Clinical Neuroscience

[Selective ultrastructural vulnerability in the cuprizone-induced experimental demyelination]

ÁCS Péter, KOMOLY Sámuel

JULY 30, 2012

Clinical Neuroscience - 2012;65(07-08)

[Background and purpose - It has been reported that multiple sclerosis has four different neuropathological subtypes, and two of them (type III and IV) are characterized by primary oligodendrocyte loss. However, the exact pathomechanism that lead to oligodendrocyte apoptosis in human demyelinating diseases is still elusive. The copper chelator cuprizone induces primary oligodendrocyte apoptosis and consequent demyelination in well defined areas of the mouse brain. Nevertheless, the precise subcellular events that result in oligodendrocyte cell death in the cuprizone model are still unknown. We aimed to study the ultrastructural alterations that might induce oligodendrocyte apoptosis in the cuprizone experimental demyelination model. Methods - C57BL/6 mice were given cuprizone for two, 21 and 35 days to induce demyelination to investigate early pathological events, and different stages of demyelination. In addition, mice were given cuprizone for 35 days and were allowed to recover for two or 14 days to study early and late remyelination. After the cuprizone treatment, mice were sacrificed and the corpus callosum, the superior cerebellar peduncle, the optic nerve and the sciatic nerve were studied by electron microscopy. Results - The ultrastructural analysis revealed that cuprizone induced oligodendrocyte apoptosis is accompanied by the formation of giant mitochondria in the affected cells in the corpus callosum and in the superior cerebellar peduncle. Apoptosis of the myelin producing cells was present through the whole cuprizone challenge. Severe demyelination occurred after three weeks of cuprizone administration associated with massive macrophage infiltration and astrocytosis of the demyelinated areas. Axons and neurons remained unaffected. Conclusion - The formation of giant mitochondria in myelin producing oligodendrocytes is the first pathological sign in the cuprizone experimental demyelination. Mitochondrium pathology in the cuprizone challenge might serve as a useful model to study the pathomechanism of multiple sclerosis subtypes (III and IV) characterized by primary oligodendrocyte degeneration.]



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Clinical Neuroscience

[Editorial message]

TAJTI János, RAJNA Péter

Clinical Neuroscience



[Neurophobia is the fear of neurological diseases. Its main symptom is that medical students and young doctors are not able to utilize their basic neurological knowledge at the bedside. According to statistics, every second student suffers from neurophobia. This attitude could explain why in the last two decades less and less young doctors wanted to become neurologist. Medical students complain that they receive no instructions, and are afraid of loosing their interest and of facing the failure of their competency. The hardship of neurology was explained by the insufficient knowledge of anatomy and the infrequent encounter with patients. Even general practitioners have anxiety about neurological patients. The loss of interest in neurosciences seems to associate with insensitivity of human-centered culture and corruption of empathic thinking. The burnout syndrome of medical doctors and students can be explained by stress, loss of respect, permanent competition, independency that interferes with responsibility, stiff hierarchy of medical society, fear of diagnostic failures and of economical difficulties. The scores of depression in female students were higher than in male. The idea of the “good neurologist” has been changed. The business oriented care, the shortage of time, and the financial restrictions corroded the conventional practice and ceased the vocational idealism. At present, personal teaching is going to transform into impersonal multimedia learning. Because of the drastic change of values, the age of inner-oriented professionals has terminated also in the medicine. Medical doctors follow even less the traditional troll of professional behavior, but according the social demands, they choose their specialization for subsistence. The highly esteemed social status of neurologists and psychiatrists is going to sink in Europe. To reduce neurophobia it would be desirable 1. to introduce neurology training in the early years of medical school; 2. to teach neurology in all semesters, 3. to assure the effective teaching of neuro-anatomy and physiology, 4. to organize more one-to-one teacher-student communication. In the United States, residents participate in teaching during their residency training. To master neurology dedicated teachers are necessary whom neurology residents ought to meet personally with optimal frequency. However, these requirements seem to fail because of the chiefly technical characters of the actual reforms.]

Clinical Neuroscience

[Diagnosis and therapy of mitochondrial diseases]

PÁL Endre

[Mitochondrial diseases are a significant part of neuromuscular diseases. Majority of them is multisystemic disorder. The diagnosis can be established in more and more cases. Beyond the routine neurological examination imaging methods (MRI and MR-spectroscopy) and electrophysiology (EMG, ENG, EEG, evoked potential tests) might be helpful in setting the diagnosis. Raised blood lactate level supports the diagnosis. Muscle biopsy demonstrates mitochondrial abnormalities in the majority of cases. The positivity of genetic tests is low, because the amount of mitochondrial DNA alterations is different in tissues. Therefore other tissue than blood (mainly muscle) is necessary for genetic tests. The other reason is that the respiratory chain is under double -mitochondrial and nuclear - genetic control, and testing the nuclear genes are available only in selected laboratories. The treatment is limited, mainly symptomatic.]

Clinical Neuroscience

[The absence of the common LRRK2 G2019S mutation in 120 young onset Hungarian Parkinon’s disease patients]

BALICZA Péter, BEREZNAI Benjámin, TAKÁTS Annamária, KLIVÉNYI Péter, DIBÓ György, HIDASI Eszter, BALOGH István, MOLNÁR Mária Judit

[Parkinson’s disease is a promising target of applying personalized medicine. For this purpose it is crucial to reveal the genetic and environmental factors, which contribute to the disease, also to collect epidemiologic data and to preserve the patients samples and data in a proper biobank. In our investigation we examined the prevalence of the most frequent Parkinson’s disease causing LRRK2 G2019S mutation in a Hungarian Parkinson-patient group. From 120 patients, we haven’t detected this substitution in anyone. Our investigation suggest that the mutation LRRK2 G2019S may be a rare cause of Parkinson disease in the Hungarian population.]

Clinical Neuroscience

[Results of intrathecal baclofen therapy on spasticity in patients with brain injury]

DÉNES Zoltán, KLAUBER András, BOTH Béla, ERÕSS Loránd

[Objectives - To evaluate the results of intrathecal baclofen (ITB) therapy on the spasticity in patients with brain injury. Method - Retrospective study in Brain Injury Rehabilitation Unit between January 2001 and December 2010. Results - During the last ten years, in our unit 13 patients were involved into ITB therapy on severe spasticity, after brain injury, while more than 100 Baclofen pumps were implantated in Hungary with Hungary with coordination of the Multidisciplinary Team. ITB therapy was indicated in severe spasticity developed after seven cases of traumatic brain injuries, five cases of strokes and one case of anoxic brain injury. The mean age of patients was 26 years (18- 52). At the time of pump implantation three patients were in vegetative state. The shortest period elapsed between the brain injury and pump implantation was three months and the longest period was nine years, mean 15 months. Baclofen pump had to be changed in six cases after six years, and was removed in three cases due to decreasing spasticity. Catheter revision was performed in two cases due to flow problem. We had no complication in association with ITB therapy. Conclusions - Intrathecal baclofen therapy seems to be an effective and safe treatment in patients with severe spasticity of cerebral origin. We suggest team (neurosurgeon and rehabilitation professionals) decision in a spasticity center before involving the patient into ITB therapy, and follow up in the rehabilitation unit. The severity of spasticity as a consequence of brain injury can change during years and it is necessery to follow it with dosage and dynamics of baclofen therapy. Baclofen pump removal is suggested if the ITB therapy is further not reasonable.]

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[Change of therapeutic algorithm in sclerosis multiplex based on two case reports]

BIERNACKI Tamás, BENCSIK Krisztina, KINCSES Zsigmond Tamás, SANDI Dániel, FRICSKA-NAGY Zsanett, FARAGÓ Péter, VÉCSEI László

[The aim of our case reports is to demonstrate the therapeutic use and possibilities one has with alemtuzumab, should it be used either as a first or second line therapy. Our first patient's disease in the beginning seemed to be benign. It was not the case however, over several years the diesase showed high activity both radiologically and clinically, she was treated with alemtuzumab as part of an esclationbased therapeutic strategy. The second patient's disease on the other hand showed formidable activity since the very beginning both radiologically and clinically. Therefore we were facing a very disastrous prognosis on the long run, accordingly he received alemtuzumab treatment very early into his illness.]

Clinical Neuroscience

[Clinical significance of the cardiovascular effects of fingolimod treatment in multiple sclerosis]


[Fingolimod is a sphingosine-1 phosphate receptor modulator, which is effective in the treatment of severe relapsingremitting form of multiple sclerosis. Once daily oral use of fingolimod decreased the annualized relapse rate, inflammatory brain lesion activity and the rate of brain atrophy compared both to placebo and intramuscular administered interferon beta-1a. The drug targets the cardiovascular system as well via sphingosine- 1 phosphate receptors. After initiation of fingolimod therapy transient sinus bradycardia and slowing of the atrioventricular conduction develops. The onset of the effect is as early as 1 hour post administration, while heart rate and conduction normalized in 24 hours in most of the cases. According to the clinical trials symptomatic bradycardia developed in 0.5% of the cases, responding to the appropriate therapy. The incidence of Mobitz I type II atrioventricular blocks and blocks with 2:1 atrioventricular conduction was 0.2% and 0.1%, respectively. All of these cardiovascular events showed regression during observation and no higher degree atrioventricular blocks were detected at the approved therapeutic dose. Following the first dose effect, fingolimod had a moderate hypertensive effect on long-term. For the safety of fingolimod treatment detailed cardiovascular risk stratification of all patients, adequate patient monitoring after the first dose and competency in treating the possible side effects is necessary. In patients with increased cardiovascular risks, treatment should be considered only if anticipated benefits outweigh potential risks and extended monitoring is required.]

Clinical Neuroscience

[Application of the Multiple Sclerosis Functional Composite in Debrecen]


[Introduction - The Multiple Sclerosis Functional Composite (MSFC) has been recommended by the National Multiple Sclerosis Society as a new clinical outcome measure. It is based on measurements in three clinical dimensions: leg function/ambulation (timed 25-foot walk), arm function (9-hole peg test), and cognitive function (paced auditory serial addition test). Scores on component measures are converted to standard scores (Z-scores) that reflect patient performance. This method has not yet been introduced into routine clinical practice. Patients and method - MSFC calculation was applied to 17 patients with relapsing-remitting multiple sclerosis (age mean: 37.4±10.8 years; duration of the disease: 5.5±4.9 years, EDSS: 2.7±1.4) seen at the neuroimmunological outpatient clinic to evaluate its usefulness and its correlation with the traditionally applied Expanded Disability Status Scale (EDSS) and with patient-reported quality of life. Fifteen patients received immunomodulatory treatment (interferon beta and glatiramer acetate). MSFC and EDSS were measured at 0, 3, 6, 9, 12, 18 months, and questionnaires on quality of life were filled in by the patients at 0, 6, 12, 18 months of follow- up. Results - The prospective study confirmed a strong correlation between EDSS and MSFC (Spearman correlation test, p=0.03, 0.004, 0.002, 0.004, 0.0008, 0.002; R=-0.54, -0.66, -0.68, -0.65, -0.73, -0.69) in multiple sclerosis. The MSFC was more sensitive to clinical changes than EDSS. The extent of changes on the two scales correlated only after 18 months (p<0.005, R=-0.65). The arm/hand function was the most sensitive measure for disease progression. There was no correlation between the quality of life and either of the two other clinical parameters. Conclusion - MSFC is a simple method, suitable for followup of multiple sclerosis patients in everyday clinical practice.]