Characteristic PML lesions have been described as large, subcortical, grey-matter-sparing lesions appearing hyperintense on T2 and fluid-attenuated inversion recovery and hypointense

on T1 scans; contrast enhancement may occur [47]. The anti-CD52 mAb alemtuzumab (Lemtrada®) has been shown to be highly effective and is approved for active relapsing MS in Europe [10-12, 69]. Disease activity is defined as clinical or radiological deterioration [70]. Mechanisms of action include depletion of CD52-expressing T/B lymphocytes, natural killer (NK) cells, dendritic cells and monocytes/macrophages with skewed repopulation leading to a reprogramming of the immune repertoire [71, 72]. Already in earlier studies, patients especially with an early relapsing disease course appeared

to benefit most from alemtuzumab Fulvestrant chemical structure treatment, leading to the concept of a therapeutic window relatively early during the disease, when highly active immunotherapy may exert most profound effects [72]. This was reflected in the inclusion criteria for the pivotal Phase III trials Wnt antagonist CARE-MS I and II (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis, Studies One and Two). CARE-MS I included active relapsing, therapy-naive MS patients, whereas CARE-MS II focused on relapsing MS refractory to first-line therapy [10, 12]. Especially in terms of disease progression, the latter patient group appeared to benefit most. Whereas current EMA approval is relatively broad [70], careful patient selection

is mandatory, as SADRs have been reported and thorough adherence to safety assessments is necessary. This is stressed by long-term data from the Phase II trial CAMMS223, with one additional SADR (Goodpasture syndrome), but also sustained reduction of disability accumulation and relapse rates compared to active comparator [73], revealing the dilemma of long-lasting efficacy versus potential SADRs. Alemtuzumab is applied intravenously with a first treatment cycle of 12 mg over 5 days, followed by a second therapy cycle over 3 days after 12 months [10, 12, 69]. Further cycles are not intended, but the question of when and how to continue DMD treatment after two cycles is unanswered. There is no class I evidence for different treatment protocols in this indication. During and for 1 month after treatment, acyclovir (200 mg twice daily) has to be administered prophylactically. C-X-C chemokine receptor type 7 (CXCR-7) Therapy surveillance with large treatment intervals, but necessarily close safety monitoring, will be a challenge in clinical practice [74] and emphasizes even more the importance of patient education, counselling and informed consent to assure adherence to safety measures. These include differential blood count, serum creatinine and urine analysis before first administration and monthly afterwards; regular testing of thyroid stimulating hormone (TSH) levels has to be performed before treatment initiation and every 3 months up to 4 years after the last administration [70].