Make a kardex Multiple Sclerosis A 51-year-old man of Mediterranean origin with an 8-year history of relapsing-remitting MS (RRMS) was admitted to our hospital on suspicion of a relapse. After diagnosis in 2009, the patient had initially been treated with glatiramer acetate. The family medical history offered that the patient's mother and uncle (blood related) both suffered from MS. The patient's uncle died at the age of 52 years after being bedridden for a longer time. The patient had four relapses under glatiramer acetate necessitating treatment with intravenous (IV) steroids initially with a good treatment response. The first relapse leading to the diagnosis of a clinically isolated syndrome (CIS) was an acute central vestibular syndrome leading to dizziness and an ataxic gait dysfunction. At this time, MRI already revealed multiple white matter lesions in the supratentorium, cerebellum, and cervical as well as thoracic spinal cord. In 2012, owing to an increasing relapse rate and incomplete clinical remissions, the medication was changed to natalizumab. At this time, the last relapses under glatiramer acetate had led to a residual paraparesis with emphasis on the left and a left side internuclear ophthalmoplegia. At the last relapse, brain MRI scan of the brain showed multiple white matter lesions with a cystic aspect and incomplete ring-like gadolinium enhancement. After the medication was switched to natalizumab, the disease course stabilized, and he suffered no more relapses. However, when the anti-JC virus (JCV) antibody level index (Stratify™) rose to 4.5, natalizumab was discontinued early in 2017. Subsequently, fingolimod was started 3 months prior to admission and 4 weeks after discontinuation of natalizumab. The first symptoms appeared 8 days before admission: a progressive left lower limb weakness and deterioration of walking ability became evident. At that time, the patient was able to stand without help and walk a few steps with unilateral assistance [Expanded Disability Status Scale (EDSS) 6.0]. At this time (after treatment with natalizumab and rising anti-JCV antibody level index), the differential diagnoses were an MS relapse or progressive multifocal leukoencephalopathy (PML). The MRI scan of the brain on the day of admission showed bihemispheric confluent T2 white matter lesions without changes, typical for PML (Figure 1A). Cerebrospinal fluid (CSF) analysis revealed a normal white blood cell count (2/μl) with mildly increased lactate and glucose levels. The albumin quotient was normal, but oligoclonal bands were positive with intrathecal synthesis of immunoglobulins G and M. Polymerase chain reaction (PCR), microbiological, and serological study findings were all negative (including JCV PCR, JCV CSF/serum antibody index, HSV-1 PCR, HSV-2 PCR, VZV PCR, EBV PCR, and HIV PCR). Evoked potentials revealed an impairment of the corticospinal tract to the right leg, bilaterally impaired tibial nerve somatosensory reactions, and evidence of a bilateral affection of the visual system.
At this time (after treatment with natalizumab and rising anti-JCV antibody level index), the differential diagnoses were an MS relapse or progressive multifocal leukoencephalopathy (PML). The MRI scan of the brain on the day of admission showed bihemispheric confluent T2 white matter lesions without changes, typical for PML (Figure 1A). Cerebrospinal fluid (CSF) analysis revealed a normal white blood cell count (2/μl) with mildly increased lactate and glucose levels. The albumin quotient was normal, but oligoclonal bands were positive with intrathecal synthesis of immunoglobulins G and M. Polymerase chain reaction (PCR), microbiological, and serological study findings were all negative (including JCV PCR, JCV CSF/serum antibody index, HSV-1 PCR, HSV-2 PCR, VZV PCR, EBV PCR, and HIV PCR). Evoked potentials revealed an impairment of the corticospinal tract to the right leg, bilaterally impaired tibial nerve somatosensory reactions, and evidence of a bilateral affection of the visual system. The following differential diagnoses were considered for our patient: • tumefactive MS relapse, • neurocysticercosis, • neurosarcoidosis, • intracerebral lymphoma, • atypic PML, and • other viral encephalitis. The negative results of the CSF analysis and serology argued against a neurocysticercosis, lymphoma, or PML. Cysticercosis is the most common parasitic infection of the CNS. However, the presentation on MRI imaging was judged unusual. Electroencephalography (EEG) was normal. For sarcoidosis, a CT scan of the chest and laboratory tests for ACE and sIL2R were added; both proved negative. The negative CSF findings and radiological presentation also argued against an intracerebral lymphoma but did not definitely exclude one. A tumefactive MS relapse is a rare course and commonly presents with a large intracerebral lesion (>2 cm) with mass effect and perilesional edema and/or ring enhancement with gadolinium. To further differentiate between a tumefactive MS relapse and a less likely intracerebral lymphoma, a stereotactic biopsy of a lesion in the right frontal lobe was performed. The biopsy revealed a sharply demarcated inflammatory demyelinating lesion consistent with MS. Inflammatory infiltrates within the lesion consisted of CD3 dominated by CD8-positive T cells as well as CD138-positive plasma cells (Figure 2). Deposits of complement and immunoglobulins identified the lesion as an antibody/complement mediated type of MS, described previously as pattern II MS (2). PCR analysis revealed low copy numbers of human herpesvirus 6 (HHV-6) DNA in tissue (32 copies/μg DNA). However, axons were preserved, thus ruling out a necrosis. Also, no evidence was found for lymphoma. Figure 2. Histology showed an active demyelinating multiple sclerosis (MS) lesion corresponding to immunopathological pattern II. Arrows indicate the sharply demarcated inflammatory subcortical plaque on the left; the cerebral cortex is present on the right [H&E stain, ×10 (A)]. Axons were preserved within the lesion [Bielschowsky silver stain, ×10 (B)], whereas myelin was lost [proteolipid protein, ×10 (C); cyclic nucleotide phosphodiesterase stain, ×40 (D)]. The lesion showed early active demyelination as indicated by the presence of major (C) and minor myelin proteins (D) within the macrophages. Complement [c9neo complement stain, ×40 (E)] and immunoglobulin G [IgG; IgG stain ×40 (F)] were found within the macrophages, suggesting a complement and immunoglobulin-mediated demyelination (pattern II).