Clinical Neuroscience

[Immunomodulatory treatment in multiple sclerosis ]

CSÉPÁNY Tünde, BERECZKI Dániel

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

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

FAZEKAS András

[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

[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.]

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

[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

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

SIPOS László, VITANOVICS Dusan, ÁFRA Dénes

[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.]

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Matrix metalloproteinases and their tissue inhibitors in relapsing remitting multiple sclerosis: Possible markers and treatment agents

SANLI Arzu, OZTURK Musa, SOYSAL Aysun, DOVENTAS Yasemin, BASOGLU Fulya, GOZUBATIK-CELIK R. Gokcen, BAYBAS Sevim

Matrix metalloproteinases (MMPs), which are synthesized by many cell groups and responsible for the destruction of matrix proteins, and endogen tissue inhibitors of MMPs (TIMPs) have a role in the pathogenesis of Multiple Sclerosis (MS) by affecting the blood-brain barrier. We aimed to investigate the role of MMPs and TIMPs in the immunopathogenesis and in the course of multiple sclerosis (MS). We enrolled 25 relapsing remitting MS patients, who had a definite MS diagnosis according to McDonald criteria and 25 healthy subjects similar for age and gender as control group. MMP-9- and TIMP-1 levels were measured twice in patient group (one time during an attack and one in remission) and once in healthy subjects. MMP-9- and TIMP-levels of patients during attack and remission period and MMP-9/TIMP-1 ratio were found significantly higher than in the control subjects. In patient group MMP-9 and TIMP-1 levels and MMP-9/TIMP-1 ratio during attacks were not significantly different than during remission period. However, when subdivided according to their number of attacks, patients with 2 attacks had significantly higher levels during attack period comparing to remission period (p<0.05); in case of patients with more than 2 attacks did not have a statistically significant difference in attack and remission periods. Matrix metalloproteinases are important actors in MS immunopathogenesis, particularly in the early period and inhibitor agents for these enzymes can be used as a treatment option.

Clinical Neuroscience

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

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[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

[Controversies in neurology: Diagnosis, follow up and therapy of multiple sclerosis with pathomechanismal approach]

VÉCSEI László

[The clinical boundaries between the relapsing and progressive course of multiple sclerosis are often indistinct. Despite the variable patterns of evolution, there are no biological reasons for discerning different multiple sclerosis phenotypes. Indeed, both primary progressive and secondary forms of the disease share similar pathological features in respect of the extent of inflammatory infiltrates, axonal damage, and cortical demyelination. The data indicating that primary progressive multiple sclerosis is preceded by an asymptomatic relapsing remitting phase. The proposed definition of secondary progressive multiple slcerosis, the attainment of at least EDSS of 4 is required to mark the transition to the progressive phase. Therefore, the clinical progress can be uncovered in the early phase of the disease. Furthermore, a continuous progression independent of relapsing activity is commonly observed during the relapsing remitting phase. A continuous smouldering process underpins the subtle clinical deterioration, which stands out as an important unmet treatment target. Concerning cognitive dysfunction of the patients pro-inflammatory cytokines have been associated with worse cognition in active multiple sclerosis, and this inflammatory milieu could also contribute to altered mentation during relapses. Therefore, long before people with multiple sclerosis become physically disabled, they have usually acquired hidden disabilities related to cognitive impairment. Silent progression appears during the relapsing remitting phase and it associates with brain atrophy. This suggests that the same process that underlies secondary progressive multiple sclerosis likely begins far earlier than is generally recognized. This supports a unitary view of multiple sclerosis biology. ]

Clinical Neuroscience

[Current questions of multiple sclerosis: the secunder progressive form of the disease]

VÉCSEI László

[Recent data suggest that long-term worsening is common in relapsing-remitting multiple sclerosis patients and is largely independent of relapses or new lesion formation on brain MRI. The current definition of secunder progressive multiple sclerosis is worsening of disability independent of relapses over at least 6-month interval. Early focal inflammatory disease activity and spinal cord lesion are predictors of very-long term disease outcomes in relapse - onset multiple sclerosis. The potential of PET imaging to visualize hidden inflammation in MS brain in vivo is an important contribution for better understanding the progression of the disease. Therefore, PET imaging is a promising tool in detecting the conversion from relapsing remitting multiple sclerosis to secunder progressive form of multiple sclerosis. Furthermore, neuro-axonal damage is the pathological substrate of permanent disability in different neurological disorders including multiple sclerosis. The neurofilament proteins have promise in this context because their levels rise upon neuro-axonal damage not only in the cerebrospinal fluid but also in blood. Patients with increased serum levels of neurofilament at baseline, independent of other clinical and MRI variables, experience significantly more brain and spinal cord volume loss over 2 years and 5 years of follow-up. The kynurenine-pathway abnormalities may be associated with the swich from early-mild stage multiple sclerosis to debilitating progressive forms of the disease. Analysis of these metabolites in serum may have application as multiple sclerosis disease biomarkers. Free radical action has been suggested as a causal factor in the illness. Increased free radical production and consumption of the scavenger molecules were found during the active phase of the disease. Based on the clinical findings (EXPAND Study) and pathomechanism of the disease siponimod is approved by the US Food and Drug Administration for the treatment of relapsing remitting forms of multiple sclerosis, to include secunder progressive multiple sclerosis with active disease, relapsing-remitting multiple sclerosis and clinically isolated syndrome.]

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.]