Humoral immunity to SARS-CoV-2 mRNA vaccination in multiple sclerosis: the relevance of time since last rituximab infusion and first experience from sporadic revaccinations.

INTRODUCTION: The effect of disease-modifying therapies (DMT) on vaccine responses is largely unknown. Understanding the development of protective immunity is of paramount importance to fight the COVID-19 pandemic. OBJECTIVE: To characterise humoral immunity after mRNA-COVID-19 vaccination of people with multiple sclerosis (pwMS). METHODS: All pwMS in Norway fully vaccinated against SARS-CoV-2 were invited to a national screening study. Humoral immunity was assessed by measuring anti-SARS-CoV-2 SPIKE RBD IgG response 3-12 weeks after full vaccination, and compared with healthy subjects. RESULTS: 528 pwMS and 627 healthy subjects were included. Reduced humoral immunity (anti-SARS-CoV-2 IgG <70 arbitrary units) was present in 82% and 80% of all pwMS treated with fingolimod and rituximab, respectively, while patients treated with other DMT showed similar rates as healthy subjects and untreated pwMS. We found a significant correlation between time since the last rituximab dose and the development of humoral immunity. Revaccination in two seronegative patients induced a weak antibody response. CONCLUSIONS: Patients treated with fingolimod or rituximab should be informed about the risk of reduced humoral immunity and vaccinations should be timed carefully in rituximab patients. Our results identify the need for studies regarding the durability of vaccine responses, the role of cellular immunity and revaccinations.

Six versus 2 weeks treatment with doxycycline in European Lyme neuroborreliosis: a multicentre, non-inferiority, double-blinded, randomised and placebo-controlled trial.

BACKGROUND: There is limited evidence regarding optimal duration of antibiotic treatment in neuroborreliosis. We aimed to compare efficacy and safety of oral doxycycline for 2 and 6 weeks in European Lyme neuroborreliosis (LNB). METHODS: The trial had a randomised, double-blinded, placebo-controlled, non-inferiority design. Patients with LNB were recruited from eight Norwegian hospitals and randomised to doxycycline 200 mg once daily for 2 weeks, followed by 4 weeks of placebo, or doxycycline 200 mg once daily for 6 weeks. The primary endpoint was clinical improvement as measured by difference in a Composite Clinical Score (0-64 points) from baseline to 6 months. The non-inferiority margin was predetermined to 0.5 points. RESULTS: One hundred and twenty-one patients were included. Fifty-two treated for 2 weeks and 53 for 6 weeks were included in the intention-to-treat analyses, and 52 and 51 in per-protocol analysis. Mean difference in clinical improvement between the groups was 0.06, 95% CI -1.2 to 1.2, p=0.99 in the intention-to-treat population, and -0.4, 95% CI -1.4 to 0.7, p=0.51 in the per-protocol population and non-inferiority could not be established. There were no treatment failures and no serious adverse events. The groups did not differ in secondary outcomes including clinical scores at 10 weeks and 12 months, cerebrospinal fluid data and patient-reported outcome measures. Patients receiving 6 weeks doxycycline reported slightly more side effects in week 5. CONCLUSION: Our results strongly indicate that there are no benefits of doxycycline treatment beyond 2 weeks in European LNB. TRIAL REGISTRATION NUMBER: 2015-001481-25.

Enhancement of cranial nerves in Lyme neuroborreliosis: incidence and correlation with clinical symptoms and prognosis.

PURPOSE: Symptoms of cranial neuritis are a common presentation of Lyme neuroborreliosis (LNB). Imaging studies are scarce and report contradictory low prevalence of enhancement compared to clinical studies of cranial neuropathy. We hypothesized that MRI enhancement of cranial nerves in LNB is underreported, and aimed to assess the prevalence and clinical impact of cranial nerve enhancement in early LNB. METHODS: In this prospective, longitudinal cohort study, 69 patients with acute LNB were examined with MRI of the brain. Enhancement of cranial nerves III-XII was rated. MRI enhancement was correlated to clinical findings of neuropathy in the acute phase and after 6 months. RESULTS: Thirty-nine of 69 patients (57%) had pathological cranial nerve enhancement. Facial and oculomotor nerves were most frequently affected. There was a strong correlation between enhancement in the distal internal auditory canal and parotid segments of the facial nerve and degree of facial palsy (gamma = 0.95, p < .01, and gamma = 0.93, p < .01), despite that 19/37 nerves with mild-moderate enhancement in the distal internal auditory canal segment showed no clinically evident palsy. Oculomotor and abducens nerve enhancement did not correlate with eye movement palsy (gamma = 1.00 and 0.97, p = .31 for both). Sixteen of 17 patients with oculomotor and/or abducens nerve enhancement had no evident eye movement palsy. CONCLUSIONS: MRI cranial nerve enhancement is common in LNB patients, but it can be clinically occult. Facial and oculomotor nerves are most often affected. Enhancement of the facial nerve distal internal auditory canal and parotid segments correlate with degree of facial palsy.

Subjective health complaints and exposure to tick-borne infections in southern Norway.

OBJECTIVES: Whether tick-borne infections can cause chronic subjective health complaints is heavily debated. If such a causal connection exists, one would expect to find more health complaints among individuals exposed to tick-borne infections than among non-exposed. In this study, we aimed to assess if exposure to tick-borne infections earlier in life, evaluated by examination of serum for IgG antibodies to tick-borne microbes, was associated with self-reported somatic symptom load. MATERIALS & METHODS: All individuals with residential address in Søgne municipality in southern Norway, aged 18-69 years, were invited to participate in the study. Blood samples were analyzed for IgG antibodies to different tick-borne microbes, and somatic symptom load was charted by the Patient Health Questionnaire-15 (PHQ-15). RESULTS: Out of 7424 invited individuals, 2968 (40.0%) were included in the study. We detected IgG antibodies to Borrelia burgdorferi sensu lato (Bb) in 22.9% (95% CI 21.4-24.4). Bb seropositive individuals reported less frequently moderate to severe somatic symptom load (ie, PHQ-15 sum score ≥ 10) than seronegative individuals (12.5% versus 17.7%, difference 5.2% [95% 2.1-8.0]). However, when adjusting for several other variables in a multivariable linear regression model, presence of serum IgG antibodies to Bb was not associated with somatic symptom load. Presence of IgG antibodies to other tick-borne microbes than Bb, or seropositivity to at least two microbes, was also not associated with somatic symptom load. CONCLUSION: Presence of serum IgG antibodies to tick-borne microbes was not associated with self-reported somatic symptom load.

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy.

INTRODUCTION: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. METHODS: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. RESULTS: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. DISCUSSION: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59:354-357, 2019.

Examination of patients with acute dizziness in a neurological department. / Utredning av pasienter med akutt svimmelhet ved en nevrologisk avdeling.

BACKGROUND: Acute dizziness may have a number of causes, including cerebrovascular stroke which can present as isolated acute vestibular syndrome. It is recommended that acute episodic dizziness be assessed using positioning tests, and acute persistent dizziness with a focus on the HINTS (Head Impulse, Nystagmus, Test of Skew) battery of tests, which can distinguish cerebrovascular stroke from vestibular neuritis. We wished to identify the prevalence, diagnostic spectrum and approach to acute dizziness in a neurological department. MATERIAL AND METHOD: We undertook a retrospective review of the medical records of all patients with acute dizziness as the primary symptom who where admitted to the department of neurology at Sørlandet Hospital, Kristiansand in 2015. RESULTS: Of 2 231 patients admitted to the department of neurology in 2015, altogether 243 (11 %) had dizziness as the primary symptom. A total of 106 patients (44 %) were examined using HINTS in its entirety. A cranial CT was performed in 213 (88 %) and MRI in 91 (37 %), and these showed relevant pathology in 1 and 4 patients, respectively. Upon discharge, 122 patients (50 %) were given a non-specific symptom diagnosis, 59 (24 %) received the diagnosis vestibular neuritis, 41 (17 %) benign paroxysmal positional vertigo, and 5 (2 %) were diagnosed with cerebrovascular stroke. Four out of five cases of cerebrovascular stroke could be classified retrospectively as acute vestibular syndrome, whereof three had typical findings determined by the HINTS test. INTERPRETATION: Acute dizziness is a frequent symptom in patients admitted to the department of neurology. Evidence-based diagnostic recommendations for the assessment of acute dizziness were not satisfactorily implemented in practice.

Persistent postural-perceptual dizziness / Persisterende postural-perseptuell svimmelhet.

Persistent symptoms of dizziness may be due to inappropriate compensatory strategies following an episode of acute dizziness. Common symptoms are dizziness in an upright position that is aggravated by visual stimuli and passive movement. In the World Health Organization's new disease classification, ICD-11, the condition has been named persistent postural-perceptual dizziness. It is important to recognise this condition in order to avoid unnecessary investigation and to initiate the correct treatment.

Chronic headache with medication overuse: Long-term prognosis after withdrawal therapy.

Background Knowledge about long-term outcomes after medication withdrawal therapy for chronic headache, including tension type and migraine headache is lacking. Methods We re-examined 56 patients an average of nine years after they participated in a medication withdrawal study with a one-year follow-up. We collected and compared data on headache, use of medication, quality of life, quality of sleep, anxiety, depression, and labor participation one and nine years after the start of withdrawal therapy. Results Headache days per month decreased from 16.7 (14.0-19.3) at one year to 13.3 (10.6-15.9) at nine years (P = 0.007). The proportion of patients meeting the criteria for chronic headache decreased from 27/56 (48%) at one year to 18/56 (32%) at nine years (P = 0.004). Medication overuse was reported in seven (13%) patients at one year and 18 (32%) at nine years (P = 0.013). The majority of patients overusing medication at nine years (10/18) belonged to a group of 14 patients who had a poor early response to withdrawal therapy and had sustained chronic headache after nine years. After excluding patients receiving retirement pensions, the proportion who received disability benefits increased from 21/55 (38%) at one year to 30/49 (61%) at nine years (P = 0.003). Conclusion Improvements after withdrawal therapy for chronic headache last at least nine years, with a parallel increase in the use of disability benefits. However, a high proportion of patients with a poor initial response to withdrawal therapy and sustained chronic headache overuse medication.

[Autoimmune myopathy associated with statin use]. / Autoimmun myopati ved statinbruk.

It is well known that statins can have a toxic effect on musculature, but less widely known that they can also trigger progressive autoimmune myopathy. Statin-associated autoimmune myopathy is characterised by proximal muscle weakness, antibodies to 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) in serum, and necrosis without lymphocytic infiltration on muscle biopsy.

[Myasthenia gravis - optimal treatment and accurate diagnosis]. / Myasthenia gravis - diagnostikk og behandling.

Around 700 people in Norway have myasthenia gravis, an autoimmune disease that affects neuromuscular transmission and results in fluctuating weakness in some muscles as its sole symptom. The diagnosis is based on typical symptoms and findings, detection of antibodies and neurophysiological examination. Symptomatic treatment with acetylcholinesterase inhibitors is generally effective, but most patients also require immunosuppressive drug treatment. Antigen-specific therapy is being tested in experimental disease models.

Serum neurofilament light chain associates with symptom burden in Lyme neuroborreliosis patients: a longitudinal cohort study from Norway.

OBJECTIVES: Serum neurofilament light chain (sNfL), an indicator of neuronal damage, is increasingly recognized as a potential biomarker for disease activity in neurodegenerative disorders. In this study, we wanted to investigate sNfL as a prognostic marker in a large, well-defined population of 90 patients with Lyme neuroborreliosis (LNB). In addition, we sought to explore associations between symptoms and sNfL levels during the acute phase of LNB. MATERIALS AND METHODS: Patients diagnosed with definite or possible LNB were recruited from a double-blinded, placebo-controlled, multi-center trial, in which the participants were randomly assigned to 2 or 6 weeks of oral doxycycline treatment. The sNfL levels were measured using a single molecule array assay at both diagnosis and 6-month follow-up, and analysed against clinical parameters, variations in symptom burden and long-term complaints as assessed by a composite clinical score. RESULTS: At the time of diagnosis, approximately 60% of the patients had elevated sNfL levels adjusted for age. Notably, mean sNfL levels were significantly higher at diagnosis (52 pg/ml) compared to 6 months after treatment (12 pg/ml, p < 0.001), when sNfL levels had normalized in the majority of patients. Patients with objective signs of spinal radiculitis had significantly higher baseline sNfL levels compared to patients without spinal radiculitis (p = 0.033). CONCLUSION: Our findings suggest that sNfL can serve as a biomarker for peripheral nerve tissue involvement in the acute phase of LNB. As found in an earlier study, we confirm normalization of sNfL levels in blood after treatment. We found no prognostic value of acute-phase sNfL levels on patient outcome.

Comparison of interictal vestibular function in vestibular migraine vs migraine without vertigo.

BACKGROUND: Patients with vestibular migraine (VM) suffer attacks of vertigo that often occur in isolation from headache attacks. We aimed to assess and compare vestibular function interictally in patients with VM and patients with migraine without vertigo (M). METHODS: Thirty-eight patients diagnosed with definite VM according to the Neuhauser criteria, and 32 patients diagnosed with M according to the International Headache Society criteria were examined between attacks using a broad battery of bedside vestibular tests, a caloric test, and videonystagmography. RESULTS: Overall, 70% of the VM patients and 34% of the M patients showed abnormalities on one or more of the 14 performed vestibular tests (P = .006). Abnormal findings were more frequent in VM than in M patients on Romberg's test, test for voluntary fixation suppression of the vestibular ocular reflex and test for static positional nystagmus (P = .03, .01 and .04, respectively). There were no differences in the distribution of central and peripheral vestibular signs between VM and M patients. CONCLUSIONS: Vestibular abnormalities were present interictally among both VM and M patients, but were found about twice as frequently among VM patients. This may indicate that subclinical vestibular dysfunction is an integral part of migraine pathology in general, and not solely in VM.

Leukoaraiosis is associated with short- and long-term mortality in patients with intracerebral hemorrhage.

BACKGROUND: There are few recent European studies of mortality after intracerebral hemorrhage (ICH), particularly long-term follow-up studies. No previous European studies have included information on leukoaraiosis. METHODS: We studied all consecutive patients hospitalized with a first-ever intracerebral hemorrhage between 2005 and 2009 in a well-defined area and assessed the prognostic value of various baseline clinical and radiologic factors. Leukoaraiosis was scored on the baseline computed tomographic (CT) scan as described by van Swieten et al, with an overall score from 0 to 4. RESULTS: One hundred thirty-four patients were followed up for a median of 4.7 years (interquartile range 2.5-6.6). Overall mortality was 23% at 2 days, 30% at 7 days, 37% at 30 days, 46% at 1 year, and 53% at 2 years. Factors independently associated with increased 30-day mortality were warfarin use, leukoaraiosis score, intraventricular hemorrhage, and Glasgow Coma Scale (GCS) score. Factors independently associated with long-term mortality in the 85 patients who survived the first 30 days were leukoaraiosis score, coronary heart disease, and initial GCS score. Recurrent ICH occurred in 4.5% and was significantly more frequent after lobar ICH than after ICH in other locations (11.1% v 0%; P = .025). CONCLUSIONS: In unselected patients in Southern Norway with first-ever ICH, severe leukoaraiosis is independently associated with both 30-day and long-term mortality in 30-day survivors. Warfarin is independently associated with 30-day mortality and coronary heart disease with long-term mortality in 30-day survivors. Recurrent ICH is more frequent after lobar ICH than after ICH in other locations.

Assessment of cognitive function, structural brain changes and fatigue 6 months after treatment of neuroborreliosis.

BACKGROUND: Complete recovery after adequately treated neuroborreliosis is common, but studies report that some patients experience persistent symptoms like self-reported cognitive problems and fatigue. Persisting symptoms are often termed post-Lyme disease syndrome, of which etiology is not clearly understood. The aim of this study was to investigate cognitive function, possible structural changes in brain regions and level of fatigue. We have not found previous studies on neuroborreliosis that use standardized neuropsychological tests and MRI with advanced image processing to investigate if there are subtle regional changes in cortical thickness and brain volumes after treatment. METHODS: We examined 68 patients treated for neuroborreliosis 6 months earlier and 66 healthy controls, with a comprehensive neuropsychological test protocol, quantitative structural MRI analysis of the brain and Fatigue Severity Scale. RESULTS: We found no differences between the groups in either cognitive function, cortical thickness or brain volumes. The patients had higher score on Fatigue Severity Scale 3.8 vs. 2.9 (p = 0.001), and more patients (25.4%) than controls (5%) had severe fatigue (p = 0.002), but neither mean score nor proportion of patients with severe fatigue differed from findings in the general Norwegian population. CONCLUSION: The prognosis regarding cognitive function, brain MRI findings and fatigue after adequately treated neuroborreliosis is favorable.

Intracerebral hemorrhage in southern Norway--a hospital-based incidence study.

BACKGROUND/AIMS: Newer Scandinavian data on intracerebral hemorrhage (ICH) are scarce. We aimed at providing updated community-based data on the incidence, characteristics and outcome of ICH leading to hospitalization in the southernmost region in Norway. METHODS: We analyzed data from all consecutive patients hospitalized with a first-ever ICH in the five-year period 2005-2009 in a well-defined area served by one single hospital. Cases were found by computerized search in a register covering all in- and outpatients. RESULTS: Adjusted to the standard European population the annual incidence rate per 100,000 was 16.9 for men, 8.8 for women (p < 0.001) and 12.5 for both sexes. The incidence rates rose continuously with increasing age through all age groups in both sexes. The proportion with warfarin-associated ICH was 26.9%. The overall 30-day case fatality rate was 36.6%. The hematoma location was lobar in 36.6%, deep cerebral in 45.5%, cerebellar in 9.7%, and brain stem in 8.2%. CONCLUSIONS: The incidence of ICH in the southernmost region in Norway is in the midrange in Europe and lower than in previous Scandinavian studies. Men are at higher risk than women. The proportion with warfarin-associated ICH is higher than previously reported from Scandinavia.

Cognitive function in patients with neuroborreliosis: A prospective cohort study from the acute phase to 12 months post treatment.

BACKGROUND: Long-term cognitive problems after neuroborreliosis treatment remain a subject of debate. We have previously shown that cognitive problems are not present in the acute phase of neuroborreliosis, although fatigue is common. The aim of this study was to re-assess the same patient cohort and evaluate long-term outcomes. METHODS: In this follow-up, we re-assessed 58 patients with well-characterized neuroborreliosis 12 months after completing treatment. The same protocol with eight subtests measuring attention and processing speed and the Fatigue Severity Scale (FSS) were used to compare the results from the acute phase to 12 months post treatment. RESULTS: We found no changes in attention or processing speed but a reduction in the level of fatigue (median score on FSS: 4.9 vs. 3.9, p < .001) from the acute phase to 12 months post treatment. CONCLUSION: The patient group did not develop problems with attention or processing speed post treatment, while the level of fatigue decreased.