How does fingolimod (gilenya(®)) fit in the treatment algorithm for highly active relapsing-remitting multiple sclerosis?

Multiple sclerosis (MS) is a neurological disorder characterized by inflammatory demyelination and neurodegeneration in the central nervous system. Until recently, disease-modifying treatment was based on agents requiring parenteral delivery, thus limiting long-term compliance. Basic treatments such as beta-interferon provide only moderate efficacy, and although therapies for second-line treatment and highly active MS are more effective, they are associated with potentially severe side effects. Fingolimod (Gilenya(®)) is the first oral treatment of MS and has recently been approved as single disease-modifying therapy in highly active relapsing-remitting multiple sclerosis (RRMS) for adult patients with high disease activity despite basic treatment (beta-interferon) and for treatment-naïve patients with rapidly evolving severe RRMS. At a scientific meeting that took place in Vienna on November 18th, 2011, experts from ten Central and Eastern European countries discussed the clinical benefits and potential risks of fingolimod for MS, suggested how the new therapy fits within the current treatment algorithm and provided expert opinion for the selection and management of patients.

Fingolimod in the treatment algorithm of relapsing remitting multiple sclerosis: a statement of the Central and East European (CEE) MS Expert Group.

Fingolimod is the first oral treatment of multiple sclerosis. It is the first-in-class sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phophate receptors on lymphocytes and via downregulation of the receptor prevents lymphocyte egress from lymphoid tissues into the circulation. This mechanism reduces the infiltration of potentially auto-aggressive lymphocytes into the central nervous system. Two large phase III studies with fingolimod have shown superior efficacy of the drug in two dosages compared to placebo and to weekly intramuscular injections of Interferon beta-1a. Among possible side effects of the drug is a transient bradycardia after the first dose of fingolimod including possible AV blockade and therefore monitoring of pulse rate and blood pressure for 6 h following the first application is needed. During treatment, attention has to be given to specific infections, elevated liver enzymes, and ophthalmologic changes. Recommendations on the use of fingolimod including safety aspects are given in this article.

The effect of anti-inflammatory (aspirin and/or statin) therapy on body weight in Type 2 diabetic individuals: EAT, a retrospective study.

AIMS: Obesity is associated with inflammation. Anti-inflammatory interventions such as aspirin and statins (anti-IFRx) might be a novel approach to the treatment of obesity and Type 2 diabetes mellitus (T2DM). The present study was designed to determine whether exposure to anti-IFRx is associated with weight loss in T2DM patients. METHODS: Exposure to anti-IFRx was compared between T2DM patients with a history of weight loss (n = 100) and those with no weight loss or with weight gain (n = 102) during a 1-year follow-up period. Logistic regression was used to develop odds ratios for weight loss status. RESULTS: Subjects who lost weight were more frequently exposed to anti-IFRx (85.0 vs. 71.5%, P = 0.018) than subjects who maintained or gained weight during follow-up. The 158 subjects exposed to anti-IFRx were older (64.2 +/- 9.4 vs. 60.6 +/- 11.2 years, P = 0.04), had longer duration T2DM (14.5 +/- 9.5 vs. 9.0 +/- 9.4 years, P = 0.001), had greater prevalence of dyslipidaemia (72 vs. 19%, P < 0.0001) hypertension (57.3 vs. 38.1%, P = 0.03) and cardiovascular disease (37.7 vs. 9.5%, P < 0.0001) than subjects not exposed to anti-IFRx. In a logistic regression model for weight change status, anti-IFRx exposure was significantly associated with weight status (odds ratio = 2.3, 95% confidence interval 1.1-4.8, P = 0.02, an association that persisted), even after controlling for age, sex, baseline body mass index, years since diagnosis, OHA therapy and co-morbidities. CONCLUSIONS: Exposure to anti-IFRx more than doubled the odds of weight loss in T2DM patients. Results of this study justify a randomized clinical trial to determine definitively the role of anti-IFRx in weight loss in subjects with T2DM.

[Hashimoto's encepahlopthy--a rare and unusual syndrome]. / Hashimotova encefalopatia--vzácny a neobvyklý syndróm.

Hashimoto's encephalopathy (HE) is a brain disease associated with autoimmune thyroid disease. Over 100 articles have been published on the topic, especially in connection with hypothyroidism. In addition to an overview of the relevant literature, we also report a case of a female patient with a rare association of HE with thyreotoxicosis. The patient presented with varied clinical-neurological symptoms: she had convulsions, psychotic symptoms, altered consciousness Examinations (laboratory tests, CT, MRI, EEG, CSL exams) detected increased level of proteins in the liquor, episodes of rhythmic delta activity on EEG, increased antithyreoidal antibody titre (TOOab, TGAb, TRAb) in serum. After initial treatment with carbimazole and hydrocortizone, the patient's condition dramatically improved and she was disconnected from artificial lung ventilation, conscious and convulsion-free. During the following 30 days, the patient would get worse after attempts to withdraw glucocorticoids. In spite of thyreotoxicosis, we classified the condition as HE and the patient was fully stabilised after pulse treatment with methylprednisolone. Clinically, the patient was subject to further outpatient follow up, without symptoms of encephalopathy; glucocorticoids were gradually withdrawn and were discontinued completely after another four months. The authors conclude that HE, even though rare, may pass unnoticed due to its symptoms which are similar to many other and more frequent diseases. HE should be considered in patients with potential or known autoimmune thyroidism and atypical neuropsychiatric manifestation responding to corticoid treatment.

Mitral annular calcifications and aortic plaques as predictors of increased cardiovascular mortality.

OBJECTIVES: Mitral annular calcifications (MAC) and aortic plaques are predictive for higher incidence of recurrent embolic events, the presence and severity of coronary artery disease and total cardiac deaths. However, no data exist comparing the impact of combined presence of both aortic plaques and MAC on embolic events, deaths associated with cerebral embolism or cardiac deaths during the follow-up. PATIENTS AND METHODS: In 100 consecutive patients with aortic plaques detected by transesophageal echocardiography (mean age 69.8 + 8.9 years, range 39-93 years, 49 males, 51 females) and in 49 age- and sex-matched control subjects (mean age 69.4 + 7.8 years, range 46-89 years, 27 males, 22 females) without aortic plaques (control group), the incidence of embolic events, deaths associated with embolic events and total cardiac deaths were evaluated during a mean follow-up of 32 +/- 9.7 months. The effect of the presence or absence of MAC on these parameters was also evaluated. RESULTS: Compared with the control group, patients with aortic plaques had a higher frequency of hypertension (p < 0.001), hypercholesterolemia (p < 0.01), smoking history (p < 0.01), MAC (p < 0.00001) and the presence of atherosclerotic changes in the carotid arteries (p < 0.05). During the follow-up, patients with aortic plaques had a higher incidence of stroke or transient ischemic attack (p < 0.0001), deaths associated with stroke (p < 0.005) and total cardiac deaths (p < 0.05) compared with the control group. Patients with both aortic plaques and presence of MAC had during the follow-up a significantly higher incidence of deaths associated with stroke (p < 0.0001, 16.0 times higher) and total cardiac deaths (p < 0.005, 4.7 times higher) compared with those without MAC and the presence of aortic plaques. Multivariant regression analysis showed MAC (p < 0.01) and hypercholesterolemia (p < 0.05) were the only independent predictors of stroke. MAC (p < 0.05) and age (p < 0.000001) were the only independent predictors of total cardiac death and stroke. Independent predictors of both aortic plaques and MAC were coronary artery disease (p < 0.00001), stroke (p < 0.005), hypertension (p < 0.001), female gender (p < 0.01) and hypercholesterolemia (p < 0.005). CONCLUSIONS: The findings of both aortic plaque and mitral annular calcification are highly predictive not only for strokes, but also for deaths associated with cerebral embolism and total cardiac deaths and are probably strong markers for higher severity of coronary artery disease. They are more predictive if both are present simultaneously compared to the presence of either MAC or aortic plaque alone.

[Immunopathogenesis of myasthenia gravis and the Lambert-Eaton myasthenic syndrome]. / Imunopatogenéza myasthenia gravis a Lambertovho-Eatonovho myastenického syndrómu.

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune diseases manifestant a disorder of neuromuscular transmission. In MG, the autoimmune process is directed against the postsynaptic part whereas in LEMS, it is focused at the presynaptic part of this connection. Current immunological studies have confirmed the polyclonal and heterogenous characters of the autoimmune process. In patient with MG, the presence of antibodies against various epitopes of acetylcholine receptor, as well as against other muscular fiber protein (e.g. ryanodine receptor, titin, myosin, etc.) were confirmed. Patients with LEMS yielded antibodies against the proteins of various types of voltage-dependent calcium channels located in the presynaptic part of the motor nerve ending, as well as those against synaptotagmin. These findings indicate the necessity of a more complex immunological examination of patients in order to clarify both variability of clinical picture and prospective planning of specific immunotherapy. (Tab. 4, Fig. 3, Ref. 25.)

[Reflex response in the masseter muscle after tapping the chin in healthy persons--an electromyographic study]. / Reflexné odpovede v m. masseter po poklepe na bradu u zdravých osôb--elektromyografická stúdia.

In a group of healthy subjects the author evoked reflex responses in both masseters by percussion of the chin with a reflex hammer. The reflexes were evoked during relaxation, slight or intense contraction of the masseters with the mouth open or closed. By percussion of the chin from above extension reflexes were evoked and by percussion of the chin from below contracting reflexes. The response was recorded by means of an electromyographic apparatus. The short-term stretch responses were evoked from the relaxed and slightly contracted masseters with the mouth open or closed. During intense contraction of the masseters the short-latency reflex stretch response was not evoked. In that case at first a short-latency inhibition of the basal activity of the masseter was observed followed by a medium and late-latency excitation response. With the masseters relaxed a long-latency stretch response was observed only with the mouth open. Percussion of the chin from beneath with slight contraction of the masseter caused initial inhibition of its basal activity followed then by a short-latency excitation response. Based on the assembled results the author analyzed the mechanism of the reflex control of the masseters.

[Reflex response of the masseter muscle after percussion of the chin and electrical stimulation of the upper lip in patients with central motor disorders]. / Reflexné odpovede v m. masseter po poklepe na bradu a elektrickej stimulácii hornej pery u pacientov s centrálnou poruchou hybnosti.

In 23 patients with central motor disorders (spastic hemiparesis, pseudobulbar syndrome and parkinsonism) reflex responses in both masseters were evoked during their relaxation and contraction by percussion with a reflex hammer on the chin and by electric stimulation of the upper lip. For recording of the reflex responses the electromyographic method was used. On the side of the spastic hemiparesis, as compared with the finding on the non-paretic side, the author found changes in the short-, medium and late-latency excitation and inhibition segments of the reflex response. In patients with parkinsonism the medium-latency portion of the reflex response after percussion of the chin from above as well as from below was satisfactory. The late latency excitation response after percussion of the chin from below was greater than its corresponding part evoked by percussion of the chin from above. In patients with the pseudobulbar syndrome the inhibitory parts of the reflex responses after percussion of the chin were weak. The results of the examination provided thus more detailed information on disorders of supranuclear control of masseter muscles.

[The stretch reflex response in the abductor pollicis brevis muscle in persons with organic and probably functionally conditioned central motor impairment (electromyographic study)]. / Natahovacia reflexná odpoved v m. abductor pollicis brevis u osôb sorganicky a pravdepodobne funkcionálne podmienenou centrálnou poruchou hybnosti.(Elektromyografická stúdia).

Stretch reflex responses in the m. abductor pollicis brevis were elicited by percussion with the reflex hammer on the distal digit of the thumb. On the side of spastic hemiparesis the author revealed more marked short-latency and suppression of medium- and late-latency parts of the reflex response. On the side of weak central hemiparesis also the short-latency part of the reflex response was suppressed. In functionally conditioned pareses the author found dishabituation of medium and late latency parts of the reflex response. On the side of the cerebellar lesions there was a relatively higher amplitude of the second part of the medium-latency response. In patients with the diagnosis of definite multiple sclerosis in addition to suppression of medium and late- latency parts of the reflex response there was a typical prolongation their latency.

[The reflex response in the abductor pollicis brevis muscle after tapping the distal segments of the fingers, the ulnar olecranon and scapular acromion. Electromyographic study]. / Reflexné odpovede v m. abductor pollicis brevis po poklepe na distálne clánky prstov ruky, olecranon ulnae a acromion scapulae. Elektromyografická stúdia.

The author made an electromyographic investigation of reflex responses in the abductor pollicis brevis muscle abductor pollicis brevis muscle after percussion with a hammer on the dorsal, lateral, palmar, medial and distal surface of the distal digit of the thumb, on the dorsal and palmar area of the distal digits of the other fingers and also on the olecranon ulnae and acromion scapulae. The investigation was made to detect the influence of the site of percussion on the character of the reflex response. The reflex responses were examined during slight isometric contraction of the muscle. After averaging rectification and of the recorded potentials the reflex responses were identified as excitatory and inhibitory modulation of the basal muscular activity depending on the inducing stimulus. Excitatory parts of the reflex response with a short latency were recorded after percussion on the lateral, dorsal and palmar area of the distal digit of the thumb and after percussion of the dorsal area of distal digits of the other fingers and after percussion of the palmar area of the little finger. As to other sites where reflexes were evoked first the inhibitory part of the reflex response was recorded. Excitation parts of reflex responses with a medium latency were obtained from all sites where reflexes were evoked. Late-latency parts of the reflex response had an inconstant occurrence. The results of the investigation provided evidence of a short-latency proprioceptory; influence of the abductor pollicis brevis muscle from synergic muscles.(ABSTRACT TRUNCATED AT 250 WORDS)

[Reflex reaction in the abductor pollicis brevis muscle after mechanical and electrical stimulation in patients with central hemiparesis and Parkinsonism. Electromyographic study]. / Reflexné odpovede v m. abductor pollicis brevis po mechanických a elektrických podnetoch u pacientov s centrálnou hemiparézou a parkinsonizmom. Elektromyografická stúdia.

The reflex responses in the abductor pollicis brevis muscle were examined in 22 patients with mild central hemiparesis and in nine patients with Parkinson's disease. In the group of patients with central hemiparesis there were 15 subjects with a spastic and seven subjects with a flaccid type of affection. The reflex responses in the abductor pollicis brevis muscle were evoked during isometric contraction. The recorded muscular potentials were unidirectionally rectified and averaged. The reflex responses were then identified as excitatory and inhibitory modulations of basal activity of the muscle after the evoking stimulus. The reflexes were evoked by percussion with a hammer on the lateral area of the base of the distal digit of the thumb, by electrical stimulation of the median nerve on the wrist and by electric stimulation of the cushion of the thumb and the superficial radial nerve on both sides. On the side of the spastic or flaccid central hemiparesis the long-latency parts of the reflex responses after percussion on the distal digit of the thumb and after electrical stimulation of the median nerve were either not elicitable or had a lower amplitude than on the non-paretic extremity. In three subjects on the affected side also the of long-latency part of the reflex response was prolonged after percussion of the distal digit of the thumb. The short-latency parts of the reflex response on the side of the spastic hemiparesis were more expressed, contrary to the finding on the side with the flaccid hemiparesis where suppressed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Reflex responses in the trapezius muscle after percussion of various parts of the body]. / Reflexné odpovede v m. trapezius po poklepe na rôzne oblasti tela.

In a Group of 20 healthy subjects and 16 patients with different central motor disorders a reflexological investigation was made in the upper part of the trapezius muscle. The reflex responses were produced by percussion with a reflex hammer on several sites on the head, trunk and upper extremities and identified as excitatory and inhibitory modulations of recorded EMG activity resulting from the stimulus, after averaging of 50 responses. In the group of healthy subjects after percussion of the chin, upper lip, cheek, mastoid process, back of the skull, the processus spinosus of vertebras C7 and Th12 and both sides of the volar area of the wrist, reflex responses with a short and long latency were recorded. In the group of patients with central motor disorders the reflexological finding was different, depending on the type of central disorder. On the side of spastic hemiparesis after a hemispheric ischaemic cerebrovascular lesion only responses with a short latency were recorded. In patients with parkinsonism mostly only reflex responses with a long latency were elicited. In patients with the dystonic form of torticollis spastica a side asymmetry was found. The results of the investigation provided evidence of reflex connections of remote parts of the body with trapezius muscle in healthy subjects and of the incidence of specific deviations of reflex responses in this muscle in patients with various central lesions. This is important in the differential diagnosis of central motor disorders.