenic than IFN-beta1a not only when administered s.c. every other day, but also when administered i.m. at a lower weekly dose; i.m. injection, however, significantly delayed the appearance, and induced lower serum levels of IFN-beta-Abs. In patients treated with s.c. IFN-beta1b, Ab levels peaked 3 to 9 months after therapy initiation, and then slowly, but progressively, declined to pre-therapy levels that in some patients were reached after three years. Patients treated with i.m. or s.c. IFN-beta1a only rarely developed IFN-beta-Abs, and then at very low titers. Overall, the i.m. weekly administration of IFN-beta1a was the less immunogenic treatment. In IFN-beta1b-treated patients, a wash-out period of two/three months was sufficient to bring the IFN-beta-Ab levels below the cut-off. Our findings suggest that the immunogenicity of IFN-beta1a is low, regardless of the route of administration and the dosage, while that of IFN-beta1b is high, and is significantly, but not completely reduced by i.m. administration. As IFN-beta-Abs are cross-reactive, a wash-out period is suggested when the preparation is changed from IFN-beta1b to IFN-beta1a in order to maintain the clinical benefits of the therapy.

Is the number of microembolic signals related to neurologic outcome in coronary bypass surgery?

Coronary artery bypass surgery (CABG) without cardiopulmonary bypass (CPB) may potentially reduce the number of microembolic signals (MES) associated with aortic manipulation or generated by the pump circuit, resulting in a better neurologic outcome after surgery. Our aim was to compare the frequency of MES and neurologic complications in CABG with and without CPB. Twenty patients eligible to routine CABG without CPB were randomized to surgery with CPB and without CPB and continuously monitored by transcranial Doppler. Neurologic examination was performed in all patients before and after surgery. The two groups were similar with respect to demographics, risk factors, grade of aortic atheromatous disease and number of grafts. The frequency of MES in the nonCPB group was considerably lower than in CPB patients, however, we did not observe any change in the neurologic examination during the early postoperative period. Neurologic complications after CABG may be related to the size and composition of MES rather than to their absolute numbers. A large prospective multicentric randomized trial may help to elucidate this complex issue.

Stroke as the first manifestation of calcific aortic stenosis.

Heart valve calcifications are rarely recognized as a potential source for cerebral embolism. Previous studies have identified mitral, but not aortic, valve calcifications to be risk factors for stroke. Based on these studies, heart surgery is unlikely to be indicated in patients who present with a stroke and an 'incidental' aortic valve calcification. We report a case of a 46-year-old man presenting with acute onset of left-sided weakness and numbness. A previous smoking history was the only cardiovascular risk factor found. Head CT scan revealed a right middle cerebral artery territory infarct and an adjacent high-density lesion. CT angiography demonstrated the presence of calcific embolic material in the middle cerebral artery. A search for embolic sources revealed a calcific aortic stenosis (CAS). Initially placed on coumadin, the patient developed silent myocardial infarction 2 months later, presumed to be also embolic in origin from the CAS. After aortic valve replacement, the patient has been symptom-free during a 2-year follow-up. In conclusion, CT angiography may be the method of choice for detecting calcific cerebral emboli, and demonstration of a causal relationship between CAS and an embolic stroke by CT angiography may be an important adjunct in surgical decision-making.

Are there indicators of remyelination in blood or CSF of multiple sclerosis patients?

Knowing the mechanisms and the times of remyelination is not only an intriguing scientific challenge but it has also important consequences on the therapeutic approach to multiple sclerosis (MS). The neural-cell adhesion molecule (N-CAM) shows tempting suggestions about its possible involvement in reparative mechanisms, and, finally, in remyelination. In fact, its levels progressively increase in the cerebrospinal fluid (CSF) of acute MS patients, paralleling the progressive clinical improvement after the attack. Some information is also given about the ciliary neurotrophic factor (CNTF), whose CSF levels were found to be increased in MS patients who were recovering from an acute exacerbation.

Cerebrospinal fluid markers in multiple sclerosis: an overview.

Cerebrospinal fluid (CSF), with its protein markers, is a formidable material for investigating the relationships among the various cell types involved during the initial phase of plaque formation, or, successively, in the remyelination process. Its analysis may give definite help in better focusing on therapeutic objectives and therapeutic tools. Therefore, the possible use of CSF MBP, S-100, GFAP, N-CAM, NGF, and CNTF in pathogenetic studies and in clinical follow-up is critically reviewed. The need for correct interpretation of the data, for uniformity and reliability of the analytical methods, and for easy access to them is stressed. CSF examination and MRI should not be considered as alternative tools, or in competition, but should be used together, to take the maximum advantage of their individual possibilities.

Neurologic outcome after heart transplantation in Chagas' disease. Preliminary results.

OBJECTIVE: To evaluate the neurologic morbidity after orthotopic heart transplantation (OHT), we examined consecutive Chagas' (Ch) and non-Chagas' (NCh) patients, before and after surgery. MATERIAL AND METHODS: We undertook neurological and neuropsychological evaluations in Ch and NCh patients with end-stage cardiac failure, from September 1993 to September 1995. RESULTS: Of 10 Ch patients (mean age = 33.6 years; 7 male; mean follow-up = 10.8 months) and 13 NCh patients (mean age = 50.9 years; 12 male; mean follow-up = 15 months) 3 died (rejection and sepsis) without neurologic symptoms. Neurologic complications occurred in 4 Ch and 5 NCh patients. Two Ch patients had skin and myocardial Chagas' reactivation successfully treated, without CNS involvement. NPS performance and return to work rates were similar in both groups. CONCLUSION: Although Ch patients are potentially at a higher risk of Trypanosoma cruzi reactivation, in addition to all known neurologic complications of OHT, early neurologic complications detected in this sample were similar in Ch and NCh patients and could not be specifically related to Chagas' disease.

Cerebrospinal-fluid ciliary neurotrophic factor in neurological patients.

We developed a double sandwich immunoassay for the dosage of ciliary neurotrophic factor (CNTF) in cerebrospinal fluid (CSF). The detection limit was 100 pg/ml. This assay was applied to human CSF samples from 14 normal subjects, 26 patients with multiple sclerosis (MS), 17 with Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyneuropathy (CIDP), and 22 with tumours of the central nervous system (CNS) or leucaemic meningosis (LM). Samples from normal control subjects and from patients with tumours did not contain detectable CNTF. Only 2 patients with LM were positive, and all the patients with inflammatory diseases of the CNS and peripheral nervous system were positive. The MS group presented a mean value of 240 pg/ml CNTF and the GBS/CIDP group a value of 430 pg/ml.

Multiple sclerosis associated with peripheral demyelinating neuropathy.

We report clinical, electrophysiological, magnetic resonance imaging, and nerve biopsy findings of 2 patients with definite multiple sclerosis and peripheral demyelinating disease. Although it is not easy to assess the real incidence of peripheral neuropathy in patients with multiple sclerosis, this association seems to be rare. The combination of central and peripheral demyelination may be a fortuitous coincidence, but it appears improbable. Alternatively, these patients may represent a specific subpopulation and common immunopathogenetic mechanisms (such as immunological factors, endothelial alterations, and abnormal expression of adhesion molecules) may underly both central and peripheral myelin involvement. The study of these cases might clarify specific mechanisms of pathogenetic significance in demyelinating diseases.

[Orbital phlebography evaluation in 8 cases of Tolosa-Hunt syndrome]. / Avaliação da flebografia orbitária em oito casos de síndrome de Tolosa-Hunt.

Tolosa-Hunt syndrome (THS), or painful ophthalmoplegia is associated to a non-specific granulomatosis of unknown etiology, that involves the superior orbital fissure and its nervous and vascular structures. The clinical picture that responds to steroid therapy, is variable and is always associated with pain. Inflammatory conditions, tumors and aneurysms can produce similar symptoms. Computed tomography, cerebral angiography and orbital phlebography are the imaging methods of choice for making the diagnosis. We revised the results of these radiological examinations of eight patients seen at the Hospital São Paulo from 1989 to 1991, with the diagnosis of THS according to Hunt and Hannerz criteria. The analysis of orbital phlebographic changes based upon Hannerz et al. systematization showed non-specific features, but those were able to help the diagnosis.

Avaliaçäo da flebografia orbitária em oito casos de síndrome de Tolosa-Hunt / Orbital phlebography evaluation in 8 cases of Tolosa-Hunt syndrome

A Síndrome de Tolosa-Hunt (STH) ou oftalmoplegia dolorosa é associada a granulomatose inespecifica de etiologia desconhecida que acomete a fissura orbitária superior. Compromete estruturas nervosas e vasculares causando quadro clínico variável que sempre se associa a dor e apresenta resposta favorável à corticoterapia. Processos inflamatório, tumores e anmeurismas dessa regiäo podem causar sintomas semelhantes. A tomografia computadorizada, a angiografia cerebral e a flebografia orbitária säo métodos de imagem indicados para orientar o diagnóstico. Revisamos os resultados destes exames radiológicos de oito pacientes atendidos no Hospital Säo Paulo no período 1989 a 1991, com diagnóstico de STH segundo os critérios de Hunt e Hannerz. A análise das alteraçöes da flebografia orbitária, de acordo com a sistematizaçäo feita por Hannerz e col. Mostrou ser este exame inespecífico, porém capaz de orientar melhor mo diagnóstico

Nerve growth factor (NGF) in cerebrospinal fluid (CSF) from patients with various neurological disorders.

It has been recently shown that NGF is not only involved in the survival and development of sympathetic and neural crest-derived sensory neurons, but also in some mechanisms of the immune system. For this reason, we studied the content of NGF in CSF samples from patients with diseases in which neuroimmunological mechanisms seem to be involved (multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer disease, chronic relapsing polyradiculoneuritis, Guillain-Barré syndrome, and tumors of the nervous system), as well as from a number of normal control subjects. We setup an ELISA aimed at the beta subunit of NGF, obtaining good validation tests and a detection limit of 28 pg beta NGF per ml. None of the samples was found to contain detectable levels of NGF and, when a concentration method for sample enrichment was used, only one patient was NGF-positive. This suggests that NGF is probably not involved in the neuroimmunological mechanisms underlying some inflammatory and degenerative diseases of the nervous system.

Characterization of arteriovenous malformation feeding vessels by carbon dioxide reactivity.

PURPOSE: To characterize cerebral hemodynamics in patients immediately before microsurgical resection of moderate to large arteriovenous malformations during isoflurane anesthesia. METHODS: In angiographically defined arteriovenous malformation feeding and nonfeeding arteries, transcranial Doppler studies were performed in 25 surgeries on 22 patients. The mean blood flow velocity and pulsatility index were recorded in the middle, anterior, and posterior cerebral arteries. Transcranial Doppler velocities were measured at end-tidal carbon dioxide tensions (PetCO2) of about 25 and 35 mm Hg. Carbon dioxide reactivity was calculated as percentage mean blood flow velocity change per mm Hg PetCO2 change. RESULTS: Patient demographic and clinical data for the arteriovenous malformation group followed the expected strata of a large arteriovenous malformation population. All patients were neurologically stable before surgery. A total of 43 feeding arteries and 55 nonfeeding arteries were studied. Compared with nonfeeders, feeders exhibited higher mean blood flow velocity (68 +/- 5 vs 31 +/- 3 cm/sec, P < 0.0001) and lower pulsatility index (0.64 +/- 0.03 vs 0.88 +/- 0.04, P < 0.001); anterior and middle cerebral artery velocities at normo- and hypocapnia were significantly higher than posterior cerebral arteries for both feeders and nonfeeders (P < 0.001). Carbon dioxide reactivity was 0.2 +/- 0.2%/mm Hg in feeders and 2.1 +/- 0.2%/mm Hg in nonfeeders, with no significant difference between arteries. In four of eight patients with lesions fed by the anterior circulation (middle cerebral artery with or without anterior cerebral artery feeders), posterior cerebral artery nonfeeders exhibited low reactivity. In 2 of 5 patients with ipsilateral posterior cerebral artery feeders, contralateral posterior cerebral artery nonfeeders exhibited impaired reactivity. CONCLUSIONS: Quantitative transcranial Doppler studies are technically feasible in the operating room or interventional suite during anesthesia. Hemodynamic assessment using physiologic challenges of arteriovenous malformation feeders as well as angiographically uninvolved vessels may be useful as criteria in the assessment of malformations and arteriovenous malformation patients may exhibit abnormal vasoreactivity in distant uninvolved perfusion territories, suggesting a deranged neural control mechanism.