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Two cases of progressive multifocal leukoencephalopathy (PML) are reported in patients with psoriasis who were treated with fumarates, one with Fumaderm and the other with a compound containing dimethyl fumarate. The manufacturer of Fumaderm comments on the reports. To the Editor: Fumaric acid is considered effective and safe in the treatment of psoriasis vulgaris 1 and is licensed for this use in Germany. We diagnosed progressive multifocal leukoencephalopathy (PML) in a 74-year-old man who had received monotherapy for psoriasis with oral fumaric acid for 3 years (2007 through 2010) in doses of up to 120 mg of dimethyl fumarate and 95 mg of monoethyl fumarate, each taken two times a day. The patient had had psoriasis for more than 5 years and had been treated topically with glucocorticoids (January through May 2005) and orally with acitretin (maximum dose of . . .

The SARS-Coronavirus-2 (SARS-CoV-2) invades the respiratory system, causing acute and sometimes severe pulmonary symptoms, but turned out to also act multisystematically with substantial impact on the brain. A growing number of studies suggests a diverse spectrum of neurological manifestations. To investigate the spectrum of symptoms, we here describe the neurological manifestations and complications of patients with proven SARS-CoV-2 infection who have been hospitalized at the RWTH University Hospital Aachen, Germany. Between March and September 2020, we evaluated common symptoms, clinical characteristics, laboratory (including cerebrospinal fluid (CSF) analysis), radiological, and electroencephalography (EEG) data from 53 patients admitted with a positive SARS-CoV-2 polymerase chain reaction (PCR). We used the Montreal Cognitive Assessment Test (MoCA) to screen for cognitive impairment, when feasible. We compared critically ill and non-critically ill patients categorized according to the presence of Acute Respiratory Distress Syndrome (ARDS). Major clinical neurological features of hospitalized COVID-19 patients were coordination deficits (74%), cognitive impairment (61.5%), paresis (47%), abnormal reflex status (45%), sensory abnormalities (45%), general muscle weakness and pain (32%), hyposmia (26%), and headache (21%). Patients with ARDS were more severely affected than non-ADRS patients. 29.6% of patients with ARDS presented with subarachnoid bleedings, and 11.1% showed ischemic stroke associated with SARS-CoV-2 infection. Cognitive deficits mainly affected executive functions, attention, language, and delayed memory recall. We obtained cerebrospinal fluid (CSF) by lumbar puncture in nine of the 53 patients, none of which had a positive SARS-CoV-2 PCR. In line with previous findings, our results provide evidence for a range of SARS-CoV-2-associated neurological manifestations. 26% of patients reported hyposmia, emphasizing the neuro-invasive potential of SARS-CoV-2, which can enter the olfactory bulb. It can therefore be speculated that neurological manifestations may be caused by direct invasion of the virus in the CNS; however, PCR did not reveal positive intrathecal SARS-CoV-2. Therefore, we hypothesize it is more likely that the para-infectious severe pro-inflammatory impact of COVID-19 is responsible for the neurological deficits including cognitive impairment. Future studies with comprehensive longitudinal assessment of neurological deficits are required to determine potential long-term complications of COVID-19.

Objectives We aimed to objectify and compare persisting self‐reported symptoms in initially hospitalized and non‐hospitalized patients after infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) by applying clinical standardized measures. Methods We conducted a cross‐sectional study of adult patients with confirmed SARS‐CoV‐2 infection including medical history, neurological examination, blood markers, neuropsychological testing, patient‐reported outcome measures (PROMs), and brain magnetic resonance imaging (MRI). Results Fifty patients with persisting symptoms for at least 4 weeks were included and classified by initial hospitalization status. Median time from SARS‐CoV‐2 detection to investigation was 29.3 weeks (range 3.3–57.9). Although individual cognitive performance was generally within the normative range in both groups, mostly mild deficits were found in attention, executive functions, and memory. Hospitalized patients performed worse in global cognition, logical reasoning, and processes of verbal memory. In both groups, fatigue severity was associated with reduced performance in attention and psychomotor speed tasks (rs = −0.40, p < 0.05) and reduced quality of life (EQ5D, rs = 0.57, p < 0.001) and with more persisting symptoms (median 3 vs. 6, p < 0.01). PROMs identified fatigue, reduced sleep quality, and increased anxiety and depression in both groups but more pronounced in non‐hospitalized patients. Brain MRI revealed microbleeds exclusively in hospitalized patients (n = 5). Interpretation Regardless of initial COVID‐19 severity, an individuals' mental and physical health can be severely impaired in the long‐term limitedly objectified by clinical standard diagnostic with abnormalities primarily found in hospitalized patients. This needs to be considered when planning rehabilitation therapies and should give rise to new biomarker research.

The European Friedreich’s Ataxia Consortium for Translational Studies (EFACTS) is a prospective international registry investigating the natural history of Friedreich’s ataxia. We used data from EFACTS to assess disease progression and the predictive value of disease-related factors on progression, and estimated sample sizes for interventional randomised clinical trials. We enrolled patients with genetically confirmed Friedreich’s ataxia from 11 European study sites in Austria, Belgium, France, Germany, Italy, Spain, and the UK. Patients were seen at three visits—baseline, 1 year, and 2 years. Our primary endpoint was the Scale for the Assessment and Rating of Ataxia (SARA). Secondary outcomes were the Inventory of Non-Ataxia Signs (INAS), the Spinocerebellar Ataxia Functional Index (SCAFI), phonemic verbal fluency (PVF), and the quality of life measures activities of daily living (ADL) and EQ-5D-3L index. We estimated the yearly progression for each outcome with linear mixed-effect modelling. This study is registered with ClinicalTrials.gov, number NCT02069509, and follow-up assessments and recruitment of new patients are ongoing. Between Sept 15, 2010, and Nov 21, 2013, we enrolled 605 patients with Friedreich’s ataxia. 546 patients (90%) contributed data with at least one follow-up visit. The progression rate on SARA was 0·77 points per year (SE 0·06) in the overall cohort. Deterioration in SARA was associated with younger age of onset (–0·02 points per year [0·01] per year of age) and lower SARA baseline scores (–0·07 points per year [0·01] per baseline point). Patients with more than 353 GAA repeats on the shorter allele of the FXN locus had a higher SARA progression rate (0·09 points per year [0·02] per additional 100 repeats) than did patients with fewer than 353 repeats. Annual worsening was 0·10 points per year (0·03) for INAS, −0·04 points per year (0·01) for SCAFI, 0·93 points per year (0·06) for ADL, and −0·02 points per year (0·004) for EQ-5D-3L. PVF performance improved by 0·99 words per year (0·14). To detect a 50% reduction in SARA progression at 80% power, 548 patients would be needed in a 1 year clinical trial and 184 would be needed for a 2 year trial. Our results show that SARA is a suitable clinical rating scale to detect deterioration of ataxia symptoms over time; ADL is an appropriate measure to monitor changes in daily self-care activities; and younger age at disease onset is a major predictor for faster disease progression. The results of the EFACTS longitudinal analysis provide suitable outcome measures and sample size calculations for the design of upcoming clinical trials of Friedreich’s ataxia. European Commission.

Bei Menschen mit Epilepsie können interiktuale von periiktualen Kopfschmerzen unterschieden werden. Interiktuale Kopfschmerzen treten ohne unmittelbaren zeitlichen Zusammenhang mit epileptischen Anfällen auf, werden von 10–60 % der befragten Epilepsiepatienten berichtet und überwiegend als Migränekopfschmerz und etwas seltener als Spannungskopfschmerz angegeben. Basierend auf pathophysiologischen Betrachtungen und Befunden aus epidemiologischen Studien, wird eine signifikante Assoziation zwischen dem Auftreten von Migräne und (genetisch bedingten) Epilepsien vermutet, die bisherige Datenlage ist jedoch nicht schlüssig. Der Beitrag von Antikonvulsiva zu Kopfschmerzen bei Epilepsie ist ebenfalls nicht abschließend geklärt. Periiktuale Kopfschmerzen treten in zeitlichem Zusammenhang mit epileptischen Anfällen auf, und zwar innerhalb von 60 min bis 24 h vor Beginn des epileptischen Anfalls (präiktuale Kopfschmerzen), während des epileptischen Anfalls (iktuale Kopfschmerzen) bzw. unmittelbar nach oder 30–180 min nach Anfallsende (postiktuale Kopfschmerzen). Postiktuale Kopfschmerzen treten bei bis zu 50 % der Befragten auf, werden überwiegend als Migräne- oder Spannungskopfschmerz beschrieben, dauern typischerweise 4–24 h und weisen eine mittlere bis hohe Schmerzintensität auf. Bei etwa zwei Drittel der von postiktualen Kopfschmerzen Betroffenen treten die Kopfschmerzen regelhaft nach jedem Anfall auf und scheinen zumindest bei Temporallappenepilepsien bei einem größeren Teil der Betroffenen ipsilateral zur Anfallsursprungszone bzw. zur Hippocampussklerose zu sein. Als Risikofaktoren für das Auftreten periiktualer Kopfschmerzen wurden generalisierte tonisch-klonische Anfälle und eine antikonvulsive Polytherapie identifiziert. Die Behandlung von postiktualen Kopfschmerzen erfolgt überwiegend durch rezeptfreie Analgetika oder nichtsteroidale Antirheumatika in Selbstmedikation. Bei der medikamentösen Behandlung von Kopfschmerzen bei Menschen mit Epilepsie sind verschiedene Wechselwirkungen zwischen Analgetika und Antikonvulsiva zu beachten. So können enzyminduzierende Antikonvulsiva die Lebertoxizität von Paracetamol steigern. Paracetamol wiederum kann durch eine verstärkte Glukuronidierung die Ausscheidung von Lamotrigin steigern und den Lamotrigin-Serumspiegel senken.

To the Editor: In their letters about patients who were receiving oral dimethyl fumarate for the treatment of psoriasis, Ermis et al. 1 and van Oosten et al. 2 (April 25 issue) state that progressive multifocal leukoencephalopathy (PML) had been diagnosed in two patients. Dimethyl fumarate is the active ingredient in Fumaderm, which since 1994 has been registered for the treatment of psoriasis in Germany. Leukopenia and lymphopenia are known adverse effects of such therapy. The summary of product characteristics for Fumaderm and current guidelines recommend that in all patients receiving the drug, a differential blood count should be obtained every 2 . . .