PMC5846919_01
(a) MRI data. First row: initial MRI 4 months before alemtuzumab revealed inhomogeneous lesions pattern including large ring-enhancing lesions in juxtacortical white matter admixed with smaller lesions of infrequent nodular enhancement. Second row: MRI prior to alemtuzumab administration revealed new enhancing lesions and now extensive brainstem involvement. Third row: MRI 6 months after alemtuzumab treatment revealed reduction in lesion size as well as perifocal edema and gadolinium enhancement disappearance. Fourth row: 12 months after alemtuzumab, lesion consolidation was found. Formerly acute lesions revealed progressive T1 hypointensity.. (b) Biopsy was taken from the subcortical right middle frontal gyrus before alemtuzumab application (pre). Multiple sclerosis lesion with involvement of the humoral immune system (type II pattern): HE staining shows a macrophage-rich lesion with perivascular inflammation and a reactive gliosis. The lesion is demyelinated (LFB/PAS stain with missing blue myelin). Numerous macrophages with myelin degradation products in their cytoplasm are present, indicating an active demyelinating lesion (anti-proteolipid protein). Within the lesion, T cells are located in the perivascular space and within the parenchyma (anti-CD3). Activated complement components (anti-C9neo) and immunoglobulins (anti-immunoglobulin G) are present with macrophages, indicating a complement/immunoglobulin mediated demyelination (pattern II; arrows indicate complement and IgG-laden macrophages). Scale bar: 100 microm for HE, LFB/PAS and anti-CD3. 50 microm for anti-PLP, anti-c9neo and anti-IgG.. (c) Analysis of peripheral immune cell subtypes and CSF markers: peripheral blood immune cell subtypes including CD19+ B cells and CD3+ T cells were evaluated prior to and after alemtuzumab infusion. One month before alemtuzumab administration (-1M) lymphocyte counts were still decreased due to previous but interrupted fingolimod treatment and were normalized directly before alemtuzumab initiation (pre). CD19+ B cells were markedly decreased after the first alemtuzumab cycle but demonstrated an overshooting repopulation before the second alemtuzumab cycle (12M). Arrows indicate first and second alemtuzumab application. CSF was investigated directly before (pre) and one month (1M) after alemtuzumab. Intrathecal inflammation and damage of the blood-brain barrier were markedly decreased after alemtuzumab. Q, quotient. Reference values: CD19+ B cell in peripheral blood 0.175-0.575 GPt/L; CD3+ T cell in peripheral blood 1.5-4.0 GPt/L; CSF cell count <5 MPt/L; total protein 150-450 m/L; QAlbumin 6.5; intrathecal IgG, IgM or IgA synthesis 0%.
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One month later she suffered a severe relapse with headache, and an MRI presented a novel subset of large ring-enhancing lesions among otherwise typical multiple sclerosis lesions (Figure 1(a), first row). MRI revealed an increasing number of contrast-enhancing lesions in cerebral and spinal MRI (Figure 1(a), second row). This second biopsy confirmed the highly inflammatory, active demyelinating multiple sclerosis lesions with antibody/complement deposits (multiple sclerosis pattern II) (Figure 1(b)). MRI demonstrated lesion regression with resolved blood-brain barrier disruption, although peripheral B cells demonstrated an overshooting repopulation (Figure 1(a) third and fourth rows; Figure 1(c)).