Clinical Neuroscience

[Effective therapy in highly active pediatric multiple sclerosis ]

MERÔ Gabriella1, MÓSER Judit2, LIPTAI Zoltán3, DIÓSZEGHY Péter1, BESSENYEI Mónika4, CSÉPÁNY Tünde5

NOVEMBER 30, 2021

Clinical Neuroscience - 2021;74(11-12)

DOI: https://doi.org/10.18071/isz.74.0413

Case Reports

[Multiple sclerosis (MS) is typically a disease of young adults. Childhood MS can be defined in patients under 18 years of age, although some authors set the limit un­der the age of 16 formerly known as “early-onset multiple sclerosis” or “juvenile multiple sclerosis”, seen in 3-5% of all MS patients. Nowadays, owing to ever-evolving, better diagnostic tools and well-traced, strictly defined diagnostic criteria, childhood MS is showing an increasing incidence worldwide (0.05-2.85/100 000). MS is characterized by recurrent episodes of the central nervous system with demyelination separated in space and time. In childhood almost exclusively the relapsing-remitting (RR) type of MS occurs. Based on experience in adults, the goal in the pediatric population is also the early diagnosis, to initiate adequate DMT as soon as possible and to achieve symptom relief and good quality of life. Based on efficacy and safety studies in the adult population, inter­feron β-1a and glatiramer acetate were first approved by the FDA and EMA for the treatment of childhood MS also. The increased relapse rate and rapid progression of childhood MS and unfavorable therapeutic response to nearly 45% of the first DMT necessitated the testing of more effective and second-line drugs in the population under 18 years of age (PARADIGMS, CONNECT). Although natalizumab was reported to be effective and well-tolerated in highly active RRMS in childhood, evidence based studies were not yet available when our patients’ treatment started. In this article, we report on the successful treatment of three active RRMS patients with individually authorized off-label use of natalizumab.]

AFFILIATIONS

  1. Szabolcs-Szatmár-Bereg Megyei Kórházak és Egyetemi Oktatókórház, Jósa András Oktatókórház, Nyíregyháza
  2. Heim Pál Gyermekkórház, Budapest
  3. Semmelweis Egyetem, II. Sz. Gyermekklinika, Budapest
  4. Debreceni Egyetem, Általános Orvostudományi Kar, Gyermekgyógyászati Tanszék Debrecen
  5. Debreceni Egyetem, Általános Orvostudományi Kar, Neurológiai Tanszék, Debrecen

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Clinical Neuroscience

Fluoxetine use is associated with improved survival of patients with COVID-19 pneumonia: A retrospective case-control study

NÉMETH Klára Zsófia, SZÛCS Anna , VITRAI József , JUHÁSZ Dóra , NÉMETH Pál János , HOLLÓ András

We aimed to investigate the association between fluoxetine use and the survival of hospitalised coronavirus disease (COVID-19) pneumonia patients. This retrospective case-control study used data extracted from the medical records of adult patients hospitalised with moderate or severe COVID-19 pneumonia at the Uzsoki Teaching Hospital of the Semmelweis University in Budapest, Hungary between 17 March and 22 April 2021. As a part of standard medical treatment, patients received anti-COVID-19 therapies as favipiravir, remdesivir, baricitinib or a combination of these drugs; and 110 of them received 20 mg fluoxetine capsules once daily as an adjuvant medication. Multivariable logistic regression was used to evaluate the association between fluoxetine use and mortality. For excluding a fluoxetine-selection bias potentially influencing our results, we compared baseline prognostic markers in the two groups treated versus not treated with fluoxetine. Out of the 269 participants, 205 (76.2%) survived and 64 (23.8%) died between days 2 and 28 after hospitalisation. Greater age (OR [95% CI] 1.08 [1.05–1.11], p<0.001), radiographic severity based on chest X-ray (OR [95% CI] 2.03 [1.27–3.25], p=0.003) and higher score of shortened National Early Warning Score (sNEWS) (OR [95% CI] 1.20 [1.01-1.43], p=0.04) were associated with higher mortality. Fluoxetine use was associated with an important (70%) decrease of mortality (OR [95% CI] 0.33 [0.16–0.68], p=0.002) compared to the non-fluoxetine group. Age, gender, LDH, CRP, and D-dimer levels, sNEWS, Chest X-ray score did not show statistical difference between the fluoxetine and non-fluoxetine groups supporting the reliability of our finding. Provisional to confirmation in randomised controlled studies, fluoxetine may be a potent treatment increasing the survival for COVID-19 pneumonia.

Clinical Neuroscience

Atypical presentation of late-onset Sandhoff disease: a case report

SALAMON András , SZPISJAK László , ZÁDORI Dénes, LÉNÁRT István, MARÓTI Zoltán, KALMÁR Tibor , BRIERLEY M. H. Charlotte, DEEGAN B. Patrick , KLIVÉNYI Péter

Sandhoff disease is a rare type of hereditary (autosomal recessive) GM2-gangliosidosis, which is caused by mutation of the HEXB gene. Disruption of the β subunit of the hexosaminidase (Hex) enzyme affects the function of both the Hex-A and Hex-B isoforms. The severity and the age of onset of the disease (infantile or classic; juvenile; adult) depends on the residual activity of the enzyme. The late-onset form is characterized by diverse symptomatology, comprising motor neuron disease, ataxia, tremor, dystonia, psychiatric symptoms and neuropathy. A 36-year-old female patient has been presenting progressive, symmetrical lower limb weakness for 9 years. Detailed neurological examination revealed mild symmetrical weakness in the hip flexors without the involvement of other muscle groups. The patellar reflex was decreased on both sides. Laboratory tests showed no relevant alteration and routine electroencephalography and brain MRI were normal. Nerve conduction studies and electromyography revealed alterations corresponding to sensory neuropathy. Muscle biopsy demonstrated signs of mild neurogenic lesion. Her younger brother (32-year-old) was observed with similar symptoms. Detailed genetic study detected a known pathogenic missense mutation and a 15,088 base pair long known pathogenic deletion in the HEXB gene (NM_000521.4:c.1417G>A; NM_000521:c.-376-5836_669+1473del; double heterozygous state). Segregation analysis and hexosaminidase enzyme assay of the family further confirmed the diagnosis of late-onset Sandhoff disease. The purpose of this case report is to draw attention to the significance of late-onset Sandhoff disease amongst disorders presenting with proximal predominant symmetric lower limb muscle weakness in adulthood.

Clinical Neuroscience

Cholinesterase inhibitors and memantine for the treatment of Alzheimer and non-Alzheimer dementias

BALÁZS Nóra , BERECZKI Dániel, KOVÁCS Tibor

In aging societies, the morbidity and mortality of dementia is increasing at a significant rate, thereby imposing burden on healthcare, economy and the society as well. Patients’ and caregivers’ quality of life and life expectancy are greatly determined by the early diagnosis and the initiation of available symptomatic treatments. Cholinesterase inhibitors and memantine have been the cornerstones of Alzheimer’s therapy for approximately two decades and over the years, more and more experience has been gained on their use in non-Alzheimer’s dementias too. The aim of our work was to provide a comprehensive summary about the use of cholinesterase inhibitors and memantine for the treatment of Alzheimer’s and non-Alzheimers’s dementias.

Clinical Neuroscience

[Relationships between COVID-19 disease, nutritional status, and dysphagia, particularly in stroke patients ]

KOVÁCS Andrea, SZABÓ Pál Tamás, FOLYOVICH András

[The new coronavirus, SARS-CoV-2, which causes the COVID-19 disease can lead to severe acute respiratory distress syndrome (ARDS). It poses a serious challenge to the health care system, especially intensive care. Neurological patients, usually of advanced age and with a myriad of comorbidities, are at particular risk through the impact of the new coronavirus on their condition and nutritional capacity. Stroke is a leader in morbidity and mortality data, with a focus on dysphagia and its complications due to COVID-19 disease and acute cerebrovascular accident. In the acute phase of stroke, 30-50% of patients suffer from dysphagia, which still shows a prevalence of 10% six months later. Dysphagia results in decreased or insufficient fluid and nutrient uptake, supp­lemented by inactivity, leading to malnutrition and sarcopenia, which worsens overall condition, outcome, and rehabilitation efficiency. Screening and early detection of swallowing disorders is a fundamental issue in order to develop a personalized and timely-initiated nutritional therapy strategy. Nutritional therapy plays a key role in frequent intensive care due to COVID-19 disease, where it increases the chances of recovery and reduces the length of stay in the intensive care unit and mortality. This is especially true in critically ill patients requiring prolonged ventilation. In COVID-19 diagnosed patients, screening for dysphagia, bedside assessment, and instrumental examination, followed by swallowing rehabilitation, are of paramount importance. Stroke can also be a complication of the COVID-19 infection. Care for cerebrovascular patients has also adapted to the pandemic, “triazination” has become systemic, and dysphagia screening for stroke patients and nutritional therapy adapted to it have also shed new light. ]

Clinical Neuroscience

Diagnostic values of conventional conduction parameters in ulnar neuropathy at elbow

ALEMDAR Murat

Conventional parameters used in electrodiagnosis of ulnar neuropathy at elbow (UNE) are: (i) absolute across-elbow ulnar nerve motor conduction velocity (MCV), (ii) reduction rate of composed muscle action potential (CMAP) amplitude from above to below elbow stimulation, and (iii) MCV difference between forearm and across-elbow segment. We aimed to search the diagnostic accuracy values of these parameters on UNE, and their correlations with axonal dysfunction of ulnar nerve fibers. Arms with clinical signs of UNE and two-fold healthy controls were included. We detected the best cut off points of the measured parameters and their possible combinations. Their diagnostic accuracy values and correlations with parameters reflecting the axonal functions were analyzed, statistically. Totally, 118 arms with UNE and 236 controls were included. Absolute across-elbow MCV yielded a higher accuracy than MCV difference and reduction rate of CMAP amplitude (p = 0.010 and p˂0.001, respectively). Besides, combining it with other parameters did not increase the diagnostic yield. Correlation analyses revealed that the only parameter having positive linear correlations with sensory nerve action potential amplitudes both in the control and the disease groups is the absolute across-elbow MCV. The absolute across-elbow MCVs have also positive linear correlation with CMAP amplitudes in disease group. The absolute across-elbow MCV is the most valuable conventional parameter for the electrodiagnosis of UNE. It is also the most correlated parameter with the electrodiagnostic parameters reflecting the axonal functions of the ulnar nerve fibers.

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Clinical Neuroscience

[Is second-line immunomodulatory treatment effective in multiple sclerosis?]

RÁCZ Lilla, BERÉNYI Ervin, BARSI Péter, BERNÁTH Dávid, CSÉPÁNY Tünde

[Purpose - Natalizumab is the first evidence based monoclonal antibody, which was launched for treatment in relapsing remitting multiple sclerosis in Hungary in 2010. Standardized follow-up is required to use it. Our aim was to evaluate the efficacy and to monitor the safety of natalizumab treatment by using an electronic database established for MS registry. Clinical activity was measured by annual relapse rates, functional status of patients measured by EDSS and MFSC. Radiological activity was evaluated by standard MRI protocol. Data, results of MS patients and side effects of natalizumab treatment were recorded in iMed software. Results - 31 patients started the natalizumab treatment after 6.5±5.8 years from the onset of MS. The efficacy of treatment was evaluated after a mean of 67 (min: 14 max: 128) infusions in December 2016. The drop-out rate was low, due to the presence of neutralising antibodies in one case, pregnancy in two cases and development of malignant disease in one case which was not related to the natalizumab treatment. The treatment was well tolerated with excellent compliance without serious side effects. The annual relapse rate reduced from a mean of 1.7 to 0.03 (p<0.000001) in the first 12 months of treatment compared to the pretreatment 12 month activity, and it stayed at low level during the whole follow up. EDSS was stable or improved with an exception of two cases. In 23 subjects (77%) lack of new/enlarging T2 lesions and lack of gadolineum-enhancing lesions on MRI were observed. 18 patients (60%) had no evidence of disease activity (NEDA-3). PASAT test improved in most of the cases. Conclusion - The natalizumab therapy was very effective in all cases including those patients who had active disease under the previous immunomodulatory treatment.]

Clinical Neuroscience

[Experience with natalizumab-treatment at Semmelweis University]

GOMBOS Barbara, ILJICSOV Anna, BARSI Péter, HEGEDÛS Katalin, SIMÓ Magdolna

[Multiple sclerosis is an autoimmune demyelinating disorder of the central nervous system. During the last two decades, numerous disease modifying drugs have been introduced for the treatment of the relapsing-remitting form of the disease. Since 2010, natalizumab (NTZ) treatment has been used as a second-line therapy for patients with breakthrough disease. In comparison to conventional immunomodulant drugs, NTZ has a more specific effect in that it prevents the entry of immune cells into the central nervous system without interfering with systemic immune response. The efficacy and the safety of NTZ have been confirmed by several studies. The most severe side-effect of NTZ is progressive multifocal leukoencephalopathy, which has been associated with an increased incidence in patients with anti-JCV antibody positivity, and in those who have been undergoing NTZ treatment for over two years and who have received prior immunosuppressive therapy. In the present study, our experience with natalizumab treatment of 37 patients at the Department of Neurology of Semmelweis University during the last 6 years is presented. We have observed a significant decrease of disease activity in our patients; in many cases the disease has become inactive both clinically (36/37) and radiologically (34/37). The patients’ quality of life has improved significantly during the treatment. In accordance with the literature, we confirm that NTZ is a highly effective treatment in a carefully selected patient group, and can be administered without significant inconvenience to the patient. ]

Clinical Neuroscience

[Immunomodulatory treatment in multiple sclerosis ]

CSÉPÁNY Tünde, BERECZKI Dániel

[During the past decade, several disease-modifying agents have been established and have become available for the treatment of multiple sclerosis. The disease-modifying agents could be grouped into immunomodulatory and immunosuppressive therapies altering the long-term course of multiple sclerosis. Therapy is now available for relapsing-remitting, secondary progressive and progressive-relapsing multiple sclerosis. Different disease-modifying agents became also available for the treatment of relapsing-remitting multiple sclerosis in Hungary which makes the therapeutic decision difficult. This overview might help to give an answer for different questions in the management of multiple sclerosis: Which agent to choose? When to initiate the therapy? Which dose to apply? Are the drugs safe? How long to treat the patients with immunomodulatory drugs? We give a review from the literature to assess the efficacy of disease-modifying therapies and to compare the data from phase three trials of interferon β1b, two preparations of interferon β1a or glatiramer acetate for the treatment of multiple sclerosis. We analyzed the efficacy and safety of these agents on physical, inflammatory and cognitive measures of disease activity. Comparison of study results indicated similar effects of immunomodulatory agents on relapse-related and inflammatory measures in relapsing multiple sclerosis. Interferon β1a slowed the progression of disability in relapsing multiple sclerosis. One interferon β1a preparation (intramuscularly injected) demonstrated efficacy in slowing progression of cognitive dysfunction. The interferons reduced relapses at early phase of secondary progressive multiple sclerosis, but their efficacy have not yet been proven in the later phase of secondary progressive multiple sclerosis without relapses. Mitoxantrone demonstrated efficacy in slowing the progression of disability in secondary progressive multiple sclerosis. All of the disease modifying agents are safe and tolerable, if the indication is correct and the patients are strictly controlled.]

Clinical Neuroscience

[Natalizumab therapy, 2013]

KARÁCSONY Mária, BENCSIK Krisztina, VÉCSEI László

[Multiple sclerosis (MS) is the most common chronic disease of the central nervous system in young adults. No curative therapy is known. Currently, six drugs are available that can reduce the activity of MS. The first-line drugs can completely reduce the activity of the disease in nearly two-thirds of the patients. In the remainder, who suffer from breakthrough disease, the condition of the patient worsens, and secondline therapies must be used. The second-line drug natalizumab exhibits almost double efficacy of the first-line drugs, but also have less favourable adverse effects. As a severe side-effect for instance, natalizumab carries the risk of the development of progressive multifocal leucoencephalopathy (PML), caused by a polyoma virus, the JC virus. There are three major risk factors for PML: an anti-JCV antibody status, a long duration of natalizumab treatment and prior immunosuppressant therapy. The lowest-risk group (1:14 286) comprises of patients who are anti-JCV antibody-negative, in whom the prior immunosuppressant use and duration of natalizumab therapy do not influence the risk of PML. With no prior immunosuppressant treatment, the incidence of PML increases to 1 in 192 patients after 2 years among those who are anti-JCV antibody-positive. These data may lead the physician to decide to discontinue natalizumab treatment. The half-life of natalizumab is three months; during this time other therapies can not be administered and the patients encounter the rebound effect: as the patients receiving natalizumab therapy displayed a high disease activity before treatment, the rebound effect can lead to relapses. After the termination of natalizumab secondline disease-modifying therapy with fingolimod may be introduce; no PML cases occur in response to fingolimod treatment. In the large majority of patients taking natalizumab who do not develop PML, this drug is highly effective and can prevent the progression of MS. The benefit of therapy and the risk of PML must be considered on an individual basis, with regard to the disease activity, the progression and the MRI activity, before natalizumab therapy is implemented.]

Lege Artis Medicinae

[IMMUNE-MEDIATED NEUROLOGICAL DISORDERS]

CSÉPÁNY Tünde

[Multiple sclerosis, myasthenia gravis and chronic inflammatory neuropathies share the common feature of chronic course with potential development of disability due to the damage caused by immunological processes. Early detection and precise diagnosis is very important, because most patients respond well to proper immunomodulatory treatment. The diagnosis requires extensive knowledge of the disease and is based on the clinical symptoms recognised by the GP, as well as on complex assessment of the results of special neurophysiological, radiological and laboratory examinations. The present paper reviews the major immune-mediated neurological disorders and discusses their targeted immunological treatment.]