Clinical features of double infection with tick-borne encephalitis and Lyme borreliosis transmitted by tick bite

Background: In Latvia and other endemic regions, a single tick bite has the potential to transmit both tick-borne encephalitis (TBE) and Lyme borreliosis. Objective: To analyse both the clinical features and differential diagnosis of combined tick-borne infection with TBE and Lyme borreliosis, in 51 patients with serological evidence, of whom 69% had tick bites. Results: Biphasic fever suggestive of TBE occurred in 55% of the patients. Meningitis occurred in 92%, with painful radicular symptoms in 39%. Muscle weakness occurred in 41%; in 29% the flaccid paralysis was compatible with TBE. Only two patients presented with the bulbar palsy typical of TBE. Typical Lyme borreliosis facial palsy occurred in three patients. Typical TBE oculomotor disturbances occurred in two. Other features typical of Lyme borreliosis detected in our patients were distal peripheral neuropathy (n = 4), arthralgia (n = 9), local erythema 1-12 days after tick bite (n = 7) and erythema chronicum migrans (n = 1). Echocardiogram abnormalities occurred in 15. Conclusions: Patients with double infection with TBE and Lyme borreliosis fell into three main clinical groups: febrile illness, 3 (6%); meningitis, 15 (30%); central or peripheral neurological deficit (meningoencephalitis, meningomyelitis, meningoradiculitis and polyradiculoneuritis), 33 (65%). Systemic features pointing to Lyme borreliosis were found in 25 patients (49%); immunoglobulin (Ig)M antibodies to borreliosis were present in 18 of them. The clinical occurrence of both Lyme borreliosis and TBE vary after exposure to tick bite, and the neurological manifestations of each disorder vary widely, with considerable overlap. This observational study provides no evidence that co-infection produces unusual manifestations due to unpredicted interaction between the two diseases. Patients with tick exposure presenting with acute neurological symptoms in areas endemic for both Lyme borreliosis and TBE should be investigated for both conditions. The threshold for simultaneous treatment of both conditions should be low, given the possibility of co-occurrence and the difficulty in ascribing individual neurological manifestations to one condition or the other.Peer reviewe

Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders

Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success

Female hormonal exposures and neuromyelitis optica symptom onset in a multicenter study

Objective: To study the association between hormonal exposures and disease onset in a cohort of women with neuromyelitis optica spectrum disorder (NMOSD). Methods: Reproductive history and hormone use were assessed using a standardized reproductive survey administered to women with NMOSD (82% aquaporin-4 antibody positive) at 8 clinical centers. Using multivariable regression, we examined the association between reproductive exposures and age at first symptom onset (FS). Results: Among 217 respondents, the mean age at menarche was 12.8 years (SD 1.7). The mean number of pregnancies was 2.1 (SD 1.6), including 0.3 (SD 0.7) occurring after onset of NMOSD symptoms. In the 117 participants who were postmenopausal at the time of the questionnaire, 70% reported natural menopause (mean age: 48.9 years [SD 3.9]); fewer than 30% reported systemic hormone therapy (HT) use. Mean FS age was 40.1 years (SD 14.2). Ever-use of systemic hormonal contraceptives (HC) was marginally associated with earlier FS (39 vs 43 years, p = 0.05). Because HC use may decrease parity, when we included both variables in the model, the association between HC use and FS age became more significant (estimate = 2.7, p = 0.007). Among postmenopausal participants, 24% reported NMOSD onset within 2 years of (before or after) menopause. Among these participants, there was no association between age at menopause or HT use and age at NMOSD onset. Conclusions: Overall, age at NMOSD onset did not show a strong relationship with endogenous hormonal exposures. An earlier onset age did appear to be marginally associated with systemic HC exposure, an association that requires confirmation in future studies

Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date

Optiskā neiromielīta klīniskās norises un ārstēšanas raksturojums. Promocijas darba kopsavilkums

This work has been carried out at the following locations: The first part was done at the Walton Centre for Neurology and Neurosurgery, Liverpool, UK, and the second one – in collaboration with Riga Eastern Clinical University hospital “Gaiļezers”– MS unit. Defence: at the public session of the Doctoral Committee of Medicine on 7 December 2015 at 15.00 in Hippocrates Lecture Theatre, 16 Dzirciema Street, Rīga Stradiņš University, Latvia.The doctoral theses “The clinical and treatment characteristics of neuromyelitis optica” has been dedicated to cover a topic about a condition called neuromyelitis optica (NMO) or Devic’s disease, which is a disease that is not fully understood yet. NMO is a relapsing inflammatory demyelinating disease of the central nervous system, and clinically it affects predominantly the optic nerves and spinal cord. Despite significant work, which has been previously made to diagnose NMO, it is still often not recognised, or accidentally diagnosed as multiple sclerosis. In fact, many clinical, laboratory or radiological characteristics are common in both NMO and multiple sclerosis. Devic’s disease, if not treated promptly or accidentally treated as multiple sclerosis, is a very disabling disease with a high mortality rate (Palace, Leite et al. 2010, Barnett, Prineas et al. 2012, Jacob, Hutchinson et al. 2012, Kleiter, Hellwig et al. 2012, Min, Kim et al. 2012, Izaki, Narukawa et al. 2013, Jurynczyk, Zaleski et al. 2013, Lee, Laemmer et al. 2014, Dubey, Kieseier et al. 2015). Treatment of the disease is based on anecdotal case reports. Due to severity and high disability of the disease, randomised placebo controlled treatment trials are unethical (Jacob, McKeon et al. 2013, Mealy, Wingerchuk et al. 2014). Many characteristics of NMO have probably not been identified and studied yet. Criteria to select the best treatment for patients with different phenotypes are also unknown. The purpose of this work was to analyse and characterise clinical features, efficacy of treatment of NMO/NMO spectrum, as well as to analyse the data entered into the Latvian MS register, for the purpose to improve diagnostic accuracy, treatment efficacy, and the outcomes of patients with NMO/NMOS. As a result of this work, several previously ignored NMO features have been described which may lead to earlier identification of the disease and therefore an earlier initiation of treatment. This is the first report describing NMO seasonality in western populations. The results, in contrast to MS, indicated higher NMO relapse activity during October and November but lower in June and July (Koziol and Feng 2004, Fonseca, Costa et al. 2009, Handel, Disanto et al. 2011, Damasceno, Von Glehn et al. 2012). For the first time it has been established that gradual NMO onset over 4 or more weeks represents around one fifth of the cases. The study also confirmed that secondary progressive disease occurs in 4% of the patients (Wingerchuk, Pittock et al. 2007). This is the first report describing the frequency and characteristics of neuropathic pruritus (NP) in patients with NMO/NMOS. Results showed that NP and also tonic spasms are common representing features of NMO/NMOS and can be the first sign of upcoming relapse. This study also looked at clinical phenotype of patients tested positive for MOG-IgG. In contrast to the previous reports (Kitley, Woodhall et al. 2012, Kitley, Waters et al. 2014), it was found that MOG-IgG are present in the sera of both, monophasic and relapsing NMO patients. Results confirmed that azathioprine is an effective immunosupresant in up to 89% (relapse free 61%) of patients (Mandler, Ahmed et al. 1998, Bichuetti, Lobato de Oliveira et al. 2010, Costanzi, Matiello et al. 2011), but also showed that its efficacy is significantly reduced in patients with more active and frequently relapsing disease (relapse free 44%). Despite its good efficacy, side effects were the most common reason for discontinuation of azathioprine. These are the first case series-describing efficacy of intravenous immunoglobulins in treatment of NMO relapse. IVIG were effective if used early in almost half of the patients. The analysis of Latvian MS register showed that the quality and quantity of data entered into the register is not sufficient for retrospective identification of suspected NMO/NMOS cases. As the result of work, recommendations to improve the quality of Latvian MS register, early recognition and treatment of NMO were made.The doctoral thesis was supported by ESF project “Support for doctoral students in obtaining the scientific degree at RSU” and national NMO UK programme

Finance, Production and Reproduction in the Context of Globalization and Economic Crisis

This paper analyses the gendered global interaction of the spheres of finance, production and reproduction in the context of the financial crisis in 2008/9. It examines the gendered origins of the crisis in the West; and the gendered impact of the crisis in Asia. It argues that the crisis was generated by an economic system in which fi nance had come to dominate over production and reproduction; and in which the safety nets of last resort have been provided by unpaid work in the sphere of reproduction. It suggests that securing a more gender-equitable recovery from the crisis in Asia requires more than changing the gender-division of labour and gender norms in production. It requires a more fundamental reorganization of the relations between the three spheres, so that finance and production serve the needs of reproduction, the sphere in which the care essential to human well-being is provided

The Clinical and Treatment Characteristics of Neuromyelitis Optica. Summary of the Doctoral Thesis

Promocijas darbs izstrādāts Valtonas Neiroloģijas un neiroķirurģijas centrā Liverpūlē, Lielbritānijā sadarbībā ar Rīgas Austrumu klīniskās universitātes slimnīcas klīniku “Gaiļezers”, MS vienību. Aizstāvēšana: 2015. gada 7. decembrī plkst. 15.00 RSU Medicīnas promocijas padomes atklātā sēdē Rīgā, Dzirciema ielā 16, Hipokrāta auditorijā.Promocijas darbs ir veltīts aktuālai, tomēr līdz šim nepietiekami izpētītai slimībai – optiskajam neiromielītam (NMO) jeb Devika slimībai. NMO ir iekaisīga un demielinizējoša centrālās nervu sistēmas slimība, kas klīniski izpaužas galvenokārt ar recidivējošu redzes nervu un muguras smadzeņu bojājumu. Tomēr, neskatoties uz diagnostisko metožu uzlabošanos, slimība joprojām ir nepietiekami atpazīta un nereti sākotnēji kļūdaini uzskatīta par multiplo sklerozi (MS). To apgrūtina fakts, ka daudzas klīniskās, laboratoriskās un radioloģiskās pazīmes abām slimībām ir līdzīgas. Savlaicīgi neārstēta vai ārstēta ar medikamentiem, kas paredzēti MS ārstēšanai, Devika slimība ir ar augstu invaliditātes un mirstības risku (Palace, Leite et al. 2010, Barnett, Prineas et al. 2012, Jacob, Hutchinson et al. 2012, Kleiter, Hellwig et al. 2012, Min, Kim et al. 2012, Izaki, Narukawa et al. 2013, Jurynczyk, Zaleski et al. 2013, Lee, Laemmer et al. 2014, Dubey, Kieseier et al. 2015). Randomizēti, placebo kontrolēti pētījumi slimības smagās norises un augstā invaliditātes riska dēļ būtu neētiski, tādēļ ārstēšanas izvēle balstās uz atsevišķu gadījumu aprakstiem un klīnicistu iepriekšējo pieredzi (Jacob, McKeon et al. 2013, Mealy, Wingerchuk et al. 2014). Daudzas NMO klīniskās un norises īpatnības joprojām nav apzinātas. Pietiekami nav apzinātas arī NMO terapijā pielietojamo medikamentu priekšrocības un riski pacientiem ar dažādu klīnisko norisi. Šī darba mērķis ir izpētīt un raksturot NMO/NMOS klīniskās norises īpatnības un ārstēšanas efektivitāti, kā arī Latvijas MS reģistrā ievadāmos datus, ar nolūku uzlabot NMO/NMOS pacientu diagnostiku, ārstēšanu un slimības iznākumu. Apkopojot promocijas darbā iegūtos rezultātus, raksturotas iepriekš mazāk pazīstamas NMO klīniskās pazīmes, kas varētu ietekmēt savlaicīgu NMO diagnostiku un līdz ar to agrīnu terapijas uzsākšanu. Pētījuma rezultātā pirmo reizi izpētīta NMO sezonalitāte rietumu populācijā un noskaidrots, ka augstāka NMO/NMOS paasinājumu aktivitāte, pretēji MS, reģistrēta oktobrī un novembrī, bet zemāka – jūnijā un jūlijā (Koziol and Feng 2004, Fonseca, Costa et al. 2009, Handel, Disanto et al. 2011, Damasceno, Von Glehn et al. 2012). Pirmo reizi noskaidrots, ka piektdaļai NMO/NMOS slimnieku pirmie simptomi attīstās progresējoši – 4 un vairāk nedēļu laikā, un apstiprināts, ka sekundāri progresējoša slimības norise attīstās līdz 4% slimnieku (Wingerchuk, Pittock et al. (2007). Pirmo reizi izpētīts neiropātiskās niezes (NN) biežums un īpatnības, un noskaidrots, ka NN un toniskas spazmas ir raksturojoši NMO/NMOS simptomi, kas var izpausties kā paasinājuma pirmā pazīme. Pētījuma rezultātā izpētīts MOG-IgG pozitīvu pacientu fenotips un, pretēji iepriekš uzskatītajam, secināts, ka MOG-IgG antivielas sastop gan monofāzisku, gan recidivējošu NMO slimnieku serumā (Kitley, Woodhall et al. 2012, Kitley, Waters et al. 2014). Vienlaicīgi pētījuma rezultāti parādīja, ka azatioprīns, līdzīgi kā ziņots iepriekš (Mandler, Ahmed et al. 1998, Bichuetti, Lobato de Oliveira et al. 2010, Costanzi, Matiello et al. 2011), samazina slimības aktivitāti līdz pat 89% slimnieku (pilnīga klīniska remisija 61%), tomēr tā efektivitāte ir ievērojami zemāka slimniekiem ar izteiktāku slimības aktivitāti pirms ārstēšanas etapā (pilnīga klīniska remisija 44%). Noskaidrots, ka blakusefekti ir biežākais azatioprīna pārtraukšanas iemesls. Pirmo reizi izpētīts un, pētījuma rezultātā noskaidrots, ka intravenozi imūnglobulīni ir efektīvi NMO/NMOS paasinājumu agrīnā terapijā. Savukārt, izanalizējot Latvijas MS reģistrā ievadāmo datu kvalitāti un kvantitāti, jāsecina, ka tie nav pietiekami, lai retrospektīvi atklātu NMO/NMOS gadījumus. Darba noslēgumā sniegtas rekomendācijas gan Latvijas MS reģistra uzlabošanā, gan klīniski praktiskas rekomendācijas NMO/NMOS slimnieku diagnostikas un ārstēšanas uzlabošanai.Promocijas darbs veikts ar ESF projekta “Atbalsts doktorantiem studiju programmas apguvei un zinātniskā grāda ieguvei RSU” un Lielbritānijas NHS nacionālās NMO programmas atbalstu