The 49-year-old patient was diagnosed with relapsing-remitting multiple sclerosis (RRMS) in 2006 that was initially treated with interferon beta-1a. Due to continuous relapse activity, the therapy was escalated to monthly natalizumab infusions in 2007. Thereafter, he had been stable with only one relapse in the first year of natalizumab treatment. In December 2012, he presented in our neurological emergency department with a progressive bilateral visual loss and slight confusion lasting for two weeks. Prior to admission he had been treated in a neurological practice with high dose methylprednisolone due to suspected relapse.
On neurological examination, he demonstrated a previously described residual left-sided hemiparesis, pronounced in the left leg with brisk reflexes, an amaurosis of his right eye and markedly reduced vision of his left eye. The ophthalmological examination of the anterior segment of both eyes showed no inflammation. The posterior segment revealed an occlusive periarteriitis and a patchy necrotizing retinitis (Figure  1A-B). Besides the known non-active multiple sclerosis (MS)-typical lesions, the cranial magnetic resonance imaging (MRI) displayed multiple new dot-shaped cortical and subcortical lesions with diffusion restrictions that were not limited to a large-vessel vascular territory (Figure  2A-D). Neither these lesions nor the basal vessels revealed any contrast enhancement.
Cerebrospinal fluid (CSF) analysis demonstrated a normal cell count, positive oligoclonal bands in the CSF (type 2), a total protein elevation of 0.87 g/L, an albumin quotient (CSF/serum) of 12.3 and varicella zoster virus (VZV) DNA was tested positive by PCR amplification. All other virological and microbiological CSF investigations were negative (antibody indices for CMV/HSV/VZV, CMV pp65 antigen, EBV antibodies and PCR, JCV PCR, HIV antigen ELISA, tuberculosis culture and PCR, aspergillus antigen ELISA, leptospirosis antibodies, cryptococcus antigen immunodiffusion, toxoplasmosis antibodies, borrelia antibodies, culture for neisseria and brucella and an unspecific culture for other pathogenic and non-pathogenic bacteria). Transesophageal echocardiography, electrocardiography, Doppler/duplex sonography of the deep leg veins and carotid arteries, coagulopathy screening, autoimmune antibodies (anti-neutrophil cytoplasmic antibody, anti-nuclear antibodies, ENA antibodies, anti-DNA antibodies, anti-NMDAR antibodies, anti-AMPAR antibodies, anti-LG1 antibodies, anti-CASPR2 antibodies, anti-GABAR antibodies, anti-phospholipid antibodies, anti-transglutaminase antibodies and anti-gliadin antibodies) and blood sedimentation rate were normal.
As we suspected a vasculitis based on the fundoscopic examination and the MRI, we performed a digital subtraction angiography and a MRI-guided diagnostic brain biopsy of the parenchyma and the meninges. Both were carried out during the initial immunosuppressive and antiviral treatment due to the rapid progression of the visual loss. Neither the conventional angiography nor the biopsy showed definite signs of a vasculitis; however, the biopsy did not include deep white matter.
For treatment of the VZV infection, aciclovir (800 mg three times a day iv for 14 days) was initiated. We also applied a high dose of intravenous methylprednisolone (1 g/day for five days followed by 2 g/day for five days) and subsequently an oral steroid (prednisolone 80 mg/day). Moreover, five cycles of plasma exchange therapy were performed to accelerate natalizumab clearance. After the steroid treatment and plasma exchange therapy, we applied a bolus of cyclophosphamide (500 mg/m2). In parallel, we treated the patient with acetylsalicylic acid (100 mg/day) and simvastatin (20 mg/day). Before transferral to the neurological rehabilitation clinic, he was almost completely blind and reported typical signs of a Charles-Bonnet syndrome with complex vivid hallucinations.
At follow-up after two months, the CSF of the clinically stable patient showed a more than six-fold increase of intrathecal antibody indices against VZV from 0.900 at first presentation to 5.900, while the viral PCR results, including John Cunningham virus (JCV) PCR, were negative. The follow-up MRI after two and four months did not reveal any diffusion restrictions, whereas the dot-shaped lesions were persistently contrast-enhancing in contrast to the initial presentation. This was interpreted as an ongoing immune response related to the apparently still active vasculitis (Figure  2E-F). Therefore, the patient further received cyclophosphamide on a monthly basis. Since we assume that the infection associated vasculitis is a transient phenomenon and the active MS requires further long term treatment, it is planned to switch the treatment to teriflunomide.