Guido Ahle

Fulminant tumefactive multiple sclerosis: Therapeutic implications of histopathology

JO N 2 88 3 A 33-year-old Caucasian woman first presented with optic and sensory symptoms in September 2004. An optic neuritis in 2003 had not been evaluated neurologically. Family history was positive for MS, oligoclonal bands (OCB) were present in the CSF. Expanded disability status scale (EDSS) was 2.0, with a rapid remission of symptoms after intravenous methylprednisolone (IVMP) for 5 days. Cranial (c)MRI at time of diagnosis fulfilled MS criteria with about 20 disseminated T2-lesions [4]. No alternative diseases were found. All findings supported the diagnosis of MS according to Mc Donald criteria [5]. Since pregnancy was intended, no immunoprophylaxis was initiated. After two further exacerbations, a large left parietal lesion was externally suspected to be neoplastic in June 2005 (Fig.1A), however not biopsied as symptoms regressed after IVMP. Subcutaneous interferonbeta 1a (22 μg) was started and increased to 44 μg in spring 2006. Three distinct exacerbations occurred within 37 days between June 29 (EDSS 2.5) and August 5, 2006 (EDSS 5.0). Mitoxantrone was initiated with a cumulative dose of 17.5 mg per m2 body surface but no clinical benefit was achieved over three months. Intravenous immunoglobulins (IVIG) did not prevent new bouts either. After a single dose of natalizumab in December 2006 the patient was readmitted 10 days later with a focal status epilepticus and a subsequent stupor. Further serological diagnostics did not reveal new aspects, CSF-JCV testing and aquaporin antibodies were negative. A brain biopsy was performed. Histopathology revealed early active demyelination with little inflammation. Large numbers of macrophages with incorporated myelin fragments were demonstrated (Fig.2). Some macrophages labelled positive for the acute macMichael R. Haupts Sebastian K. Schimrigk Nils Brune Andrew Chan Guido Ahle Kerstin Hellwig Fatima B. Konig Uwe Schlegel Wolfgang Bruck Ralf Gold

Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for primary central nervous system lymphoma

BACKGROUND Primary central nervous system lymphomas (PCNSLs) are highly aggressive tumors. Chemotherapy has improved prognosis significantly; however, early diagnosis is crucial for effective treatment. Presently, the diagnosis of PCNSL depends on histopathology of tumor biopsies. We have previously demonstrated differential expression of microRNAs in cerebrospinal fluid (CSF) samples from patients with PCNSL. Based on promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic, colorectal, and lung cancer, we investigated RNU2-1f in the CSF of PCNSL patients. METHODS CSF was collected from patients with PCNSL (n = 72) and control patients with various neurologic disorders (n = 47). Sequential CSF samples were collected from 9 PCNSL patients. RNU2-1f levels were measured by real-time polymerase chain reaction. RESULTS Measurement of RNU2-1f levels in CSF enabled the differentiation of patients with PCNSL from controls with an area under the curve (AUC) of 0.909 with a sensitivity of 68.1% and a specificity of 91.4%. The diagnostic accuracy was further improved by combined determination of RNU2-1f and miR-21, resulting in AUC of 0.987 with a sensitivity of 91.7% and a specificity of 95.7%. In consecutive measurements of RNU2-1f, which were performed in 9 patients at different stages of the disease course, RNU2-1f CSF levels paralleled the course of the disease. CONCLUSIONS Our data suggest that the measurement of RNU2-1f detected in CSF can be used as a diagnostic marker and also as a possible marker for treatment monitoring. These promising results need to be evaluated within a larger patient cohort.

Vitreous microRNA levels as diagnostic biomarkers for vitreoretinal lymphoma

To the editor: Primary vitreoretinal lymphoma (PVRL) is often associated with primary central nervous system lymphoma (PCNSL) and is a rare high-grade diffuse large-cell B-cell lymphoma occurring within the vitreous and/or retina.[1][1][⇓][2]-[3][3] Overlapping clinical signs observed in PVRL

Cytomorphology and flow cytometry of brain biopsy rinse fluid enables faster and multidisciplinary diagnosis of large B‐cell lymphoma of the central nervous system

Central nervous system lymphomas are aggressive tumors requiring a prompt diagnosis for successful treatment. Stereotactic biopsy remains the standard procedure, but the time needed for histopathology is usually over 2 days. We evaluated the contribution of cytomorphology and flow cytometry to histopathology of the brain biopsy in particular on the rinse fluid usually removed.

Acute left hemispheric syndrome with cortical lesions in a patient with secondary porphyrinuria.

Sirs: Oberndorfer et al. report a patient with the full clinical picture of a hereditary acute hepatic porphyria whose brain MRI was normal [1]. They conclude that a secondary abnormality of porphyrin metabolism should be the origin of their patient’s symptoms although secondary alterations of porphyrin metabolism are reported not to produce any porphyria-like symptoms [2]. We here present the case of another patient in whom we presume a secondary porphyrinuria was the cause of a neurological disorder mimicking the clinical and neuroradiological picture of a hereditary porphyria [3–5]. A 45 year old female was admitted to our neurological intensive care unit with an acute right-sided hemiparesis combined with aphasia. Cardiovascular risk factors could not be determined, her medical history included a series of generalized epileptic seizures before her admission to our hospital and an alcohol-dependency. Further medical history was not known as the patient was living alone. On admission, cerebral CT showed no abnormalities, especially no signs of a cerebral ischemia. On cerebral MRI in proton density and diffusion-weighted images a diffuse signal change was found bifrontally, in the left-hemispheric cortex and thalamus as well as in the right cerebellar cortex, FLAIR sequences showed corresponding changes. MR-Angiography was not tolerated by the patient as she was in an agitated state. Correlating with MRI findings, cerebral perfusion of the left hemisphere and the rightsided cerebellar hemisphere was diminished as shown on perfusion-SPECT while EEG showed diffuse slowing with a left frontotemporal theta-delta-focus without epileptic discharges. Cardiovascular investigations (Ultrasound-examination of cervical vessels, echocardiography, and ECG) showed no specific abnormalities; transcranial Doppler sonography could not be performed owing to the thickness of the temporal bone squama. Cerebrospinal fluid was normal as well, whereas liver-enzymes were elevated (Bili. tot. 13.53 mg/dl [0.00–1.10], Bili. dir. 11.87 mg/dl [0.00–0.25]; ASAT/GOT 348 U/l [10–50]; ALAT/GPT 295 U/l [10–50]; AP 386 U/l [40–129]; GGT 610 U/l [0–66]; LDH 647 U/l [135–225]; CK 1025 U/l [0–174], CK-MB 30 U/l [0–24]; normal values for creatinine.) As the patient was known to be an alcoholic and presented with seizures, elevated liver enzymes and dark urines, we checked for porphyrin abnormalities. During these investigations elevated urinary uroand coproporphyrins and total porphyrins were found (coproporphyrin 415 μg/d (< 120), uroporphyrin 113 μg/d (< 33), heptacarboxyporphyrin 17 μg/d (< 10), calculated total porphyrins 551 μg/d (< 170), normal values for hexacarboxyporphyrin and pentacarboxyporphyrin. In the course we found normal values for liver enzymes in 24h-urine for deltaaminolaevulic-acid, porphobilinogen, total porphyrins, porphobilinogen deaminase). We interpreted these laboratory findings as signs of cholestasis and the porphyrins as secondary coproporphyrinuria with a disturbed decarboxylation during cholestasis. Abdominal ultrasound showed an intrahepatic biliary obstruction causative for cholestasis. During her stay on our intenLETTER TO THE EDITORS

Successful treatment of hyperventilation-induced nystagmus in vestibular schwannoma with oxcarbacepine

JO N 2842 tion was performed and the lesion was monitored clinically and radiologically. To treat paroxysmal symptoms, oxcarbacepine (2 x 150 mg) was prescribed and well-tolerated. The nystagmus could no longer be provoked by hyperventilation. After a pause in medication, the hyperventilation-induced nystagmus reoccurred. Nystagmus is very infrequently induced by hyperventilation. However, patients with demyelinating lesions of the vestibular nerve (due to compression by a tumor or a small blood vessel) or in central structures (multiple sclerosis) may show hyperventilation-induced nystagmus (HIN) [4]. In acoustic neuroma, the presumed mechanism of HIN is improved axonal conduction in the partially demyelinated vestibular nerve by hyperventilation. Carbon dioxide levels have been shown to decrease after a 30-second period of hyperventilation. CSF pH rises in association with this reduction in PCO2, which leads to a reduction in extracellular ionized Ca2+. Hyperventilation hence results in a transient increase in activity from partially demyelinated axons as a result of the lowering of extracellular Ca2+ [5]. Hyperventilation can cause nystagmus beating towards the side of a vestibular nerve lesion (i.e., excitatory nystagmus) and is the only test that unmasks unilateral vestibular disease without testing the dynamic properties of the vestibulo-ocular Guido Ahle Wenke Visser Annika Juergens Uwe Schlegel

Myelin oligodendrocyte glycoprotein antibodies in neuromyelitis optica spectrum disorder

Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory disease of the central nervous system characterized, in particular, by disabling episodes of optic neuritis and longitudinal extensive transverse myelitis. Its main pathogenic characteristic is the presence of anti-aquaporin-4 antibodies (AQP4-Abs) in the serum of affected patients. However, a proportion of patients with the typical NMOSD phenotype are, in fact, negative (seronegative) for AQP4-Abs and, within this category of patients, a proportion of them instead express antibodies to myelin oligodendrocyte glycoprotein (MOG-Abs). The presence of MOG-Abs in the sera of seronegative NMOSD patients is more frequently associated with monophasic disease and moderate symptom severity, and also appears to predict a better outcome. The present report is a review of the clinical and immunological features of MOG-Ab-positive NMOSD.

MicroRNA-30c as a novel diagnostic biomarker for primary and secondary B-cell lymphoma of the CNS

Primary lymphomas of the central nervous system (PCNSL) are highly aggressive tumors affecting exclusively the CNS, meninges, and eyes. PCNSL must be separated from secondary spread of systemic lymphoma to the CNS (SCNSL), which may occur at diagnosis or relapse of systemic lymphomas. At present, there are no valid methods to distinguish PCNSL from SCNSL based on tumor biopsy because of similar histological presentation. However, SCNSL and PCNSL are different in terms of prognosis and adequate therapy protocols. MicroRNA expression profiles of CSF samples collected from SCNSL and PCNSL patients were compared using microRNA arrays. MiR-30c revealed the largest differential expression and was selected for validation by RT-PCR on 61 CSF samples from patients with PCNSL and 14 samples from SCNSL. MiR-30c was significantly increased in patients with SCNSL compared to PCNSL (p < 0.001). MiR-30c levels in CSF enabled the differentiation of patients with PCNSL from SCNSL with an area under the curve (AUC) of 0.86, with a sensitivity of 90.9% and a specificity of 85.5%. Our data suggest that miR-30c detected in the CSF can serve as biomarker for distinction between PCNSL and SCNSL. The validation in a larger cohort is needed. With respect to its function, miR-30c may facilitate lymphoma cells to engraft into CNS by interaction with CELSR3 gene that controls the function of ependymal cilia and, thus, affects the circulation of CSF.

Optic Nerve Infiltration in Primary Central Nervous System Lymphoma

Importance Visual impairment in primary central nervous system lymphoma (PCNSL) is caused mostly by intraocular lymphomatous involvement (vitritis and retinal infiltration), whereas optic nerve infiltration (ONI) is a rare condition. Objective To describe the clinical presentation of ONI, its imaging characteristics, and outcome. Design, Setting and Participants A total of 752 patients diagnosed with PCNSL were retrospectively identified from the databases of 3 French hospitals from January 1, 1998, through December 31, 2014. Of these, 7 patients had documented ONI. Exclusion criteria were intraocular involvement, orbital lymphoma, or other systemic lymphoma. Clinical presentation, neuroimaging, biological features, treatment, and outcomes were assessed. Main Outcomes and Measures Treatment response was evaluated clinically and radiologically on follow-up magnetic resonance imaging (MRI) according to the International PCNSL Collaborative Group response criteria. Results The 7 patients included 5 women and 2 men. Median age at diagnosis was 65 years (range, 49-78 years). Two patients had initial ONI at diagnosis, and 5 had ONI at relapse. Clinical presentation was marked by rapidly progressive and severe visual impairment for all patients. The MRI findings showed optic nerve enlargement in 3 patients and contrast enhancement of the optic nerve in all patients. Additional CNS lesions were seen in 4 patients. Examination of cerebrospinal fluid samples detected lymphomatous meningitis in 2 patients. Clinical outcome was poor and marked by partial recovery for 2 patients and persistent severe low visual acuity or blindness for 5 patients. Median progression-free survival after optic nerve infiltration was 11 months (95% CI, 9-13 months), and median overall survival was 18 months (95% CI, 9-27 months). Conclusions and Relevance Optic nerve infiltration is an atypical and challenging presentation of PCNSL. Its visual and systemic prognosis is particularly poor compared with vitreoretinal lymphomas even in response to chemotherapy. Although intraocular involvement is frequent in PCNSL and clinically marked by slowly progressive visual deterioration, lymphomatous ONI is rare and characterized by rapidly progressive severe visual impairment.

Intravascular Large B-Cell Lymphoma Presenting as Dementia and Hemolytic Anemia

Background: Intravascular lymphoma (IVL) is an uncommon disease characterized by atypical lymphoid cells growing inside the lumina of small vessels. The diversity of clinical presentation due to possible involvement of multiple organs often complicates its diagnosis. Case Report: Here, we report on a case of IVL with rapidly progressive dementia and Coombs-negative hemolytic anemia. Interestingly, the erythrocytes exhibited a decreased osmotic resistance. Bone marrow histopathology revealed increased erythropoiesis and, finally, a small monoclonal B lymphocyte population. Cerebral magnetic resonance imaging (MRI) demonstrated few micro-bleedings. Computed tomography (CT) showed bilateral ground-glass opacity of the lungs. Within a few days, the patient developed respiratory failure and died. On post-mortem examination, intravascular large B-cell lymphoma with almost complete infiltration of the brain and lungs was diagnosed. Conclusion: IVL should be considered early in situations of unexplained neuropsychiatric disease along with markedly elevated levels of lactic dehydrogenase, anemia, and hemolysis.