Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity.

Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.

Brainstem nuclei changes in migraine detected by transcranial sonography.

The aim of this study was to estimate the role of transcranial sonography in detecting basal ganglia changes as structural biomarkers in migraine. Transcranial sonography was performed on Aloka prosound α-10. Semiquantitative and planimetric methods were applied when basal ganglia changes were detected. Comparison between groups was performed by unpaired Student's t test and Spearman's correlation test. We analyzed 30 migraine patients and 30 age-/sex-matched controls. Substantia nigra hyperechogenicity was detected in 36.7% migraineurs and in 13.3% controls (t test, p = 0.036888). Hyperechogenic substantia nigra was found in 70% aura patients and in 20% patients without aura (p = 0.007384). Mean substantia nigra echogenic size of all migraine patients was 0.16 ± 0.07 and 0.12 ± 0.043 cm2 in controls (t test, p = 0.0011). Lentiform nucleus hyperechogenicity was seen in 50% migraine patients and 13.3% controls (t test, p = 0.002267). Mean lentiform nucleus echogenic size of all migrenous patients was 0.34 ± 0.08 cm2 and in controls 0.20 ± 0.008 cm2 (t test, p = 0.0021). Caudate nucleus hyperechogenicity was found in 26.7% migraine patients and in 6.6% controls (t test, p = 0.037667). Mean frontal horn width in migraine patients was 8.73 ± 1.76 mm and in controls 7.10 ± 1.71 (t test, p = 0.0006). Substantia nigra hyperechogenicity correlated with disease duration (rho = -0.35521, p = 0.05467) and third ventricle width (rho = -0.68221, p = 0.02976). No other differences between migraineurs and controls were found. Our study has revealed differences in transcranial findings between migraineurs and controls, but overall significance of those findings are still to be evaluated.

Strategies for treatment of dystonia.

Treatment of dystonias is generally symptomatic. To produce sufficient therapy effects, therefore, frequently a multimodal and interdisciplinary therapeutic approach becomes necessary, combining botulinum toxin therapy, deep brain stimulation, oral antidystonic drugs, adjuvant drugs and rehabilitation therapy including physiotherapy, occupational therapy, re-training, speech therapy, psychotherapy and sociotherapy. This review presents the recommendations of the IAB-Interdisciplinary Working Group for Movement Disorders Special Task Force on Interdisciplinary Treatment of Dystonia. It reviews the different therapeutic modalities and outlines a strategy to adapt them to the dystonia localisation and severity of the individual patient. Hints to emerging and future therapies will be given.

Parkinsonian syndrome and ataxia as a presenting finding of acquired hepatocerebral degeneration.

The term "acquired hepatocerebral degeneration" (AHD) was coined to describe clinical entity distinct from genetically defined Wilson's disease. AHD is chronic neurological disorder, characterized by extrapyramidal and neuropsychiatric symptoms accompanied with advanced liver disease with portosystemic shunts. In majority of AHD cases, extrapyramidal symptoms appear in the presence of known liver disease. Here we present a patient with subacute onset of bilateral, asymmetric, hypokinetic-rigid syndrome and ataxia as initial presentation of liver cirrhosis. Manganese toxicity have major role in AHD pathogenesis. Failure of liver detoxification and presence of portosystemic shunting enables neurotoxic substance of manganese to avoid hepatic metabolism and to enter and accumulate in central nervous system. Predilection brain regions for manganese deposits are globus pallidum (GP) and substantia nigra (SN). Characteristic MRI findings of bilateral, symmetrical hyperintensities of GP and SN on T1-weighted sequences supported the diagnosis of AHD in our patient. In addition, increased T2 signal in dendate nuclei seen in our patient is rare radiological finding. So far, no consensus guidelines regarding medical treatment of AHD exist. We initiated low-dose levodopa treatment, but failed to provide beneficial effect. In conclusion, AHD is distinct clinical entity that should be included in differential diagnosis of both typical and atypical parkinsonian syndromes. Furthermore, our case highlights the importance of performing MRI in patients with atypical parkinsonism.

The COVID-19 pandemic impact on continuity of care provision on rare brain diseases and on ataxias, dystonia and PKU. A scoping review.

One of the most relevant challenges for healthcare providers during the COVID- 19 pandemic has been assuring the continuity of care to patients with complex health needs such as people living with rare diseases (RDs). The COVID-19 pandemic accelerated the healthcare sector's digital transformation agenda. The delivery of telemedicine services instead of many face-to-face procedures has been expanded and, many healthcare services not directly related to COVID-19 treatments shifted online remotely. Many hospitals, specialist centres, patients and families started to use telemedicine because they were forced to. This trend could directly represent a good practice on how care services could be organized and continuity of care could be ensured for patients. If done properly, it could boast improved patient outcomes and become a post COVID-19 major shift in the care paradigm. There is a fragmented stakeholders spectrum, as many questions arise on: how is e-health interacting with 'traditional' healthcare providers; about the role of the European Reference Networks (ERNs); if remote care can retain a human touch and stay patient centric. The manuscript is one of the results of the European Brain Council (EBC) Value of Treatment research project on rare brain disorders focusing on progressive ataxias, dystonia and phenylketonuria with the support of Academic Partners and in collaboration with European Reference Networks (ERNs) experts, applying empirical evidence from different European countries. The main purpose of this work is to investigate the impact of the COVID-19 pandemic on the continuity of care for ataxias, dystonia and phenylketonuria (PKU) in Europe. The analysis carried out makes it possible to highlight the critical points encountered and to learn from the best experiences. Here, we propose a scoping review that investigates this topic, focusing on continuity of care and novel methods (e.g., digital approaches) used to reduce the care disruption. This scoping review was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews (PRISMA-ScR) standards. This work showed that the implementation of telemedicine services was the main measure that healthcare providers (HCPs) put in place and adopted for mitigating the effects of disruption or discontinuity of the healthcare services of people with rare neurological diseases and with neurometabolic disorders in Europe.

[Huntington's disease]. / Huntingtonova bolest.

Huntington's disease and/or chorea (HD) is autosomal dominant neurodegenerative disease that never skips generations. The first description was provided by George Huntington in the year 1872. Its prevalence in the world is 8-10 per 100000 inhabitants and in Croatia 4.46 per 100 000 inhabitants. It starts between 30 and 50 years of age and ends after 15-20 years with death. It is a disease of CAG triplet repeats and is characterized by poliglutamine repeats. The number of CAG trinucleotid repeats correlates with the age of the onset of the first symptoms, as well as with the clinical picture. The selective therapy for Huntington's chorea still does not exists and for symptomatic treatment the blockers of dopamine have turned out to be the most useful.

Restless legs syndrome.

Being of the most frequent causes of insomnia, which in the end leads to chronic fatigue, inadequate performance of daily activities, and serious disruption of quality of living, restless legs syndrome (RLS) is nowadays not only a serious medical problem but a socio-economical one as well. Prevalence of the disorder in general population is estimated at 5 to 15%. Family history is positive in over 50% of idiopathic RLS patients which points to genetic basis of the disorder. The characteristics of the secondary or acquired form of RLS are symptoms that start later in life as well as a rapid progression of the disease. On the other hand, idiopathic RLS more often starts at a younger age and the prognoses are better. Over twenty disorders and conditions are brought in connection with secondary RLS. Although the cause of primary RLS is still unknown, there is a strong connection between central metabolism of iron as well as dopamine levels and RLS manifestation. A differential diagnosis of RLS includes a wide specter of motor and sensory disorders. Diagnosis is based on clinical features and the history of disease. To correctly diagnose idiopathic RLS one must first eliminate secondary causes of RLS and then also exclude any disorders with clinical features that mimic those of RLS. It has been estimated that some 20 to 25% of patients need pharmacological therapy. Best initial therapy is the application of nonergot dopamine agonists. Anticonvulsants, benzodiazepines and opioides can be given to patients who are refractory to dopaminergic therapy, those suffering from RLS with emphasized painful sensory component and those with RLS connected with insomnia.

Update on the Management of Parkinson's Disease for General Neurologists.

Management of Parkinson's disease (PD) is complicated due to its progressive nature, the individual patient heterogeneity, and the wide range of signs, symptoms, and daily activities that are increasingly affected over its course. The last 10-15 years have seen great progress in the identification, evaluation, and management of PD, particularly in the advanced stages. Highly specialized information can be found in the scientific literature, but updates do not always reach general neurologists in a practical and useful way, potentially creating gaps in knowledge of PD between them and neurologists subspecialized in movement disorders, resulting in several unmet patient needs. However, general neurologists remain instrumental in diagnosis and routine management of PD. This review provides updated practical information to identify problems and resolve common issues, particularly when the advanced stage is suspected. Some tips are provided for efficient communication with the members of a healthcare team specialized in movement disorders, in order to find support at any stage of the disease in a given patient, and especially for a well-timed decision on referral.

Lack of Accredited Clinical Training in Movement Disorders in Europe, Egypt, and Tunisia.

BACKGROUND: Little information is available on the official postgraduate and subspecialty training programs in movement disorders (MD) in Europe and North Africa. OBJECTIVE: To survey the accessible MD clinical training in these regions. METHODS: We designed a survey on clinical training in MD in different medical fields, at postgraduate and specialized levels. We assessed the characteristics of the participants and the facilities for MD care in their respective countries. We examined whether there are structured, or even accredited postgraduate, or subspecialty MD training programs in neurology, neurosurgery, internal medicine, geriatrics, neuroradiology, neuropediatrics, and general practice. Participants also shared their suggestions and needs. RESULTS: The survey was completed in 31/49 countries. Structured postgraduate MD programs in neurology exist in 20 countries; structured neurology subspecialty training exists in 14 countries and is being developed in two additional countries. Certified neurology subspecialty training was reported to exist in 7 countries. Recommended reading lists, printed books, and other materials are the most popular educational tools, while courses, lectures, webinars, and case presentations are the most popular learning formats. Mandatory activities and skills to be certified were not defined in 15/31 countries. Most participants expressed their need for a mandatory postgraduate MD program and for certified MD sub-specialization programs in neurology. CONCLUSION: Certified postgraduate and subspecialty training exists only in a minority of European countries and was not found in the surveyed Egypt and Tunisia. MD training should be improved in many countries.

Nondemented Parkinson disease patients: is cognitive performance associated with depressive difficulties?

BACKGROUND: Poorer cognitive performance in depressed versus nondepressed nondemented Parkinson disease (PD) patients has been suggested. OBJECTIVE: Investigate the relationship between level of depression assessed on a depression-measuring scale and cognitive performance in nondemented PD patients. METHODS: Nondemented idiopathic PD patients (n=110) were evaluated for the level of depression [cognitive-affective items of the Beck's Depression Inventory (BDI)] and performance in a set of tests evaluating cognitive domains typically affected in PD (memory, visuospatial, and executive functions). RESULTS: Multiple regression analysis of BDI scores demonstrated independent association of poorer cognitive performance, more severe parkinsonism, and poorer education with higher BDI scores. The association between poorer cognition and higher BDI scores was conditional on education, that is, was apparent only in less educated patients (<12 y of formal education). CONCLUSIONS: Poorer cognitive performance in nondemented idiopathic PD patients is associated with more severe depressive difficulties. Poorer education is also associated with more severe depression. Education modifies the cognition-depression relationship.

Defining spasticity: a new approach considering current movement disorders terminology and botulinum toxin therapy.

Spasticity is a symptom occurring in many neurological conditions including stroke, multiple sclerosis, hypoxic brain damage, traumatic brain injury, tumours and heredodegenerative diseases. It affects large numbers of patients and may cause major disability. So far, spasticity has merely been described as part of the upper motor neurone syndrome or defined in a narrowed neurophysiological sense. This consensus organised by IAB-Interdisciplinary Working Group Movement Disorders wants to provide a brief and practical new definition of spasticity-for the first time-based on its various forms of muscle hyperactivity as described in the current movement disorders terminology. We propose the following new definition system: Spasticity describes involuntary muscle hyperactivity in the presence of central paresis. The involuntary muscle hyperactivity can consist of various forms of muscle hyperactivity: spasticity sensu strictu describes involuntary muscle hyperactivity triggered by rapid passive joint movements, rigidity involuntary muscle hyperactivity triggered by slow passive joint movements, dystonia spontaneous involuntary muscle hyperactivity and spasms complex involuntary movements usually triggered by sensory or acoustic stimuli. Spasticity can be described by a documentation system grouped along clinical picture (axis 1), aetiology (axis 2), localisation (axis 3) and additional central nervous system deficits (axis 4). Our new definition allows distinction of spasticity components accessible to BT therapy and those inaccessible. The documentation sheet presented provides essential information for planning of BT therapy.

Restless legs syndrome in hemodialysis patients: association with calcium antagonists. A preliminary report.

Uremia-related restless legs syndrome (RLS) is a known form of secondary RLS. This cross-sectional survey included patients (n = 82) on stable hemodialysis (HD; >3 months, Kt/V >1.2) who were iron-replete, free of neurodegenerative or psychiatric disorders, severe polyneuropathy and radiculopathy, not exposed to antipsychotics/antidepressants, and not severely anemic. Forty-nine (60%) were RLS 'positive', and 25 (31%) had severe/very severe symptoms (International Restless Legs Syndrome Study Group criteria). None had been diagnosed previously. In a multivariate analysis, the prevalence of RLS was higher in diabetic patients [vs. nondiabetics; prevalence ratio (PR) 2.32, 95% CI 1.50-3.60, p < 0.001] and those exposed to Ca2+ antagonists (vs. nonexposed; PR 2.02, CI 1.47-2.76, p < 0.001), and also increased with dialysis duration (PR 1.05, 95% CI 1.02-1.09, p < 0.001). Association of Ca2+ antagonists and RLS in uremic patients has not been reported previously and deserves further research.

[Tremor--clinical features]. / Klinicke znacajke tremora.

Tremor is the commonest hyperkinesia in humans, often very impressive in its manifestation not only for patients and their families but also for physicians themselves. As a variety of etiological factors, diseases, conditions and substances that can cause it, this clinical entity is a recurrent differential diagnostic problem, that sometimes, unfortunately, results in diagnostic and therapeutic failures. Relative therapeutic resistance of some types of tremor, along with ineffective treatment and frequent iatrogenic potential, makes an additional problem in everyday clinical practice. Thus, there is a need for understanding and further research of the patophysiology of tremor occurrence, and continuous investigation of new medications and other therapeutic procedures. Knowledge of differential diagnostic and therapeutic guidelines for this disorder, however, gives a contribution to solving the problems almost daily encountered by specialists in various fields, but particularly family doctors. The paper presents diagnostic criteria for various types of physiological and pathological tremor, their classification, clinical and electrophysiological methods of evaluation, as well as the most recent therapeutic guidelines.

[Botulinum toxin type A and cholinergic system]. / Botulinum toksin tipa A i kolinergicni sustav.

Anaerobic bacterium Clostridium botulinum produces seven different serotypes of botulinum neurotoxins (A-G), which specifically act at the peripheral cholinergic nerve terminals blocking the release of acethylcholine. Primary site of action of botulinum toxin type A (BT-A) is neuromuscular end plate where it specifically cleaves SNAP-25, one of the proteins necessary for neuroegzocytosis. The consequence is long-lasting muscle paralysis. Although BT-A is one of the most potent toxins in nature, over the last 20 years, intramuscular injections of nanogram quantities of BT-A have been used to treat various conditions characterized by increased muscle contraction, like dystonias, spasticity related to cerebral palsy etc but also for autonomic nervous system disorders, like hyperhydrosis. Long duration of action (several months) after peripheral application is the most prominent feature of the toxin's action. Although the acute mechanism of action on neuromuscular junction is largely investigated, there are still some unknowns related to: the passage of BT-A through epithelial barriers, specific recognition of peripheral cholinergic neurons. The mechanism of long duration of action, which is the base of therapeutic use of BT-A, is poorly understood.

When movement disorders hurt: Addressing pain in hyperkinetic disorders.

Pain is an important nonmotor symptom in movement disorders. Dystonia is a hyperkinetic movement disorder characterized by involuntary, sustained or intermittent muscle contractions causing abnormal movements, postures or both. Contrary to common views the nonmotor symptoms are present in dystonia patients. Pain is a prevailing feature of cervical dystonia (CD), the most common form of focal dystonia. The mechanism of pain in CD remains mostly unknown, but there are growing evidence that it could not be only the consequence of muscle hyperactivity. We have shown that botulinum toxin (BoNT) produced pain relief before muscle relaxation and that effect on pain relief lasted longer than the effect on motor improvement. More and more data suggest that pain relief could be attributed to the direct effect of BoNT type A on central nervous system. Pain, depression, and anxiety have been shown to be significant determinants of QoL in focal dystonia patients. Routine clinical examination in patients with dystonia should include evaluation of motor as well as non-motor symptoms. Selective rating assessment should be used in clinical practice to quantify pain. Specific assessment of pain is important to determine the effect of BoNT as the most effective treatment in focal dystonia.

Clinical Practice: Evidence-Based Recommendations for the Treatment of Cervical Dystonia with Botulinum Toxin.

Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.

Botulinum toxin therapy for treatment of spasticity in multiple sclerosis: review and recommendations of the IAB-Interdisciplinary Working Group for Movement Disorders task force.

Botulinum toxin (BT) therapy is an established treatment of spasticity due to stroke. For multiple sclerosis (MS) spasticity this is not the case. IAB-Interdisciplinary Working Group for Movement Disorders formed a task force to explore the use of BT therapy for treatment of MS spasticity. A formalised PubMed literature search produced 55 publications (3 randomised controlled trials, 3 interventional studies, 11 observational studies, 2 case studies, 35 reviews, 1 guideline) all unanimously favouring the use of BT therapy for MS spasticity. There is no reason to believe that BT should be less effective and safe in MS spasticity than it is in stroke spasticity. Recommendations include an update of the current prevalence of MS spasticity and its clinical features according to classifications used in movement disorders. Immunological data on MS patients already treated should be analysed with respect to frequencies of MS relapses and BT antibody formation. Registration authorities should expand registration of BT therapy for spasticity regardless of its aetiology. MS specialists should consider BT therapy for symptomatic treatment of spasticity.