Ilya Ayzenberg

Interleukin 6 Receptor Blockade in Patients With Neuromyelitis Optica Nonresponsive to Anti-CD20 Therapy

OBJECTIVE To report first experiences with interleukin 6 receptor inhibition in therapy-resistant neuromyelitis optica (NMO). DESIGN Retrospective case series. SETTING Neurology department at a tertiary referral center. PATIENTS Patients with an aggressive course of NMO switched to tocilizumab after failure of anti-CD20 therapy. MAIN OUTCOME MEASURES Annualized relapse rate and disability progression measured by the Expanded Disability Status Scale. RESULTS We report 3 female patients with a median age of 39 years (range, 26-40 years) and aquaporin 4-positive NMO. All patients had been treated with different immunosuppressive and immunomodulating agents, followed by 1 to 3 cycles of rituximab. Despite complete CD20-cell depletion during rituximab therapy, the median annualized relapse rate was 3.0 (range, 2.3-3.0) and the median Expanded Disability Status Scale score increased from 5.0 (range, 4.5-7.0) to 6.5 (range, 5.0-7.0). After the switch to tocilizumab (median duration of therapy, 18 months), the median annualized relapse rate decreased to 0.6 (range, 0-1.3). A total of 2 relapses occurred; however, they were mild and there were no changes in clinical disability. CONCLUSIONS Interleukin 6 receptor-blocking therapy can be effective in therapy-resistant cases of NMO. Larger controlled studies are needed to confirm the efficacy of tocilizumab.

Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures.

Trigeminal and somatic nociceptive systems were studied in controls (n = 15), episodic migraine (n = 16), analgesics (n = 14) and triptan-induced medication overuse headache (MOH) (n = 15) before and after withdrawal. Patients with MOH and comorbid depressive symptoms and depression without headache were studied to investigate the influence of depression. Trigeminal nociception was studied by simultaneous registration of pain-related cortical potentials (PREP) and nociceptive blink reflex (nBR) following nociceptive-specific electrical stimulation of the forehead. Somatic nociception was evaluated using PREP of upper limbs. We found facilitation of both trigeminal and somatic PREP but not of nBR in MOH, which normalized after withdrawal. No differences were found comparing analgesics vs. triptan MOH. No differences were observed between controls and patients with episodic migraine and depression without headache. A transient facilitation was found of trigeminal and somatic nociceptive systems in MOH, which was more pronounced on a supraspinal level.

A Novel Method of Eliciting Pain-Related Potentials by Transcutaneous Electrical Stimulation

Background.—Electrophysiological techniques such as laser and contact heat evoked pain‐related potentials are very useful for studying trigeminal and somatic pain transmission in humans. These methods are, however, partly invasive, expensive, and therefore not available for broad clinical use. We recently proposed a novel technique of noninvasive transcutaneous electrical stimulation.

The prevalence of primary headache disorders in Russia: A countrywide survey

Objective: To estimate the 1-year prevalences of primary headache disorders and identify their principal risk factors in the general population of Russia. Methods: A countrywide population-based random sample of 2725 biologically unrelated adults in 35 cities and nine rural areas were interviewed in a door-to-door survey using a previously validated diagnostic questionnaire. Results: Of the 2725 eligible adults contacted, 2025 (74.3%) responded (females 52.6%, mean age 39.5 ± 13.4 years). Of these, 1273 (62.9%) reported headache ‘not related to flu, hangover, cold, head injury’ occurring at least once in the previous year. The gender- and age-standardized 1-year prevalence of migraine was 20.8%. Female gender (odds ratio (OR) = 3.8; 95% confidence interval (CI) 2.8–5.1) and obesity (OR = 1.5; 1.1–2.1) were positively associated with this type of headache. The gender- and age-standardized 1-year prevalence of tension-type headache (TTH) was 30.8%. TTH was more prevalent in urban than in rural areas (OR = 1.6; 1.3–2.0). Headache on ≥15 days/month was reported by 213 (10.5%) respondents (gender- and age-standardized prevalence 10.4%), and associated with low socioeconomic status (OR = 3.4; 2.4–4.9), obesity (OR = 3.0; 2.1–4.3), female gender (OR = 2.9; 2.1–4.1) and age over 40 years (OR = 2.6; 1.9–3.6). The majority of these respondents (68.1%) overused acute headache medications. Conclusion: The study demonstrated a high prevalence of migraine and a very high prevalence of headache on  ≥15 days/month, and revealed unmet health-care needs of people with headache in Russia.

Long-term Therapy With Interleukin 6 Receptor Blockade in Highly Active Neuromyelitis Optica Spectrum Disorder

IMPORTANCE Neuromyelitis optica (NMO) is characterized by disabling relapses of optic neuritis and myelitis and the presence of aquaporin 4 antibodies (AQP4-abs). Interleukin 6, which is significantly elevated in serum and cerebrospinal fluid of patients with NMO, induces AQP4-ab production by plasmablasts and represents a novel therapeutic target. OBJECTIVE To evaluate the long-term safety and efficacy of tocilizumab, a humanized antibody targeting the interleukin 6 receptor, in NMO and NMO spectrum disorder. DESIGN, SETTING, AND PARTICIPANTS Retrospective observational study with 10 to 51 months of follow-up between December 2010 and February 2015, in neurology departments at tertiary referral centers. Participants were 8 female patients of white race/ethnicity with highly active AQP4-ab-seropositive NMO (n = 6) and NMO spectrum disorder (n = 2) whose disease had been resistant to previous medications, including B-cell depletion, and who switched to tocilizumab (6-8 mg/kg of body weight per dose). MAIN OUTCOMES AND MEASURES Annualized relapse rate, Expanded Disability Status Scale score, spinal cord and brain magnetic resonance imaging, AQP4-ab titers, pain levels (numerical rating scale), and adverse effects. RESULTS Patients were followed up for a mean (SD) of 30.9 (15.9) months after switching to tocilizumab. Two of eight patients received add-on therapy with monthly corticosteroid pulses (temporary) or azathioprine, respectively. During tocilizumab treatment, the median annualized relapse rate significantly decreased from 4.0 (interquartile range, 3.0-5.0) in the year before tocilizumab therapy to 0.4 (interquartile range, 0.0-0.8) (P = .008), and the median Expanded Disability Status Scale score significantly decreased from 7.3 (interquartile range, 5.4-8.4) to 5.5 (interquartile range, 2.6-6.5) (P = .03). Active magnetic resonance imaging lesions were seen in 6 of 8 patients at tocilizumab initiation and in 1 of 8 patients at the last magnetic resonance imaging. Three patients remained relapse free during tocilizumab treatment. In 5 patients, a total of 8 relapses occurred, 4 within the first 2½ months of therapy. Five attacks were associated with delayed tocilizumab administration (≥40 days), and 6 attacks were associated with reduced tocilizumab dosage (6 vs 8 mg/kg). The AQP4-ab titers (P = .02) and pain levels (P = .02) dropped significantly during tocilizumab treatment. Adverse effects included moderate cholesterol elevation in 6 of 8 patients, infections in 4 of 8 patients, and deep venous thrombosis and neutropenia in one patient each. CONCLUSIONS AND RELEVANCE Prolonged tocilizumab therapy may be safe and effective from early treatment phases onward for otherwise therapy-resistant highly active NMO and NMO spectrum disorder. Relapse patterns indicate that adherence to a regular therapeutic regimen with monthly infusions of tocilizumab (8 mg/kg) may increase efficacy.

Diagnosis, prevalence estimation and burden measurement in population surveys of headache: presenting the HARDSHIP questionnaire

The global burden of headache is very large, but knowledge of it is far from complete and needs still to be gathered. Published population-based studies have used variable methodology, which has influenced findings and made comparisons difficult. The Global Campaign against Headache is undertaking initiatives to improve and standardize methods in use for cross-sectional studies. One requirement is for a survey instrument with proven cross-cultural validity. This report describes the development of such an instrument. Two of the authors developed the initial version, which was used with adaptations in population-based studies in China, Ethiopia, India, Nepal, Pakistan, Russia, Saudi Arabia, Zambia and 10 countries in the European Union. The resultant evolution of this instrument was reviewed by an expert consensus group drawn from all world regions. The final output was the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, designed for application by trained lay interviewers. HARDSHIP is a modular instrument incorporating demographic enquiry, diagnostic questions based on ICHD-3 beta criteria, and enquiries into each of the following as components of headache-attributed burden: symptom burden; health-care utilization; disability and productive time losses; impact on education, career and earnings; perception of control; interictal burden; overall individual burden; effects on relationships and family dynamics; effects on others, including household partner and children; quality of life; wellbeing; obesity as a comorbidity. HARDSHIP already has demonstrated validity and acceptability in multiple languages and cultures. Modules may be included or not, and others (eg, on additional comorbidities) added, according to the purpose of the study and resources (especially time) available.

The burden of headache in Russia: validation of the diagnostic questionnaire in a population-based sample.

Background:  We report validation of the Russian‐language version of the Lifting The Burden headache screening and diagnostic questionnaire in a population‐based sample of 501 individuals in four cities (Smolensk, Tchelyabinsk, Nishny Novgorod and Tver) and three rural areas (Tula, Tver and Gornyi) of Russia.

Headache‐attributed burden and its impact on productivity and quality of life in Russia: structured healthcare for headache is urgently needed

The study evaluated headache‐attributed burden and its impact on productivity and quality of life (QoL) in Russia. Its purpose was to support recommendations for change.

Value of MRI as a surrogate marker for PML in natalizumab long-term therapy.

Five years after the introduction of natalizumab into therapy of active multiple sclerosis (MS), the number of natalizumab-associated progressive multifocal leukoencephalopathy (PML) cases has reached more than 150, with a mortality rate of 20% [1]. There is clear evidence that delay in making the diagnosis of PML is a critical parameter for prognosis. Despite the development of JC-virus (JCV) testing as a putative surrogate marker, there is still a critical need for better detection of early stages of PML. Here we report an asymptomatic case of PML with an initially negative JCV DNA PCR test in cerebrospinal fluid recognized by frequent MRI scans and describe the further benign disease course. A 28-year-old previously healthy Caucasian female was diagnosed with MS in 1995. She was treated with IFN-b-1a (Rebif 22 l) and experienced no relapses until 2007. In December 2007 the patient suffered from a severe relapse with dysarthria and paraparesis. These symptoms subsided after methylprednisolone therapy; however, a control MRI in February 2008 showed new contrast-enhancing brainstem lesions. Owing to disease progression natalizumab therapy was started in March 2008. Annual MRI controls from 2008 through 2010 revealed no new lesions. An elective control MRI in March 2011 showed a new hyperintense T2 lesion (1.0 9 0.5 cm) in the white matter of the left frontal lobe (Fig. 1b). PML infection was suspected; however, high-sensitivivity JCVPCR (university laboratory) was negative, and treatment was continued. The subsequent MRI in May 2011 revealed slight enlargement of the lesion with a mild increase of signal at the borders after contrast injection, suggesting peripheral enhancement (Fig. 1c). These changes were erroneously interpreted as a new MS lesion, and a possible switch of the therapy was discussed with the patient. Yet a control MRI in July 2011 revealed marked progression of the lesion (5 9 3 cm, Fig. 1d). Therefore, the patient was admitted to our hospital with suspected PML. The patient exhibited no neurological symptoms on admission. Family members did not report any behavioral changes; she continued working and planned traveling for holidays. The only possibly new finding was a slight deterioration of short-term verbal memory in neuropsychological testing. The JCV-PCR revealed 6230 copies/ml in CSF. JCV serology was also positive. The natalizumab therapy (total of 37 infusions) was discontinued, and plasma exchange immediately started. During the last control visit (3 weeks after PLEX) the patient was still asymptomatic, and MRI demonstrated an unchanged white matter lesion in the frontal lobe without contrast enhancement. Our case report illustrates several interesting points. Firstly, the radiological manifestation of PML can be present before clinical deterioration. Depending on the localization of lesions, patients may stay asymptomatic for quite a long period of time. Our patient had no deterioration for at least 4 months after the first changes in MRI had been detected. Secondly, PML can manifest as a monofocal condition and may be difficult to differentiate from a new MS lesion. The observation that PML lesions generally occur in areas not previously affected by multiple sclerosis may be helpful [2]. Thirdly, the first CSF analysis may be I. Ayzenberg (&) N. Trampe R. Gold K. Hellwig Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Bochum, Germany e-mail: ilya_ayzenberg@yahoo.com

Visual evoked potentials in neuromyelitis optica and its spectrum disorders.

Optic neuritis (ON) is a key feature of neuromyelitis optica (NMO). Recently, NMO patients of predominantly Afro-Brazilian origin were evaluated by visual evoked potentials (VEPs) and showed marked amplitude reductions. Here, we analyzed VEPs in a predominantly Caucasian cohort, consisting of 43 patients with definite NMO, 18 with anti-aquaporin (AQP) 4 antibody-seropositive NMO spectrum disorders and 61 matched healthy controls. We found reduced amplitudes in only 12.3%, prolonged latencies in 41.9% and a lack of response in 14.0% of NMO eyes. Delayed P100 latencies in eyes without prior ON suggested this was a subclinical affection. The data indicate heterogenous patterns in NMO, warranting further investigation.