Abstract: PURPOSE: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors. PATIENTS AND METHODS: BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry. RESULTS: Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P < .01) were identified at doses >/= 200 mg bid continuous. Forty-five patients were assessable for efficacy; one patient had a partial response (hepatocellular carcinoma at 400 mg bid continuous), 25 patients had stable disease, with eight lasting > 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient. CONCLUSION: Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies.
Abstract: This study investigated the relationship between clinical symptoms and cognitive dysfunction in multiple sclerosis. Cognitive dysfunction and visual evoked potentials (VEPs) were studied in patients free of physical disability and mildly to moderately disabled patients with multiple sclerosis (MS). Disability-free patients (EDSS < or = 1.5; n = 13), mildly to moderately disabled patients (EDSS ranging from 2 to 6; n = 13) and a healthy matched control group (n = 16) were examined with respect to attention, verbal and nonverbal memory and early visual processing (VEPs). Disability-free patients showed mild impairments on phasic alertness and divided attention. Deficits were more pronounced in mildly to moderately disabled patients who were additionally impaired with respect to non-verbal memory. Despite adequate visual acuity, one half of all patients showed abnormal VEP latencies for both eyes at the same time. The findings suggest that cognitive deficits are already present in multiple sclerosis even in the absence of physical disability. Even with normal visual acuity, perceptual impairments should be considered as part of the CNS affection.
Abstract: Cytokines play an important role in the onset, regulation, and propagation of immune and inflammatory responses within the central nervous system (CNS). The main source of cytokines in the CNS are microglial cells. Under inflammatory conditions, microglial cells are capable of producing pro- and antiinflammatory cytokines, which convey essential impact on the glial and neuronal environment. One paramount functional feature of astrocytes is their ability to form a functionally coupled syncytium. The structural link, which is responsible for the syncytial behavior of astrocytes, is provided by gap junctions. The present study was performed to evaluate the influence of inflammation related cytokines on an astroglial/microglial inflammatory model. Primary astrocytic cultures of newborn rats were cocultured with either 5% (M5) or 30% (M30) microglial cells and were incubated with the following proinflammatory cytokines: tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interferon-gamma (IFN-gamma), and the antiinflammatory cytokines transforming growth factor-beta1 (TGF-beta1) and IFN-beta. Under these conditions, i.e., incubation with the inflammatory cytokines and the high fraction of microglia (M30), microglial cells revealed a significant increase of activated round phagocytotic cells accompanied by a reduction of astroglial connexin 43 (Cx43) expression, a reduced functional coupling together with depolarization of the membrane resting potential (MRP). When the antiinflammatory mediator TGF-beta1 was added to proinflammatory altered M30 cocultures, a reversion of microglial activation and reconstitution of functional coupling together with recovery of the astroglial MRP was achieved. Finally IFN-beta, added to M5 cocultures was able to prevent the effects of the proinflammatory cytokines TNF-alpha, IL-1beta, and IFN-gamma.
Abstract: Assessment of cerebral blood flow velocities (CBFV) can be used as a non-invasive tool to evaluate specific drug effects, like caffeine (CAF), acetazolamide (AA) as well as cognition. Their influences on each others CBFV were evaluated in detail, using a randomized, double-blind, double-dummy, placebo-controlled three-fold cross-over study design in 18 right-handed healthy male volunteers. CBFV (maximal, mean, minimal) and pulsatility index of both middle cerebral arteries were recorded by transcranial Doppler ultrasound simultaneously, during a verbal memory test, oral CAF, intravenous AA or placebo. AA led to increase in CBFV of 25-32%. Caffeine resulted in decreased V(mean) and V(min) of 10-13%. Cognitive stimulation resulted in a slight increase of CBVF of about 4%, but was overruled by effects of AA and CAF. We conclude that pharmacological effects can easily be assessed by TCD during clinical pharmacological studies of vasoactive drugs. However intraindividual variability and effects of neuropsychological stimulation needs to be taken into account.
Abstract: BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800 mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400 mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.
Abstract: Long-term development of psychological deficits in disability-free early multiple sclerosis (MS) was evaluated in 27 female patients over a period of 7 years and compared with healthy controls. Physical and cognitive parameters deteriorated significantly but not depression scores. In particular, the self-assessed somatic complaints remained non-similar between patients and controls. This indicates that although depression is clinically relevant and frequent in MS, in contrast to cognition it is not related to physical disease progression.
Abstract: OBJECTIVES: Patients diagnosed with multiple sclerosis (MS) but without disability (Expanded Disability Status Scale score <2) form a specific group within those patients suffering from relapsing-remitting MS. Several neuroimmunologic effectors, including cytokines and melatonin, are known for their influence on the initiation of relapses and progression of the disease. METHODS: We evaluated 41 female patients with benign MS with respect to their clinical course, treatments and neuroimmunological parameters, including cytokines and melatonin. One subgroup was followed up for 7 years, and another group was evaluated during acute clinical relapse. RESULTS: The benign MS course in this homogeneous group of young patients was demonstrated by mild disease progression in 16% over 7 years. Initially, patients treated with azathioprine (AZA) revealed significantly reduced melatonin serum levels (p = 0.04) compared to untreated patients, but not at follow-up. During acute relapse, treatment with corticosteroids (CS) resulted in increased levels of type 2 cytokines as well as reduced type 1 cytokine levels. CONCLUSIONS: Our study supports the functional role of CS acting as an antiinflammatory protagonist during MS relapse, by inducing a shift towards predominance of type 2 cytokines. AZA showed a more subtle modulation of immune functions, reflected by reduced levels of the immune active hormone melatonin. During follow-up, it became apparent that stabilized levels of the interacting Th1/Th2-derived cytokines and melatonin are maintained in concordance with the benign course of MS. These findings are in accordance with the hypothesis that benign MS is characterized by a balanced cytokine and neuroendocrine network, which is supported by immune-modulating therapies.
Abstract: BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.
Abstract: OBJECTIVES: In multiple sclerosis (MS), several neuroimmunomodulatory effectors are known, including melatonin. They are able to influence disease-related neurophysiogical changes (disability or impaired vision) as well as neuropsychological performance (e.g. cognition and depression). In this study we assessed the relationship between immunomodulation on psycho-neuroimmunological functions in benign multiple sclerosis. METHODS: We evaluated 26 young female patients with benign MS treated with/without immunomodulating therapies with regard to their physical disabilities (Expanded Disability Status Scale, EDSS), their visually evoked potentials (VEP), their plasma melatonin concentrations as well as their performance regarding emotional and cognitive tests and compared them with healthy matched controls. RESULTS: Patients with MS showed deficits in cognitive and emotional functions compared to healthy controls, which were in accordance with their increase in EDSS over time. However, in contrast to untreated patients, patients receiving immunotherapy showed significantly increased dysfunction with respect to actual mood (p = 0.02) and a tendency to increased depression scores (p = 0.072). However, neither treatment subgroup had cognitive deficits. In untreated patients, melatonin levels correlated with reduced scores in the cognitive tests (p = 0.045) but not with depression or VEP latencies. Patients with long-standing MS (>10 years) showed a significant correlation (p = 0.01) to their increased depression scores and their melatonin levels, but no correlation with VEP or cognitive dysfunction, compared to patients with shorter disease duration (< or =10 years). CONCLUSION: These results indicate that in MS all aspects of the psycho-neuroimmunological network can be affected. Despite the potential influence of immunomodulation on depression, no connection with melatonin representing the retinohypothalamic tract/pineal gland circuits could be detected. However, visual perception as well as visuoconstructive abilities were affected in MS patients. Neuropsychological tests in MS should concentrate on cognitive variables, which reflect the clinical status more accurately and may be used to monitor disease-modifying therapies.
Abstract: Under inflammatory conditions, activated microglia are capable of producing proinflammatory cytokines that are reported to influence cell-to-cell communication. The present study was performed to evaluate the influence of microglial activation on the coupling efficiency of the astroglial network. Primary astrocyte cultures of newborn rats were cocultured with either 5% (M5) or 30% (M30) microglia. Microglial activation (rounded phagocytotic phenotype) was investigated using the monoclonal anti-ED1 antibody, and immunofluorescence with a polyclonal anti-Cx43 antibody was used to study astroglial Cx43 expression and distribution. Functional coupling of astrocytes was evaluated by monitoring the transfer of microinjected Lucifer yellow into neighboring cells. The data obtained can be summarized as follows: astroglia/M30 cocultures contained significantly fewer resting microglia and significantly more activated microglia than the M5 cocultures; significantly reduced astroglial Cx43 staining was found in M30 cocultures concurrently with a reduced number of dye coupled astrocytes; and the positive correlation of percent activated microglia with reduced astroglial Cx43 expression was highly significant, indicating that the degree of intercellular communication in the astroglial network may be modulated by the activation of microglia under in vitro conditions.
Abstract: Cognitive and emotional capabilities were evaluated in 73 female patients with stable relapsing-remitting definite, and/or laboratory-supported multiple sclerosis (MS) and were compared with 32 matched healthy controls. Patients were categorized according to their score in the expanded disability status scale (EDSS) to either no (EDSS 0, n = 33) or few clinical signs (EDSS 1-2, n = 40) of MS without physical disability. Patients with EDSS > 0 were characterized by significantly (p < 0.001) higher scores on "von Zerssen's" depression scale, compared to controls. Patients with higher EDSS scores (1-2) showed significantly decreased performance with respect to the total score of Kimura's Recurring-Figures-Test (p < 0.001), in addition. Regarding visuo-constructive functioning, patients with EDSS=0 performed to a significantly lower level (p < 0.001), compared to controls. These results indicate that depression may present as an early sign in MS followed by cognitive impairment, in particular visuo-spatial short-term memory, before physical disability appears. Neuropsychological tests as mentioned here could serve as early diagnostic tools to detect subtle disease progression and to initiate and monitor disease modifying therapies.
Abstract: The lack of phenotype/genotype association in X-linked adrenoleukodystrophy (X-ALD) has prompted the search for disease modifying factors. We previously demonstrated increased serum antibody responses against myelin oligodendrocyte glycoprotein (MOG) in various clinical phenotypes of X-ALD allowing speculations that myelin specific humoral immune responses might be involved in phenotype generation of X-ALD. In the present study, we investigated the possible association of (1) a naturally occurring variable number tandem repeat (vntr) polymorphism (C allele) in the 3' flanking region of the interleukin-6 gene (IL-6), previously demonstrated to modify the course of Alzheimer's disease, systemic lupus erythematodes and Multiple Sclerosis (MS), (2) a tetranucleotide repeat polymorphism (TAAA)(n) in the 3' flanking region of the MOG gene and (3) HLA class II alleles with adult clinical phenotypes and serum antibody responses to MOG in 70 adult X-ALD patients. HLA class II alleles, (TAAA)(n) MOG gene polymorphisms, and IL-6 C allele were not associated with clinical phenotypes. Anti-MOG antibodies were detectable in 17/54 X-ALD patients (31.5%). Anti-MOG antibodies were associated with the 226 bp (TAAA)(n) MOG gene polymorphism but not with distinct clinical phenotypes.
Abstract: Interleukin-6 (IL-6) plays an important role in the regulation of the inflammatory response in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous reports indicated that the C allele of a variable number tandem repeat (vntr) polymorphism located in the 3'flanking region of the IL-6 gene ( IL-6) is associated with reduced activity of IL-6 in vivo. Since disease-modifying genes are likely to contribute to phenotypic differences in MS patients, we tested the hypothesis that the IL-6 C allele is associated with the clinical course of MS. The IL-6 C allele was equally distributed between 217 MS patients of German Caucasian origin and 111 age-mached healthy controls. Stratification of patients according to the course of disease revealed no significant difference of IL-6 C allele distribution between patients with primary progressive and those with either relapsing-remitting or secondary progressive MS although IL-6 C allele was more frequent in patients with RR-MS. Since IL-6 C allele has been associated with a benign course in Sardinian MS patients, we further analysed an independent sample of 125 Sardinian MS patients revealing that IL-6 C allele was much more frequent than in German MS patients. Taken together, a disease-modifying effect of IL-6 C allele could not be demonstrated in MS patients of German Caucasian descent.
Abstract: In the pathogenesis of multiple sclerosis (MS) genetic factors are known to influence autoreactive T-cell-actions like proliferation and chemotaxis across the blood-brain barrier via chemokine receptors (CCR) and G-protein coupled activating mechanisms. For the first time, we studied the frequencies of a recently described C825T polymorphism in the G-protein encoding gene for the beta3 subunit (GNB3) together with frequencies of a 32-base-pair deletion in the CCR5 gene (delta32 CCR5) in patients with MS (n = 253: relapsing-remitting (RR), n = 124 and chronic progressive course, n = 129). Apart from a trend to a reduced frequency of delta32 CCR5 and increased GNB3 825T polymorphism in primary chronic progressive patients, numbers did not reach statistical significance in any group of MS. These results could not support differences in the genetic background of MS based on that CCR5 mutation or the described GNB3 polymorphism.
Abstract: Neuromyelitis optica (NMO) is a rare syndrome characterized by the combination of acute optic neuritis and transverse myelitis, usually not seen in Multiple Sclerosis (MS) and other demyelinating syndromes of the central nervous system (CNS). A high prevalence of various autoantibodies has been described in patients with NMO suggesting a polyclonal activation of the humoral immune system. We examined autoantibody responses to myelin (MBP, MOG with isotypes and epitopes) and astroglial (S100beta) antigens in four patients with NMO by ELISA and Immunoblot. All patients showed a positive anti-MOG response, with one showing reaction to the MOG epitope corresponding to amino acid sequence 63-87. MBP-autoantibodies were only detected in two and S100beta-autoantibodies in one patient. Despite the limited number of samples, these findings suggest a predominant anti-MOG rather than anti-MBP or anti-S100beta autoantibody response in NMO, though no NMO-specific antibody pattern was found, which is in keeping with a widespread acute immune activation, including a strong B-cell response.
Abstract: Antibodies directed against the extracellular immunoglobulin (Ig)-like domain of the myelin oligodendrocyte glycoprotein (MOG(Igd)) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) and are implicated in the immunopathogenesis of multiple sclerosis (MS). In this study we investigated the epitope specificity of MOG(Igd)-specific autoantibodies immunopurified from MS patients (n=17) and normal healthy controls (HD; n=9). ELISA, using a panel of synthetic MOG(Igd) peptides, revealed that the epitope specificity of this response was heterogeneous in both groups. The most frequently recognised epitopes were located in amino acid sequences (a.a.) 1-26 (13/17) and 63-87 (15/17) in MS patients, and 14-39 (6/9) and 63-87 (6/9) in HDs, but there was no association between MS and any particular peptide specificity. We therefore investigated the ability of the immunopurified antibodies to recognise native MOG(Igd) expressed on at the membrane surface by FACS. Unexpectedly, antibodies fulfilling this essential criterion for a demyelinating antibody response were detected only in one of the MS samples. These results indicate that the epitope specificity of the human B cell response to MOG is not only heterogeneous, but may only mediate demyelination in a limited subset of MS patients.
Abstract: We analyzed the sera of 51 patients with various phenotypes of X-linked adrenoleukodystrophy (X-ALD), 20 patients with multiple sclerosis (MS) and 22 healthy volunteers for the presence of autoantibodies specific for the recombinant extracellular immunoglobulin-like domain of human myelin oligodendrocyte glycoprotein (rhMOG(Igd)) and myelin basic protein (MBP). Anti-rhMOG(Igd) autoantibodies were significantly more frequent in X-ALD and MS patients as opposed to healthy individuals (p<0.05). Anti-MBP autoantibodies were present in about one-fourth of X-ALD and MS patients but in less than 10% of healthy individuals. Anti-rhMOG(Igd) autoantibody responses were not accompanied by increased T cell reactivity against rhMOG(Igd). These findings may have important implications for the understanding of humoral anti-myelin immunoreactivity in demyelinating diseases of the central nervous system such as X-ALD and MS.
Abstract: Myelin-oligodendrocyte glycoprotein (MOG) specific antibodies (abs) are involved in autoantibody-mediated demyelination possibly contributing to lesion development in multiple sclerosis (MS). Interleukin-6 (IL-6) has been reported to play a crucial role for the pathogenesis of a MOG-induced animal model of MS. To investigate the link between anti-MOG abs production and IL-6 up-regulation in MS we determined the presence of anti-MOG abs and measured concentrations of IL-6 and its soluble receptors (sIL-6RC) in paired serum and cerebrospinal fluid (CSF) samples of MS patients and serum samples of age-matched healthy controls (HC). Anti-MOG abs were detected in 75% of MS sera, 57% of MS CSF samples and 20% of HC sera. There was no difference in IL-6 and sIL-6RC levels between anti-MOG abs positive and negative samples. Thus, no association between the presence of anti-MOG abs and serum/CSF levels of IL-6/sIL-6RC was found.
Abstract: Neuromyelitis optica (NMO, or Devic's syndrome) is a rare syndrome characterized by the combination of acute or subacute optic neuritis and transverse myelitis. This strict confinement of lesions together with immunologic parameters such as frequent absence of oligoclonal banding despite increased signs of CSF inflammation suggest that NMO is distinct from multiple sclerosis (MS). Magnetic resonance imaging (MRI) data support NMO and MS as separate entities due to lesion distribution and signal characteristics. This is further supported by epidemiological and genetic evidence associating HLA-DRB1*1501 with disseminated "western" MS in contrast to NMO associated with DRB1*802, DPB1 501, and DPA1 202, the "Asian" type. Most findings suggest a heterogeneous pathogenesis of NMO and, in spite of the distinct localization, rather unspecific immune reactions seem to be involved. As to the frequent relapses of NMO, therapeutic options besides prednisolone are difficult to assess and favor long-term immune suppression or modulation.
Abstract: We report a comparative study of the B- and T-cell responses to the extracellular immunoglobulin (Ig)-like domain of human myelin-oligodendrocyte glycoprotein (MOG(Igd)) in the blood of patients with multiple sclerosis and healthy controls using a bacterial recombinant human protein (rhMOG(Igd)). The frequency of anti-rhMOG(Igd)-seropositive samples, as determined by Western blotting, was significantly higher in the multiple sclerosis group (54%) than in normal random controls (excluding laboratory workers exposed to MOG) (22%; P = 0.02). In contrast, there was no difference in rhMOG(Igd)-induced proliferation indices of peripheral blood T cells between patients and controls. To characterize the rhMOG(Igd)-reactive T-cell repertoire, we isolated a panel of MOG-specific CD4(+) T-cell lines from multiple sclerosis patients and normal subjects, and these revealed a heterogeneous response with respect to epitope specificity, cytokine response, MHC (major histocompatibility complex) restriction and T-cell receptor Vbeta-chain usage. The majority of the T-cell lines recognized epitopes in the N-terminal region of MOG (amino acids 1-60). One epitope (represented by peptide 27-50) was exclusively recognized by T-cell lines from normal controls. Forty per cent of the MOG-specific T-cell lines analysed displayed a Th-2 or Th-0 cytokine profile and could therefore act as helper T cells in vivo.
Abstract: Multiple sclerosis (MS) is the most frequent demyelinating disorder of the central nervous system (CNS). However, at presentation, it is frequently difficult to differentiate between malignant MS (MMS) and other fulminant CNS demyelinating diseases like acute disseminated encephalomyelitis (ADEM). The literature contains many case reports of ADEM but few series. We report on four representative cases of acute demyelinating diseases, together with evaluation of treatment, course and follow-up. We also present clinical, laboratory, neuropathologic, neuroimaging and data on therapeutic options, including follow-up, in order to establish distinguishing characteristics of MMS and ADEM. Good clinical outcome from a postinfectious, monophasic episode, correlating with regressive demyelinating lesions on MRI, after more than 2 years differentiate best. Therapeutic efficacy, prior infection and initial MRI lesions seem to be of limited value. Despite the advances of neuroimaging and laboratory techniques, objective parameters are still missing, but findings on basic immunologic mechanisms of humoral and cellular response might provide further insight. Copyright 1999 Harcourt Publishers Ltd.
Abstract: PURPOSE: Retinal artery occlusion (RAO) is caused by arterio-arterial or cardiovascular emboli in about 50% of all cases, but the role of non-embolic causes remains unclear. SUBJECTS AND METHODS: We studied 27 patients with amaurosis fugax (AFX), branch retinal artery occlusion (BRAO), central retinal artery occlusion (CRAO) and anterior ischaemic optic neuropathy (AION). Patients underwent an evaluation of cerebrovascular and cardiovascular risk factors, measurement of haemorheological parameters, and Doppler/duplex sonography including ultrasound detection of cerebral microembolic signals and echocardiography. RESULTS: Forty-one per cent of the patients had internal carotid atherosclerosis but only one patient had microembolic signals, probably due to a cardiac thrombus. Vascular risk factors, especially hypertension, were present in 82% of the patients correlating with abnormal haemorheological parameters such as increased thrombocyte reactivity. CONCLUSIONS: Our results indicate that altered haemorheological parameters, especially increased thrombocyte reactivity and vascular risk factors such as arterial hypertension, are non-embolic causes of vascular disease in a significant number of patients with RAO. This should guide diagnostic and therapeutic considerations concerning RAO in cases without proven embolic sources.
Abstract: Electroconvulsive therapy (ECT) is an appropriate clinical model to investigate blood flow during seizures. In this study cerebral blood flow velocity (CBFV) was measured during 40 ECTs in 10 patients by means of transcranial Doppler sonography. EEG was recorded continuously. Under general anesthesia, the pre-convulsive blood flow velocity (Vmean) decreased significantly. After ECT, we measured a dramatic increase in Vmean which was significantly greater in the left MCA than in the right MCA. After termination of seizures, flow velocities returned to baseline levels. The striking increase in cerebral blood flow velocity reflects excessive cerebral metabolism during convulsive neuronal activation. The left hemisphere seems to be more sensitive to electrical stimuli as was indicated by its predominant augmentation of CBFVs.
Abstract: Supraventricular and ventricular tachyarrhythmia are established causes of syncope. We investigated the mean blood flow velocities (Vmean) of the middle cerebral arteries (MCA) during routine cardiac electrophysiologic studies in patients with supraventricular and ventricular tachyarrhythmias in order to evaluate the changes in cerebral hemodynamics associated with pre-syncopal and syncopal states. Thirty-two patients with a history of supraventricular (n = 14) or ventricular (n = 18) tachyarrhythmias were investigated in the nonsedated, post-absorptive state in supine position. Vmean was assessed in both MCAs by means of transcranial Doppler under resting conditions, during atrial and ventricular pacing at constant rates (n = 28) and during induction of tachyarrhythmia (n = 4). Mean arterial blood pressure (MABP) and heart rate were also recorded. Seven patients suffered pre-syncope at a heart rate of 187 +/- 45 bpm (mean +/- SD) with an average drop of 44% in the Vmean MCA, and statistically insignificant changes in MABP. Five patients suffered syncope during tachyarrhythmia (mean heart rate 283 +/- 42 bpm) with a reduction of 69% in the Vmean MCA. MABP could be assessed in two of those patients and showed a drop of 15 and 43 mmHg, respectively. During tachyarrhythmia pre-syncope and syncope are associated with an average reduction in Vmean MCA by 44% and 69%, respectively. The decrease in MCA blood flow velocity is a more important predictive factor for the development of pre-syncope and syncope than the MABP.
Abstract: BACKGROUND: A vascular component in ergotamine-induced headache has been proposed. No study has been carried out to evaluate cerebral hemodynamic changes by means of transcranial Doppler during withdrawal from migraine medication; in particular, ergotamine-containing drugs. METHOD: We examined 21 patients suffering from drug-induced headache during their in-hospital withdrawal from ergotamine (n=8) and compared them with patients during withdrawal from analgesics (n=13) and with healthy controls (n=14). Cerebral blood flow velocities were measured with transcranial Doppler, and pulsatility indices were calculated. Blood pressure, heart rate, and end-tidal carbon dioxide were documented. A subjective analog headache rating scaling was used for day-to-day evaluation of headache severity. RESULTS: Mean cerebral blood flow velocities dropped significantly after discontinuation of ergotamine-containing drugs but not after stopping common analgesics. Pulsatility indices remained unchanged. Cerebral blood flow velocities were higher in drug-ingesting patients compared to the control group and showed significant changes in patients with headache using ergotamine and in those using analgesics. Carbon dioxide, heart rate, and blood pressure remained unchanged. The headache rating scale did not show a constant trend. COMMENTS: Our results indicate that ergotamine and, to a lesser extent, common analgesics including caffeine might influence cerebral blood flow velocities and pulsatility indices causing transient and reversible disturbance of cerebral autoregulation.
