Nusinersen treatment of Spinal Muscular Atrophy Type 1 - results of expanded access programme in Poland.

AIM OF THE STUDY: This study aimed to evaluate the effects of nusinersen therapy in Polish children with SMA type 1. CLINICAL RATIONALE OF STUDY: Spinal muscular atrophy (SMA) is a neuromuscular disorder that is characterised by the loss of motor neurons, progressive muscle weakness and atrophy, leading to increased disability and mortality. Nusinersen, an antisense oligonucleotide that promotes production of the functional survival motor neuron protein is approved for the treatment of SMA 5q in the European Union. In 2017, an early access programme (EAP) for nusinersen was launched in Poland. In this study, we present the results of nusinersen treatment in Polish patients participating in the EAP. MATERIALS AND METHODS: We collected prospectively clinical data including mutational analysis of SMN1 and SMN2 genes, motor function outcomes as measured on a standardized scales, ventilatory and nutritional status, on SMA type 1 patients receiving nusinersen in three EAP centres in Poland. Scores on the CHOP-INTEND scale after 18-26 months of treatment were compared to baseline. RESULTS: We analysed data from 26 patients with SMA type 1, mean age 4.79 (2-15) years. The mutational analysis revealed two SMN2 gene copies in the majority of patients (61.54%). Three and four copies were found in 34.62% and 3.84%, respectively. Median disease duration was 21 months. Half (n = 13) of the patients required mechanical ventilation at baseline and 57.69% (n = 15) were fed by nasogastric tube or percutaneous endoscopic gastrostomy. No patient worsened during the follow-up. Mean improvement in CHOP-INTEND from baseline to the last follow-up was 7.38 points (p < 0.001). CHOP-INTEND scores did not decline for any patient. Patients with three or more SMN2 gene copies had higher scores than did the patients with two copies (p = 0.013), and they tended to show greater improvement over time, but the difference was not significant (p = 0.324). Shorter disease duration and higher CHOP-INTEND baseline score were associated with a better response (p = 0.015). Patients with a CHOP-INTEND score above the median had higher scores overall than the rest (p < 0.0013), and they improved significantly more than the rest (p = 0.037). Nusinersen was well tolerated, no new safety findings were identified. CONCLUSIONS AND CLINICAL IMPLICATIONS: Our data indicates that nusinersen treatment might be effective in SMA type 1 patients, regardless of their age and functional status.

Revision Hip Arthroplasty in Patient with Acetabulum Migration into Subperitoneal Space-A Case Report.

Revision hip arthroplasty procedures have been extensively discussed in the literature. At the same time, discussions of the management of acetabular component protrusion into the pelvic cavity, and, more specifically, the subperitoneal space, necessitating an additional abdominal approach for the revision arthroplasty, have only been published as case reports and descriptions of transperitoneal approaches have been even rarer. This paper presents the case of a 63-year-old female patient in whom a peritoneal approach was necessary to access a migrated acetabular component. The outcome of the treatment, which represented a complex orthopedic and general surgical problem, was good. We believe that the complexity of revision hip arthroplasty in patients with protrusion of the acetabular component together with the head and proximal part of the stem of the implant into subperitoneal space calls for a careful re-analysis of the category of Type III bony acetabulum defects according to Paprosky, where the recognition of two subtypes would facilitate analysis of such cases.

Spinal cord lesions in children and adolescents with multiple sclerosis - Magnetic resonance imaging.

PURPOSE: The purpose of our study was to determine the prevalence of spinal cord lesions revealed by magnetic resonance (MR) imaging in children and adolescents with clinically definite multiple sclerosis (MS). MATERIAL AND METHODS: We retrospectively evaluated the spinal cord magnetic resonance examinations in a group of MS patients consisting of 58 children (37 girls and 21 boys) aged from 7 to 17.8 years (mean 13.7 years). All children met the criteria of clinically definite MS and had typical MS lesions revealed in the brain imaging. RESULTS: Spinal cord lesions, regardless of localization, were identified in 36 (62%) patients. In 22 of 58 patients (38%) no lesions were observed. The plaques were found in the cervical spinal cord and the thoracic spinal cord in 30 out of 36 (86.1%) and in 31 out of 36 (88.6%) patients, respectively. Contrast enhancement was noticed in 10 out of 36 patients (27.7%) and was not correlated with the number of lesions present. We noticed a tendency to higher EDSS score in patients with lesions in more than 1 spinal cord region. Our study showed that spinal cord lesions are more frequently present in patients with complex neurological disability. CONCLUSION: The prevalence of spinal cord lesions in children and adolescents with MS is high. Therefore, spinal cord MRI should be included in diagnostic program of MS.

Analysis of the accuracy of the Wells scale in assessing the probability of lower limb deep vein thrombosis in primary care patients practice.

BACKGROUND: The clinical picture of deep vein thrombosis (DVT) is nonspecific. Therefore assessment of the probability of occurrence of DVT plays a very important part in making a correct diagnosis of DVT. The aim of our prospective study was to assess the accuracy of the Wells scale in primary care setting in diagnostic procedure of suspected deep vein thrombosis. METHODS: In the period of 20 - months (from 2007 to 2009) a group of residents from one of the urban districts of Warsaw, who reported to family doctors (22 primary care physicians were involved in the study) with symptoms of DVT were assessed on the probability of occurrence of deep vein thrombosis using the Wells scale. Family doctors were aware of symptoms of DVT and inclusion patients to this study was based on clinical suspicion of DVT. Patients were divided into three groups, reflecting probability of DVT of the lower limbs. To confirm DVT a compression ultrasound (CUS) test was established. We analyzed the relationship between a qualitative variable and a variable defined on an original scale (incidence of DVT versus Wells scale count) using the Mann-Whitney test. Chi-square test compared rates of DVT events in all clinical probability groups. Patient were follow up during 3 months in primary care setting. RESULTS: In the period of 20 months (from 2007 to 2009) a total number of 1048 patients (male: 250 , female: 798 mean age: 61.4) with symptoms suggestive of DVT of the lower extremities entered the study. Among the 100 patients classified in the group with a high probability of DVT of the lower extremities, 40 (40%) patients (proximal DVT - 13; distal DVT - 27) were diagnosed with it (95% CI [30.94% -49.80%]). In the group with a moderate probability consisting of 302 patients, DVT of the lower extremities was diagnosed in 19 (6.29%) patients (95% CI [4.06% -9.62%]), (proximal DVT - 1; distal DVT - 18). Of the 646 patients with a low probability of DVT of the lower extremities distal DVT was diagnosed in 1 (0.15%) patient (95% CI [0.03% -0.87%]). CONCLUSION: The Wells scale used in primary care setting demonstrated a high degree of accuracy.

Antiepileptic Effect and Safety Profile of Rapamycin in Pediatric Patients With Tuberous Sclerosis Complex.

Background: Epilepsy develops in 70-90% of children with Tuberous Sclerosis Complex (TSC) and is often resistant to medication. Treatment with mTOR pathway inhibitors is an important therapeutic option in drug-resistant epilepsy associated with TSC. Our study evaluated the antiepileptic effect of rapamycin in the pediatric population of patients diagnosed with TSC. Methods: This single center, open-label study evaluated safety and anti-epileptic efficacy of 12 months of rapamycin treatment in 32 patients aged from 11 months to 14 years with drug-resistant TSC- associated epilepsy. Results: After the first 6 months of treatment, the improvement in seizure frequency, defined as at least a 50% reduction in the number of seizures per week compared to baseline, was seen in 18 individuals (56.25%). We observed no change in 12 individuals (37.5%) and worsening, defined as increase in the number of seizures-in 2 patients (6.25%). The overall improvement defined as at least a 50% reduction in seizure frequency was found in 65.6% of all patients after 12 months with 28% of patients obtaining complete remission. Another five patients experienced at least an 80% reduction in the frequency of seizures. Concomitant treatment with vigabatrin, and to a much lesser extent topiramate and levetiracetam, was an additional favorable prognostic factor for the success of the therapy. A linear relationship between the cumulative dose of rapamycin and its therapeutic effect was observed. The safety profile of the drug was satisfactory. In none of the observed cases did the adverse events reach the level that required withdrawal of the rapamycin treatment. The reason for dropouts was insufficient drug efficacy in 3 cases. Conclusions: Long-term use of rapamycin, especially in combination with vigabatrin, might be a beneficial therapeutic option in the treatment of drug-resistant epilepsy in children with TSC.

Safety, tolerability, and efficacy of a widely available nusinersen program for Polish children with Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder with limited treatment options. Nusinersen is the first disease-modifying therapy to treat children and adults with SMA. This study aimed to review the safety, tolerability, and efficacy data of a nusinersen treatment program in Polish children. A total of 298 patients aged from 0 to 18 years were included in the nusinersen treatment program in Poland between March 1 and September 20, 2019. All patients were prospectively followed for at least one year. The mean age at treatment onset was 6.9 years. SMA type 1 symptoms were reported in 127 patients (43.5%), SMA type 2 symptoms in 68 cases (23.3%), and SMA type 3 in 93 patients (31.8%). No patient met the inefficiency criteria defined in the program. One year after treatment initiation, all patients assessed by the CHOP-INTEND scale had improved or remained stable. The mean change in CHOP-INTEND score was an increase of 8.9 points between baseline and after one-year treatment (p < 0.001). Except for 2 fatal cases, not related to the treatment, no serious adverse events were reported. The results of our study indicate that treatment with nusinersen is beneficial for children with SMA regardless of their age, baseline functional status, or the number of SMN2 gene copies. Therapy with nusinersen was effective and well tolerated by patients.

Cerebral tuber count and its impact on mental outcome of patients with tuberous sclerosis complex.

PURPOSE: The aim of the study was to reveal the relationships between the tuber count of the brain found in patients with tuberous sclerosis complex (TSC) and their cognitive outcome. METHODS: A single-center, retrospective analysis was performed of patients with documented TSC seen from 1988 to 2010 at the Children's Memorial Health Institute, Warsaw, Poland. KEY FINDINGS: Sixty-two patients were analyzed, and there was a significant correlation between younger age at the first seizure and developmental delay. The patients who did not develop seizures had normal development, despite some presenting with higher tuber load than those with seizures. There was a statistically significant negative correlation between the number of tubers within the right temporal lobe and cognition. SIGNIFICANCE: Our findings confirm our hypothesis that the cognitive outcome in TSC is more dependent on the age of the seizure onset rather than on the tuber count.

Germinoma Mimicking Brain Inflammation: A Case Report.

The authors report a case of a germinoma of the brain in the child with symptoms restricted to central nervous system. Ten-year-old girl presented initially with sight deterioration, learning difficulties, abnormal behavior, polydipsia, and polyuria. Brain magnetic resonance examination revealed T2 hyperintensity of the corpus callosum, anterior commissure, and caudate nuclei. Brain biopsy revealed extensive macrophage infiltration. Given these results and positive antinuclear antibodies in the blood, immunosuppressive and immunomodulatory treatment was implemented but it was not effective. The patient developed progressive quadriparesis, sleep disturbances, and dementia. Second brain biopsy was performed and it revealed germinoma cells. Chemotherapy was administered, but the girl died due to disseminated intravascular coagulation syndrome. The reported case shows an unusual coexistence of germinoma with prominent inflammation in the brain and highlights the importance of brain biopsy in such complex cases.

Preventive Antiepileptic Treatment in Tuberous Sclerosis Complex: A Long-Term, Prospective Trial.

BACKGROUD: Drug-resistant epilepsy is the main risk factor for future intellectual disability in patients with tuberous sclerosis complex. Clinical epileptic seizures are often preceded by electroencephalographic changes, which provide an opportunity for preventive treatment. We evaluated the neuropsychologic and epilepsy outcomes at school age in children with tuberous sclerosis complex who received preventive antiepileptic treatment in infancy. METHODS: We performed a prospective, nonrandomized clinical trial with 14 infants diagnosed with tuberous sclerosis complex in whom serial electroencephalographic recordings were performed and preventive treatment with vigabatrin initiated when active epileptic discharges were detected. An age-matched control group consisted of 31 infants with tuberous sclerosis complex in whom treatment with vigabatrin was given only after onset of clinical seizures. Results of clinical assessment of epilepsy and cognitive outcomes were analyzed. RESULTS: All patients in the preventive group (n = 14) and 25 of 31 patients in the standard treatment group were followed through minimum age five years, median 8.8 and 8.0 years in the preventive and standard groups, respectively. The median intelligence quotient was 94 for the preventive group when compared with 46 for the standard group (P < 0.03). Seven of 14 patients (50%) in the preventive group never had a clinical seizure when compared with one of 25 patients (5%) in the standard treatment group (P = 0.001). CONCLUSIONS: This study provides evidence that preventive antiepileptic treatment in infants with tuberous sclerosis complex improves long-term epilepsy control and cognitive outcome at school age.

The frequency of mitochondrial polymerase gamma related disorders in a large Polish population cohort.

Diseases related to DNA polymerase gamma dysfunction comprise of heterogeneous clinical presentations with variable severity and age of onset. Molecular screening for the common POLG variants: p.Ala467Thr, p.Trp748Ser, p.Gly848Ser, and p.Tre251Ile has been conducted in a large population cohort (n = 3123) and in a clinically heterogeneous group of 1289 patients. Recessive pathogenic variants, including six novel ones were revealed in 22/26 patients. Infantile Alpers-Huttenlocher syndrome and adulthood ataxia spectrum were the most common found in our group. Distinct molecular profile identified in the Polish patients with significant predominance of p.Trp748Ser variant (50% of mutant alleles) reflected strikingly low population frequency of the three remaining variants and slightly higher p.Trp748Ser allele frequency in the general Polish population as compared to the non-Finish European population.

Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6000 live births and associated with the development of benign tumors in several organs. It is also characterized by high rates of neurological and neuropsychiatric abnormalities, including epilepsy affecting 70-90% of patients and being one of the major risk factors of intellectual disability. The first seizures in TSC patients appear usually between the 4th and the 6th months of life. Recent studies have shown the beneficial role of preventative antiepileptic treatment in TSC patients, with the possibility for improvement of cognitive outcome. Moreover, European recommendations suggest early introduction of Vigabatrin if ictal discharges occur on EEG recordings, with or without clinical manifestation. The aim of this study was to define the most useful approach to make the diagnosis of TSC before seizure onset (before age 4th months), in order to start early EEG monitoring with possible preventative treatment intervention. METHODS: We performed a retrospective review of children who were suspected of having TSC due to single or multiple cardiac tumors as the first sign of the disease. We analyzed the medical records in terms of conducted clinical tests and TSC signs, which were observed until the end of the 4th month of age. Subsequently, we described the different clinical scenarios and recommendations for early diagnosis. RESULTS: 82/100 children were diagnosed with TSC within the first 4 months of life. Apart from cardiac tumors, the most frequently observed early TSC signs were subependymal nodules (71/100, 71%), cortical dysplasia (66/100, 66%), and hypomelanotic macules (35/100, 35%). The most useful clinical studies for early TSC diagnosis were brain magnetic resonance imaging (MRI), skin examination and echocardiography. Genetic testing was performed in 49/100 of the patients, but the results were obtained within the first 4 months of life in only 3 children. CONCLUSIONS: Early diagnosis of TSC, before seizure onset, is feasible and it is becoming pivotal for epilepsy management and improvement of cognitive outcome. Early TSC diagnosis is mostly based on clinical signs. Brain MRI, echocardiography, skin examination and genetic testing should be performed early in every patient suspected of having TSC.

Liver Angiomyolipomas in Tuberous Sclerosis Complex-Their Incidence and Course.

BACKGROUND: The purpose of this study was to evaluate the epidemiology and clinical significance of hepatic angiomyolipomas in patients with tuberous sclerosis complex. METHODS: We performed a retrospective analysis of clinical and imaging data from 187 patients with tuberous sclerosis complex. The prevalence, progression, and potential relationship between liver lesions and other clinical findings, including genetic associations, were assessed. RESULTS: Twenty-eight of 187 patients (14.9%) had hepatic lesions. There was a predominance of female over male patients in individuals with liver lesions (17 versus 11), with statistical significance in patients under five years of age (P < 0.05). All individuals having hepatic lesions who also had available genetic testing data (n = 20) were diagnosed with a TSC2 gene mutation. All patients with liver lesions had coexisting renal angiomyolipomas (AMLs) (P < 0.05). The age of onset of renal lesions was lower and their prevalence was significantly higher in patients with liver involvement (P < 0.05). In most instances, hepatic lesions measured several millimeters in diameter and were clinically asymptomatic. Progressive lesion growth was documented in six individuals but with no clinical consequences to date. CONCLUSIONS: This study confirms the association of hepatic lesions with TSC2 mutations, a common origin of liver and renal AMLs, as well as the predominance of female patients in this group. Hepatic AMLs are relatively common but mostly benign lesions.

Osteoporotic fractures - reduction of the risk is possible.

Osteoporosis is a widely known but still poorly understood disease. It is one of the most common causes of pain complaints in older persons. The aim of osteoporosis treatment is to prevent fractures, which are often the primary clinical manifestation of osteoporosis. All preventive measures are more effective when they are introduced at an early stage. An important role is assigned to achieving a high peak bone mass and eliminating nutritional risk factors in the early decades of life. It is essential to achieve broad public awareness of osteoporosis and the risk factors for subsequent fractures. The effectiveness of fracture prevention efforts, regardless of the methods applied, is a function of the timing of their introduction. It is highest in the group of patients without fractures, but should be implemented in all patients, even in cases with several broken vertebras and both distal radii. It is never too late for effective treatment. Proper procedures in the initial treatment of fractures are also important. Methods allowing for early mobilization and restoration of physical activity after fracture are of vital importance. This problem, widely discussed in the orthopedic environment, was definitively addressed by the document entitled "Recommendations for Care of the Osteoporotic Fracture Patient to Reduce the Risk of Future Fracture," developed and published in 2004 by the World Orthopedic Osteoporosis Organization (WOOO). Similar initiatives have begun to appear in Poland, initiated by the National Consultant for Orthopedics and the President of the Polish Orthopedics and Traumatology Society. The aim of this work is to prepare diagnostic and therapeutic protocols for all patients with low-energy fractures, to prevent deterioration of disease symptoms, and to minimize the risk of subsequent fractures.

The evaluation of social awareness of osteoporosis, based on the aimed questionnaire.

BACKGROUND: Osteoporosis is the most common osteopathy. Osteoporosis is recognized by World Health Organization as a civilization disease. Still, the awareness of osteoporosis in polish society is unknown. The aim of the study is demographic evaluation of people who are interested in diagnosis and treatment of osteoporosis. Another aim is to analyze data such as age, sex, fracture occurrence, style of life of people who have phoned to Osteoporosis Information Telephone (OIT). MATERIAL AND METHODS: The analysis was based on 501 individuals (446 women, 55 men). The evaluated parameters were age, sex, place of living, education, risk factor awareness, fracture occurrence and the source of knowledge about OIT. The auxiliary questions concerned previous diagnosis and treatment. RESULTS: In 83,3 % of analyzed group the general information about osteoporosis was acquired from newspapers, 13,11% from books and folders, 3 % from radio programmes, 0,4 % from TV, and 0,19% from internet. 23,5% of people acquired information about OIT from magazines including weekly TV programme. 148 people (29,5%) were examined by densitometry. 57 people (11,3%) had a previous history of bone fractures. CONCLUSIONS: Our study helps to evaluate the social awareness of osteoporosis in people interested in this problem. We hope that our results will help to rise social awareness of osteoporosis thanks to new medial advertising companies in the future and will become the base for others analyzes of osteoporosis.

[Pulmonary embolism in course of deep vein thrombosis of lower extremities in patient wit bilateral femoral bone fracture after car accident injuries]. / Zator tetnicy plucnej w przebiegu zakrzepicy zyl glebokich konczyn dolnych u chorego z obustronnym zlamaniem kosci udowej.

The incidence of deep vein thrombosis in Western World is estimated at about 1 case/1000/year and of pulmonary embolism at 0.5 case/1000/year. Mortality in untreated pulmonary embolism is 30%. With adequate treatment (anticoagulation) it can be decreased to 2-8%. Deep vein thrombosis and pulmonary embolism are frequent complications of various surgical procedures, especially of orthopedic interventions on hip joint. When surgery has to be performed in patient with high risk of pulmonary embolism, anticoagulant prophylaxis should be performed. Venous thromboembolic disease is the most important cause of mortality in trauma patients. We present a case of 46 years old man with bilateral fracture of femoral bone after car accident injury in whom signs of deep venous thrombosis and pulmonary embolism were observed despite the use of anticoagulant prophylaxis.

Mechanical properties of subchondral bone in degenerative joint disease.

Analysis of the role which subchondral bone plays in etiopathogenesis of the arthrotic joint diseases continues for a long time. Introduction of the new imaging techniques helps to evaluate those changes clearly. The work is a presentation of the current views on correlation between changes in bone and overlaying articular surfaces in consideration with potential possibilities of therapeutic intervention. It also contains a discussion on the Ball'a theory from 1966, who thought that osteoarthrosis protects against osteoporosis. Actually, it's well known, that both processes coexists and could be correlated. Kaneko's theories presented in this paper, helps to evaluate the role of inflammatory cytokines and proteinases in subchondral destruction and arthrosis. Probably in this field we can find the possible way to modify this process in modern therapies.

Results of vertebral fractures treatment in osteoporosis in own material.

Background. Vertebral fractures in patients with osteoporosis are the most serious complication of this disease. It seems to be an important therapeutic problem, because of the intensity of the pain syndrome. Introduction presents classification, imaging and differential diagnostics, presentation of therapeutic intervention used in clinical practice.
Material and methods. The work is a retrospective clinical analysis of vertebral fractures treatment results from the period 1997- 2000. Material consists of 64 (58 women and 6 men) in average age of 69 (56-77) cases with spine fractures and osteoporosis treated with, presented in introduction protocol.
Results. 41% of this group declared the pain occurring rare, and 59% - frequently.

Problems in the treatment of lower limb fractures in osteoporosis.

The fractures are the clinical manifestation of osteoporosis, the most common metabolic bone disease. It leads do decreased mechanical resistance of bone and increased ability of fractures. Identification of risk factors, bone mineral density and bone markers measures helps to identify and control the severity of the problem. However, the characteristics of the disorder obliges the specific conditions in treatment of the traumatic lesions to the locomotor system related to osteoporosis. The first rule is the need to achieve the fastest mobilization of the patient. The choice of the treatment method should take the age and general condition of the patient to consideration. The work presents the principles of proceedings in treatment of traumatic lesions of the lower extremities resulting from osteoporosis with consideration of the antithrombotic prophylaxis. Matching the method with relation to fracture type, general condition of the patient, coexisting diseases as well as the center ability and experience is still valid condition.

Treatment of osteoporotic vertebral fractures.

The problem of vertebral fractures is a frequent topic in scientific publications that deal with osteoporosis. After a series of reports regarding successful vertebro- and kyphoplasty in 2001-2002, more is now being said and written about the need to unify treatment protocols for these disorders. The present study gives the authors' own classification for the stages in the treatment of osteoporotic vertebral fractures, along with a detailed description of the actions to be taken during each phase of the treatment protocol.

Principles of diagnostic - therapeutic proceedings in back pain.

"Back pain" is a common cause of specialistic medical consultations. Diagnostics and treatment requires and individualized proceedings, but it's rules should be followed.
The principles, with consideration to national reality of medical care system, were formed due to initiative of Orthopaedics Department of Warsaw Medical University, on multidisciplinary meeting (called Back Pain School) in 1998, and precisely edited by Spondyloorthopaedics Section of PTOiTr (Polish Society of Orthopaedics and Traumatology of the Locomotor System).
The principles are in use in both orthopaedic departments, in Warsaw and in Poznan since the end of 1998. They assume the parallel diagnostic and therapeutic action in assessment of acute back pain syndromes. They involve the use of an aggressive pharmacotherapy with NSAIDs, myorelaxants, other methods of pain control (radicular, truncal and intrathecal blocks) and manual therapy. Just after a carefull clinical evaluation and decrease of pain, the conventional radiological diagnostics is required. It allows to classify correctly a clinical diagnosis and the treatment orientation. It also permits to reduce costs of the proceedings which usually, especially in other medical specialties, comprise an advanced imaging diagnostics including magnetic resonance and computed tomography.
The aim of this work is to remind a history of action and backgrounds, which lead to a system of diagnostic - therapeutic proceedings in back pain creation in our country.