Clinical Neuroscience

[Immunomodulatory treatment in multiple sclerosis ]


DECEMBER 10, 2004

Clinical Neuroscience - 2004;57(11-12)

[During the past decade, several disease-modifying agents have been established and have become available for the treatment of multiple sclerosis. The disease-modifying agents could be grouped into immunomodulatory and immunosuppressive therapies altering the long-term course of multiple sclerosis. Therapy is now available for relapsing-remitting, secondary progressive and progressive-relapsing multiple sclerosis. Different disease-modifying agents became also available for the treatment of relapsing-remitting multiple sclerosis in Hungary which makes the therapeutic decision difficult. This overview might help to give an answer for different questions in the management of multiple sclerosis: Which agent to choose? When to initiate the therapy? Which dose to apply? Are the drugs safe? How long to treat the patients with immunomodulatory drugs? We give a review from the literature to assess the efficacy of disease-modifying therapies and to compare the data from phase three trials of interferon β1b, two preparations of interferon β1a or glatiramer acetate for the treatment of multiple sclerosis. We analyzed the efficacy and safety of these agents on physical, inflammatory and cognitive measures of disease activity. Comparison of study results indicated similar effects of immunomodulatory agents on relapse-related and inflammatory measures in relapsing multiple sclerosis. Interferon β1a slowed the progression of disability in relapsing multiple sclerosis. One interferon β1a preparation (intramuscularly injected) demonstrated efficacy in slowing progression of cognitive dysfunction. The interferons reduced relapses at early phase of secondary progressive multiple sclerosis, but their efficacy have not yet been proven in the later phase of secondary progressive multiple sclerosis without relapses. Mitoxantrone demonstrated efficacy in slowing the progression of disability in secondary progressive multiple sclerosis. All of the disease modifying agents are safe and tolerable, if the indication is correct and the patients are strictly controlled.]



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Clinical Neuroscience

[Early onset dementias: Case studies]

MERKLI Hajnalka, PÁL Endre, GÁTI István, KOSZTOLÁNYI Péter, KÖVÉR Ferenc

[Introduction - Dementia is a decline of intellectual abilities. The etiology of dementia syndrome is diverse. The authors describe three patients with early-onset dementia. Case reports - The first patient was a 44 years old male with mild gait, body ataxia, memory loss, slowness and apathy. Investigations proved AIDS dementia syndrome. In the second case of a 37 years old female patient, herpes simplex encephalitis was suspected due to sudden onset of speech arrest and to brain MRI and CSF findings. Her symptoms improved during antiviral treatment but later progressive dementia developed. CSF serological tests proved the presence of neurolues-dementia paralytica. The third patient was a 38-years-old female. Neurological examination was performed because of progressive memory loss, changed behaviour and impaired attention. Neuropsychological test showed severe dementia. Metachromatic leukodystrophy was proven by decreased arylsulfatase activity. Conclusions - It is not easy to recognize the early symptoms of dementia. In these cases, besides detailed history, neurological examination and neuropsychological tests, brain MRI and cerebral spinal fluid serological tests were indispensable for a correct diagnosis, especially in the young patients.]

Clinical Neuroscience

[Dizziness - vertigo Warning symptoms in vertebrobasilar ischemia - Part I. ]


[Dizziness and vertigo - like headache - are the most common complaints which leads patients to visit the doctor. In spite of the headache - which may be primary (e.g. migraine) or symptomatic - dizziness and vertigo do not appear to be a separate nosologic entity but rather the symptoms of several neurological disorders. For differential diagnosis, interdisciplinary thinking and activity is needed because the vestibular, neurological and psychiatric disorders might have a common role in the development of symptoms and further overlapping can also occur. The vascular disorders of the vertebrobasilar system are discussed in detail in this review. The importance, occurrence and causes of vertigo as a warning symptom is in the focus. The author draws attention to life-threatening conditions with acute onset in cases of the posterior scale ischemia and emphasizes the importance of the correct and early diagnosis. The author tries to clear up the nihilistic aspect in treating of stroke and stresses the necessity of thrombolysis and interventional radiological procedures which may be the only chance for the recovery of the patients. The pharmacological prevention of recurrent vascular events is also important and obligatory for the clinicians.]

Clinical Neuroscience

[New chapter in visual evoked potential studies - Clinical application of the multifocal vep method ]

JANÁKY Márta, PÁLFFY Andrea, BENEDEK Krisztina, BENEDEK György

[The multifocal visual evoked potentials are the evoked responses over the visual cortex in response to the stimulation of circumscribed small areas in the central 30 degree region of the retina. The recording of multifocal visual evoked potentials was made possible by the computer algorhythm elaborated by Sutter in 1991. Multifocal electroretinograpy, developed upon the same theoretical principles, is already an routine clinical examination method for the topographic analysis of functional damages in the central part of the retina and for the differential diagnostics in neuro-ophthalmology. The multifocal visual evoked potential, however, has not been introduced into the clinical practice, although it displays the function of ganglion cells in a given region of the retina in a more detailed way than the sensitivity threshold in the perimetry. This examination makes the objective verification of defects possible in the visual pathway, too. In our department the recording of multifocal visual evoked potentials was started in 2002. In this paper we present the basics of this method and also deal with the problems concerning its application and its status in the history of visual evoked potentials.]

Clinical Neuroscience

[Temozolomide chemotherapy of patients with recurrent anaplastic astrocytomas and glioblastomas]


[Introduction - Anaplastic astrocytomas and glioblastomas are the most frequent and most malignant hemispherial tumours. Unfortunately, astrocytic tumours are of infiltrative character and radical removal is not possible. Recurrent malignant gliomas are rarely suitable for reoperation. In most of the cases of recurrent gliomas chemotherapy is the last choice. Patients and method - Seventy-five consecutive patients with recurrent malignant astrocytomas and glioblastomas had been treated at our institute with per os temozolomide for five days every month. The patients received two to 16 courses of chemotherapy. The toxicity, quality of life, response to chemotherapy and survival data were analysed. Results - Out of 75 patients four were excluded following the first treatment due to myelotoxicity, and allergic reactions. Among the patients treated with temozolomide in seven cases complete response, 17 partial response, 14 progressive disease were observed. In 33 cases the disease stabilized and out of them in 27% a significant neurological improvement was detected. The time to progression was 6.8 months and the median survival time 8.75 months for patients with glioblastoma and with malignant astrocytoma or malignant mixed oligoastrocytoma 9.45 and 11.15 months, respectively. The overall survival for patients with originally lower grade glioma was 70.32 and for patients with glioblastoma multiforme 17.43 months. Conclusions - Temozolomide chemotherapy in patients with recurrent malignant astrocytoma and glioblastoma proved to be efficacious and similar good results were achieved as with a nitrosourea based combined chemotherapy. Even in those patients who received previous chemotherapy temozolomide is well tolerated and a relatively long time to progression was achieved in cases of recurrent malignant gliomas. In a few number of patients where BCNU had been previously failed with temozolomide stable disease was achieved. Temozolomide seems to be a promising drug in the chemotherapy of malignant gliomas and can be applied as a second line chemotherapy, as well.]

Clinical Neuroscience

[The impact of neuroleptic medication on seizure threshold and duration in electroconvulsive therapy]

GAZDAG Gábor, BARNA István, IVÁNYI Zsolt, TOLNA Judit

[Introduction - In most patients diagnosed with psychotic depression or schizophrenia and treated with electroconvulsive therapy, parallelly administered antipsychotic medication cannot be stopped. Antipsychotic drugs can influence both seizure threshold and seizure activity in different ways. Patients and method - The present study processes the data of 77 patients treated parallelly with electroconvulsive therapy and antipsychotic drugs. Oral doses of the antipsychotic medication administered the day before the electroconvulsive therapy, stimulus intensity, seizure durations, and impedance were analysed from session to session. Results - One group of antipsychotics (haloperidol, fluphenazine, risperidone, sulpirid) was not found to influence seizure activity: there was no significant difference in EEG and EMG registered seizure duration or in stimulus intensity between the treated and non-treated group. However, significant difference was found between the next treated and non-treated groups in 40% of the sessions in case of olanzapine, in 50% of the sessions in case of clozapine and in 57% of the sessions in case of zuclopenthixol in EEG or EMG registered seizure duration as well as in stimulus intensity. In the third group (quetiapine) there was a significant difference in each session (2nd session: EMG, p=0.02; 5th session: EEG, p=0.05, EMG, p=0.04). Most of the antipsychotics (olanzapine, clozapine, zuclopenthixol) have been shown to possess epileptogenic properties; only quetiapine reduces seizure activity. Conclusion - In the clinical use of olanzapine, clozapine and zuclopenthixol seems epileptogenic, whereas in the case of quetiapine seizure reducing properties must be taken into account. Together with the consideration of the accompanying somatic and neurologic disturbances and with the concomitant medications this can influence the treatment of choice.]

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Clinical Neuroscience

[Family planning in multiple sclerosis: conception, pregnancy, breastfeeding]

RÓZSA Csilla

[Family planning is an exceptionally important question in multiple sclerosis, as women of childbearing age are the ones most often affected. Although it is proven that pregnancy does not worsen the long-term prognosis of relapsing-remitting multiple sclerosis, many patients are still doubtful about having children. This question is further complicated by the fact that patients – and often even doctors – are not sufficiently informed about how the ever-increasing number of available disease-modifying treatments affect pregnancies. Breastfeeding is an even less clear topic. Patients usually look to their neurologists first for answers concerning these matters. It falls to the neurologist to rationally evaluate the risks and benefits of contraception, pregnancy, assisted reproduction, childbirth, breastfeeding and disease modifying treatments, to inform patients about these, and then together come to a decision about the best possible therapeutic approach, taking the patients’ individual family plans into consideration. Here we present a review of relevant literature adhering to international guidelines on the topics of conception, pregnancy and breastfeeding, with a special focus on the applicability of approved disease modifying treatments during pregnancy and breastfeeding. The goal of this article is to provide clinicians involved in the care of MS patients with up-to-date information that they can utilize in their day-to-day clinical practice. ]

Clinical Neuroscience

[Teriflunomide: new oral immunmodulant drug in therapy of multiple sclerosis]

BENCSIK Krisztina, RÓZSA Csilla, VÉCSEI László

[Multiple sclerosis (MS) is the autoimmune, demyelinating, neurodegenerative disorder of the central nervous system (CNS). There are nine drugs available in Hungary reimbursed by the National Health Insurance Fund of Hungary (OEP) to reduce the activity of the disease, from which seven can be used as first line therapies. We have approximately 20 years of experience with the interferon b-1a/1b and glatiramer-acetate products. Though in case of approximately 30% of the patients using one of the first line drugs, the disease remains active, that we call break-through disease. The reasons for break-through disease could be the insufficient adherence and compliance, the appearance of neutralizing antibodies or the high activity of the disease. One of the oral immunomodulating drugs for MS, teriflunomide, was registered in Europe in 2013. Because of the anti-proliferative and anti-inflammatory effect of teriflunomide, it can be used for the reduction of the disease activity in the relapsing-remitting course of MS. The effect of teriflunomide was proved in one Phase II. and four Phase III. (TEMSO, TOWER, TENERE, TOPIC) studies. Teriflunomide 14 mg once daily was able to demonstrate in two consecutive placebo-controlled phase 3 clinical trials that significantly reduces the relapse rate (31.5% and 36.3%) and in both studies significantly reduces the sustained disability progression (29.8% and 31.5%) moreover delays the appearance of the clinically definitive MS in patients with clinically isolated syndrome (CIS). According to the TENERE study there were no significant differences observed between teriflunomide 14 mg and IFNb-1a s.c. in time to failure and annualized relapse rate but the treatment satisfaction domains of global satisfaction, side-effects and convenience were significantly improved with teriflunomide compared with s.c. IFNb-1a. ]

Clinical Neuroscience

[Health status and costs of ambulatory patients with multiple sclerosis in Hungary]

PÉNTEK Márta, GULÁCSI László, RÓZSA Csilla, SIMÓ Magdolna, ILJICSOV Anna, KOMOLY Sámuel, BRODSZKY Valentin

[Background and purpose - Data on disease burden of multiple sclerosis from Eastern-Central Europe are very limited. Our aim was to explore the quality of life, resource utilisation and costs of ambulating patients with multiple sclerosis in Hungary. Methods - Cross-sectional questionnaire survey was performed in two outpatient neurology centres in 2009. Clinical history, health care utilisation in the past 12 months were surveyed, the Expanded Disability Status Scale and the EQ-5D questionnaires were applied. Cost calculation was conducted from the societal perspective. Results - Sixty-eight patients (female 70.6%) aged 38.0 (SD 9.1) with disease duration of 7.8 (SD 6.7) years were involved. Fifty-five (80.9%) had relapsing-remitting form and 52 (76.5%) were taking immunomodulatory drug. The average scores were: Expanded Disability Status Scale 1.9 (SD 1.7), EQ-5D 0.67 (SD 0.28). Mean total cost amounted to 10 902 Euros/patient/year (direct medical 67%, direct nonmedical 13%, indirect costs 20%). Drugs, disability pension and informal care were the highest cost items. Costs of mild (Expanded Disability Status Scale 0-3.5) and moderate (Expanded Disability Status Scale 4.0-6.5) disease were 9 218 and 17 634 Euros/patient/year respectively (p<0.01), that is lower than results from Western European countries. Conclusion - Our study provides current inputs for policy making and contributes to understanding variation of costof- illness of multiple sclerosis in Europe.]

Clinical Neuroscience

[Fingolimod therapy in multiple sclerosis - the issue of the pathomechanism]

TAR Lilla, VÉCSEI László

[Multiple sclerosis is an autoimmune inflammatory disease of the central nervous system with neurodegenerative chararacteristics. The newly discovered per os administrable drug fingolimod (FTY720) has a different mechanism of action than the current disease-modifying therapies. In vivo the drug binds to four out of the five sphingosine-1-phosphate receptors after phosphorylation. Fingolimod-phosphate (FTY720-P) causes internalization and degradation of the sphingosine-1-phosphate receptors in the membrane of lymphocytes thus in contrast to sphingosine-1-phosphate it acts like a functional antagonist. In experimental autoimmune encephalomyelitis - an animal model of multiple sclerosis - fingolimod blocks the sphingosine-1-phosphate gradient controlled lymphocyte egress from the lymph nodes and therefore reduces the peripheral lymphocyte count especially the encephalitogenic Th17 subset is reduced. Modulation of the sinus lining and blood-brainbarrier constructing endothelial cells also contributes to the complex mechanism of action. Additionally due to its liphohilic nature fingolimod is able to penetrate the blood brain barrier thus, beside its peripheral effects the drug can probably modulate the cells of the central nervous system directly. Presumably it can reduce neurodegeneration caused by astrogliosis through modification of astrocyte and oligodendrocyte activity. The results of current clinical studies are holding out with bright prospective in the aspect of either the favourable effects or the well tolerated side effects.]

Clinical Neuroscience

[Serum IgG and IgM ganglioside GM1 antibodies in patients with multiple sclerosis]

ZAPRIANOVA Emilia, MAJTÉNYI Katalin, DENISLAVA Deleva, OLIA Mikova, ANDON Filchev, BORISLAV Sultanov, VERA Kolyovska, SULTANOV Emil, LILIA Christova, XENIA Kmetska, DIMITAR Georgiev

[INTRODUCTION - In order to obtain more information concerning the pathogenic significance of ganglioside GM1 in multiple sclerosis serum polyclonal IgG and IgM antibodies to GM1 were evaluated in multiple sclerosis patients with relapsing-remitting and secondary progressive forms of the disease. PATIENTS AND METHODS - The evaluated sera were from 55 patients with clinically definite multiple sclerosis and from 20 healthy subjects. Forty-two of patients were with relap-sing-remitting and 13 with secondary progressive multiple sclerosis. Antibodies to GM1 were measured using a modification of the enzyme-linked immunosorbent assay technique of Mizutamari et al (1994). RESULTS - A statistically significant difference of serum IgG antibody titres to GM1 was found between the healthy subjects and the multiple sclerosis patients with relapsing-remitting form of the disease (p=0.04), as well as of serum IgG antibody titres to GM1 between the patients with relapsing-remitting multiple sclerosis in relapse and in remission (p=0.01). CONCLUSION - Bearing in mind the heterogeneity of multiple sclerosis, the pathogenic significance of serum antibo-dies to GM1 should be interpreted concerning the precise clinical form of the disease and not the whole group of MS patients. The findings in this study argue for the possible involvement of ganglioside GM1 in the pathogenesis of demyelination in relapsingremitting multiple sclerosis.]