2012, Vol 12, No 4
RETRACTED - Experimental models of ischaemic stroke
AKTUALN NEUROL 2012, 12 (4), p. 199–204
ABSTRACT

Progress in neurology and neuroradiology has had a tremendous impact on the improvement of quality of diagnosis and treatment of vascular diseases of the central nervous system. Stoke remains one of the major problems of modern medicine. It is the second most common cause of mortality and the leading cause of adult disability worldwide. Ischaemic stroke accounts for 80-85% of all cases of stroke, while haemorrhagic stroke – for the remaining 15-20% (thereof, 10% are intracerebral haemorrhages and 5% – subarachnoid haemorrhages). Thus, the vast majority of strokes are ischaemic in nature. Focal brain ischaemia is mainly caused by local reduction or cessation of blood flow due to embolism or thrombosis, which in turn leads to energy and oxygen deficit in the area of ischaemia. As estimated, at least 1/6 of the general population is at risk of at least one cerebral ischaemic event over their lifetime. Stroke is an utmost dangerous condition, not only because of mortality risk associated therewith, but also because of severe disability of stroke survivors (nearly 80% of stroke cases). To date, elucidation of pathophysiology of this process, development and introduction of effective therapies remains the focus of interest of representatives of many scientific disciplines. Experimental models of brain ischaemia are widely used mainly in biochemical and pathophysiological research, but they do not play any significant role in the search for novel stroke therapies. This paper describes most commonly used experimental models of cerebral ischaemia. Their advantages, disadvantages and possible causes of discrepancy between results of experimental and clinical studies are discussed. Development of new experimental models, their validation and correlation with results of clinical trials remain a considerable challenge for investigators. In the future, such studies may provide solution to issues and problems associated with stroke pathogenesis and treatment.

Keywords: experimental model, ischaemia, stroke, neuroprotection, cerebral blood flow
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Role of purinergic signalling and cytokines in the ischaemic stroke
AKTUALN NEUROL 2012, 12 (4), p. 205–214
ABSTRACT

Inflammation plays an important role in the aetiology of various diseases of the central nervous system including the stroke. Accumulating evidence indicates that inflammation in the central nervous system is controlled by purinergic signalling. The mediators of purinergic signalling are extracellular nucleotides (e.g. ATP, ADP, UTP and UDP) and adenosine that act via activation of P2 and P1 purinergic receptors, respectively. The activation of P2 and P1 receptors is regulated by the enzymes ectonucleotidases that hydrolyse either extracellular nucleotides or adenosine. This review focuses on the role of purinergic signalling in the ischaemic stroke. We and others have demonstrated the presence of nucleotides and adenosine in the cerebrospinal fluid. We have also shown that the concentration of ATP and other nucleotides is increased in cerebrospinal fluid of patients with ischaemic stroke. Evidence suggests that the activation of P2 and P1 receptors have an opposite role in the ischaemic stroke, i.e. while the nucleoside adenosine exert neuroprotective effects, nucleotides generally promote the proinflammatory and apoptotic responses. P2X7, P2Y2, P2Y6, P2Y11 and P2Y12 are proposed to be involved in the central nervous system inflammation as they are expressed in the brain and their activation is known to control the key inflammatory processes such as release of inflammatory mediators (e.g. cytokines, NO), migration of leukocytes, phagocytosis, apoptosis and thrombosis. The activation of P2 receptors can also increase the release of excitatory neurotransmitters that further exacerbate the inflammatory response. Three cytokines whose release is controlled by P2 receptors have a major role in the ischaemic stroke, namely tumour necrosis factor alpha (TNF-α), interleukin 1 (IL-1) and interleukin 6 (IL-6). By promoting inflammation and thrombosis, these proinflammatory cytokines contribute to the increase in lesion size and thus functional impairment of the affected tissue. Cytokines as well as extracellular nucleotides are involved in leukocyte migration to lesions. By their adherence to endothelium, leukocytes impair cerebral blood circulation and thus exacerbate damage to the brain. The hydrolysis of nucleotides to adenosine by the ectonucleotidases leads to deactivation of proinflammatory responses. Similar effect can also be obtained with P2X7 and IL-1 receptor antagonists that are presently under clinical development and investigation.

Keywords: nucleotides, nucleosides, cytokines, purinergic receptors, ischaemic stroke
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Concept of dynamic localization of function in rehabilitation of aphatic speech disorders
AKTUALN NEUROL 2012, 12 (4), p. 215–221
ABSTRACT

Prompt and effective therapeutic intervention in patients with aphasia provides several benefits. First and foremost it reduces the risk of development of pathological patterns of verbal response, increasing the chances for earlier recovery of psychomotor functions and affecting favourably the patient’ comfort. There are several theories explaining the mechanism of development of aphasias and several techniques of assistance offered to people affected. Great variety of speech disorders necessitates implementation of diverse therapies and adjusting them to individual patient’s needs. The dynamic theory of location of cognition and the concept of functional system presented in this paper, establish a rationale for treatment of disorders resulting from brain injury. According to the premises of the dynamic localization theory, execution of all higher mental functions, including speech, involves variable activation several brain areas. Disturbed functions may undergo restorative processes as a result of structural rearrangement within the framework of the dynamic system, utilizing unaffected regions of both cerebral hemispheres. Hence, the dynamic theory of location of function encourages initiation of rehabilitation, also in patients with substantial functional loss, providing hope and the feeling of partnership, both to patients and their families. The authors discuss the impact of disturbed neurophysiological processes on purposeful use of articulated speech and present several practical exercises designed to help patients affected with various types of aphasia.

Keywords: aphasia, psychomotor disorders, functional system, rehabilitation, speech therapy
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Pathogenetic mechanisms of amyotrophic lateral sclerosis
AKTUALN NEUROL 2012, 12 (4), p. 222–235
ABSTRACT

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, resulting in a damage of motor neurons. Pathogenesis of ALS is most probably multifactorial, complex and not entirely elucidated. It may involve such mechanisms as oxidative stress, toxicity of glutamic acid, dysfunction of the mitochondria, stress of endoplasmic reticulum, aggregation of proteins, dysfunction of the cytoskeleton, disturbed axonal transport, role of glial cells, neuroinflammatory process, lactic acid dyscrasia, and genetic factors. An important cause of oxidative stress in ALS are mutations of superoxide dismutase 1 (SOD1) gene leading to altered activity of the enzyme and its enhanced toxicity. Abnormal SOD1 participates in inflammatory response of activated astrocytes and microglia in the spinal cord of ALS patients. Mechanisms of oxidative stress and glutamate toxicity are coupled together. Death of motor neurons occurs as a result if activation of caspases and apoptosis, while mitochondrial dysfunction merely participates in the process. Pathomorphological alterations within the endoplasmic reticulum are present already at an early phase of the disease and indicate that stress within this structure plays an important role in the ALS-related process of neurodegeneration. Another interesting feature of ALS are alterations of cytoskeleton, concerning mainly neurofilaments. According to the hypothesis of lactic acid dyscrasia, dysregulation of myoneuronal lactic acid channel results in cellular stress, toxicity and progressive degeneration. An important role in the pathogenesis of ALS may be also played by genetic mutations of proteins other than SOD1.

Keywords: amyotrophic lateral sclerosis, pathogenetic mechanisms, oxidative stress, glutamate-related toxicity, mitochondrial dysfunction, aggregation of proteins, genetic factors
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Psychiatric disorders coexisting with dementia – clinical relevance and principles of management
AKTUALN NEUROL 2012, 12 (4), p. 236–244
ABSTRACT

Psychiatric disorders (including psychosis, depression and anxiety disorders) as well as other behavioural and psychological symptoms of dementia (collectively referred to as BPSD) are common in the demented, regardless of presumed aetiology of dementia. They may appear even at the prodromal phase of dementia, while severity and incidence of many of them increases with progression of cognitive dysfunction. Development of BPSD is associated with several negative consequences, both for the patient and his/her caregivers. Presence of psychotic symptoms affects unfavourably further course of dementia, accelerating cognitive decline, increased number of hospitalizations, risk of institutionalization and mortality as well as greater degree of functional disability. A well-documented phenomenon correlated therewith is increased caregivers’ burden and increased risk of caregivers’ psychiatric problems, including depression. Treatment of BPSD is difficult and no uniformly accepted and universally effective management standard or guidelines have been proposed to date. Non-pharmacological approach is considered obligatory for most patients, while education of caregivers or institution personnel is paramount. The key issue is optimal dosage of anti-dementia drugs, including cholinesterase inhibitors and memantine. Efficacy of psychotropic drugs is largely limited and their clinical usefulness compromised by poor side effects profile of many of them. Particular care must be paid when using antipsychotics due to presumed risk of premature death secondary to cerebrovascular complications. Antidepressants, though relatively ineffective in treating depression and anxiety, might be an option in patients with agitation, aggression and psychosis as documented to date in the case of citalopram and trazodone.

Keywords: dementia, Alzheimer’s disease, psychiatric disorders, behavioural disorders, treatment, antipsychotics, antidepressants, anticonvulsants
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Treatment of dementia coexisting with medical diseases – selected issues
AKTUALN NEUROL 2012, 12 (4), p. 245–250
ABSTRACT

The aim of this study is to present dilemmas associated with the use of drugs improving cognitive functions in the elderly with medical comorbidities. Considering high incidence of multiple pathology present in the elderly, dementia, being one of the most serious medical problems at this stage of life, rarely appears as an isolated condition and most often coexists with other diseases. Treatment of dementia is usually combined with therapy of other disease entities, thus inducing an increased risk of drug interactions and adverse effects. The risk of such phenomena increases further due to altered pharmacokinetics, resulting from worse distribution of drugs in the body and age-associated multi-organ failure, which in turn may lead to impaired metabolism and elimination of drugs. Among several acetylcholinesterase inhibitors used in the treatment of dementia, interactions concern most often donepezil, due to its hepatic metabolism involving the cytochrome P450, which also plays an important role in the metabolism of many other agents used in the management of other diseases affecting the elderly. Contraindications for the use of acetylcholinesterase inhibitors include mainly severe liver failure, sick sinus syndrome, arrhythmias and conduction disorders, active peptic ulcer within the stomach or duodenum, conditions hindering flow of urine, convulsions/seizures, and bronchial asthma or COPD. Adverse effects of medications concern a considerable proportion of patients, and for some of them this may be a contraindication for continuation of the therapy. Unfortunately, the issue of drug interactions and adverse effects is often underestimated in the treatment of elderly patients with dementia.

Keywords: dementia, old age, procognitive drugs, coexisting diseases, adverse effects
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Some practical considerations on dizziness
AKTUALN NEUROL 2012, 12 (4), p. 251–258
ABSTRACT

Dizziness is one of the commonest problems encountered in everyday medical practice and constitute a highly heterogeneous group of symptoms of interdisciplinary origin. Leading causes of dizziness may be laryngological-, neurological-, internal medical-, ophthalmologic- or mental-based. The key issue in differential diagnosis of dizziness is precise description of character of ailments by the patient. Essentially, dizziness may be classified into systemic (vertigo) and non-systemic (lightheadedness, disequilibrium). One of the most common forms of dizziness is benign paroxysmal positional vertigo (BPPV). Other causes of dizziness include: psychogenic vertigo (phobic postural vertigo, chronic subjective dizziness), migraine (including basilar-type migraine and vestibular migraine), Ménière disease, vestibular neuritis, multifactorial vertigo of the elderly (presbyastasis) and vascular dizziness. The latter are overdiagnosed in Poland, while other forms are largely underdiagnosed. An example thereof is BPPV, easily diagnosed be the almost pathognomonic Dix-Hallpike test and effectively treated by canalith repositioning (Epley) or liberatory (Semont) manoeuver. In the determination of cause(s) of dizziness paramount are neuroimaging studies, particularly magnetic resonance imaging (MRI) of the head. Furthermore, very useful are laryngological examination and electronystagmography (ENG), enabling differentiation between central and peripheral vertigo. Apart of the abovementioned procedures in the treatment of dizziness, an important role is played by betahistine-based pharmacotherapy. Most frequent causes of dizziness are discussed, with a special emphasis on their differential diagnosis at patient’s bedside.

Keywords: vertigo, Ménière disease, benign paroxysmal positional vertigo, migraine, presbyastasis, betahistine
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