Repeat expansions in AR, ATXN1, ATXN2 and HTT in Norwegian patients diagnosed with amyotrophic lateral sclerosis.

Genetic repeat expansions cause neuronal degeneration in amyotrophic lateral sclerosis as well as other neurodegenerative disorders such as spinocerebellar ataxia, Huntington's disease and Kennedy's disease. Repeat expansions in the same gene can cause multiple clinical phenotypes. We aimed to characterize repeat expansions in a Norwegian amyotrophic lateral sclerosis cohort. Norwegian amyotrophic lateral sclerosis patients (n = 414) and neurologically healthy controls adjusted for age and gender (n = 713) were investigated for repeat expansions in AR, ATXN1, ATXN2 and HTT using short read exome sequencing and the ExpansionHunter software. Five amyotrophic lateral sclerosis patients (1.2%) and two controls (0.3%) carried ≥36 repeats in HTT (P = 0.032), and seven amyotrophic lateral sclerosis patients (1.7%) and three controls (0.4%) carried ≥29 repeats in ATXN2 (P = 0.038). One male diagnosed with amyotrophic lateral sclerosis carried a pathogenic repeat expansion in AR, and his diagnosis was revised to Kennedy's disease. In ATXN1, 50 amyotrophic lateral sclerosis patients (12.1%) and 96 controls (13.5%) carried ≥33 repeats (P = 0.753). None of the patients with repeat expansions in ATXN2 or HTT had signs of Huntington's disease or spinocerebellar ataxia type 2, based on a re-evaluation of medical records. The diagnosis of amyotrophic lateral sclerosis was confirmed in all patients, with the exception of one patient who had primary lateral sclerosis. Our findings indicate that repeat expansions in HTT and ATXN2 are associated with increased likelihood of developing amyotrophic lateral sclerosis. Further studies are required to investigate the potential relationship between HTT repeat expansions and amyotrophic lateral sclerosis.

Effectiveness of Natalizumab in Achieving No Evidence of Disease Activity (NEDA-3)-Data From a Local Norwegian Cohort.

Objective: We aimed to determine the effectiveness of natalizumab (NTZ) by assessing overall No Evidence of Disease Activity 3 (NEDA-3) in a local Norwegian cohort. Background: NTZ is an immunomodulating drug used in the treatment of multiple sclerosis (MS). It has typically been used as a second-line treatment, but certain patients with high disease activity have started directly with NTZ. Methods: This retrospective cohort study includes all patients who received NTZ for relapsing-remitting MS at Nordland Hospital in the period 2008-2018. In June 2019, status for every patient was assessed, and a survival curve was used to show the cumulative probability of achieving NEDA-3 over time. Results: The cohort consisted of 66 patients, 49 women and 17 men with a mean age of 40.0 ± 10.8 years. Each patient received on average 45.8 ± 36.4 NTZ infusions. Mean age and Expanded Disability Status Scale (EDSS) at first infusion was 34.8 ± 10.5 and 3.2 ± 1.9, respectively. Prior to NTZ treatment, 83% had used other disease modulating drugs and 65% were anti-JC virus (JCV) seronegative. During the study period, seven patients converted to seropositive. In 2019, 40 patients had switched or stopped treatment: 19 due to positive JCV serostatus, 9 due to disease activity, 7 due to adverse effects or complications (1 progressive multifocal leukoencephalopathy), 2 due to pregnancy, and 3 due to autologous hematopoietic cell transplantation abroad. Three patients experienced rebound in the wake of discontinuation (7.5%). Of the patients receiving NTZ for more than 3 years (n = 33), 50% had achieved NEDA-3 after 3 years. Compared to those with evidence of disease activity (EDA), these NEDA-3 patients had significant lower EDSS score before first NTZ treatment (p = 0.04). They were also slightly, but not significantly, younger at debut of their MS, at the diagnosis and at first NTZ treatment. Of all the patients who ever started on NTZ, 23% had achieved NEDA-3 5 years later. The mean EDSS in 2019 was 3.6 ± 2.5. Conclusion: Despite the high rate of treatment switch, mainly due to the risk of PML, almost one in four who started on NTZ achieved NEDA-3 after 5 years, and the overall disease progression was low in the total cohort. Treating less advanced disease seems to predict better long-term stability.

Room tilt illusion and subclavian steal - a case report.

BACKGROUND: Room tilt illusion (RTI) is a rare symptom of higher vestibular dysfunction, consisting of a transient vertical rotation of the visual scene in the sagittal or coronal plane, most often 90o or 180o, without any alteration in shape, size and color of objects. CASE PRESENTATION: A 63-year-old woman with a history of hypertension and chronic obstructive pulmonary disease went through an uncomplicated aortobifemoral graft surgery due to aortoiliac occlusive disease. Post-operatively she experienced five episodes, lasting from 10 to 30 min, with RTI; 90o forward rotation of the visual scene in the sagittal plane. Work-up revealed subclavian steal grade 3, and transient ischemia of the central vestibular system of the brainstem was the presumed mechanism. CONCLUSION: The course of episodic RTIs is often benign, but RTI may represent ischemia in the posterior cerebral circulation. Both stroke and otoneurologic workup are recommended. To our knowledge, this is the first case of RTI associated with subclavian steal reported.

Occurrence of postdural puncture headache-A randomized controlled trial comparing 22G Sprotte and Quincke.

OBJECTIVE: To assess the incidence of postdural puncture headache (PDPH) using 22-gauge atraumatic needle (Sprotte, 22GS) compared with 22-gauge traumatic needle (Quincke, 22GQ). BACKGROUND: Diagnostic lumbar puncture (dLP) is commonly complicated by PDPH. Despite evidence to support the use of 22GS, European neurologists seem to keep using 22GQ. METHODS: This was a randomized, double-blind study. Adults (age: 18-60 years) scheduled for dLP were included. dLP and CSF acquisition were performed in accordance with highly standardized procedures. Patients were followed up on days 2 and 7. RESULTS: In total, 172 patients were randomized and lumbar punctured, and 21 were excluded due to wrong inclusion (n = 11), needle switch (n = 7), failed dLP (n = 1), withdrawal (n = 1), and missed follow-up (n = 1). Among the remaining 151 patients (mean age: 40.7 ± 12.4 years), 77 had dLP using 22GQ and 74 using 22GS. Incidence of PDPH among patients punctured with 22GS (18%) was significantly lower (p = .004) than among patients punctured with 22GQ (39%). Relative risk was 0.45, 95% CI 0.26-0.80. Patients with PDPH had significantly lower weight (p = .035), and there was no significant difference related to age (p = .064), sex (p = .239), height (p = .857), premorbid episodic migraine (p = .829), opening pressure (p = .117), operators (p = .148), amount of CSF removed (p = .205), or number of attempts (p = .623). CONCLUSIONS: The use of 22GS halves the risk of PDPH compared with 22GQ. This study provides strong support to make a change in practice where traumatic needles are still in regular use.

Sudden Caffeine Withdrawal Triggers Migraine-A Randomized Controlled Trial.

Objective: Assessing the effects of caffeine withdrawal on migraine. Background: The effects of caffeine withdrawal on migraineurs are at large unknown. Methods: This was a randomized, double-blind, crossover study (NCT03022838), designed to enroll 80 adults with episodic migraine and a daily consumption of 300-800 mg caffeine. Participants substituted their estimated dietary caffeine with either placebo capsules or capsulated caffeine tablets for 5 weeks before switching the comparators for 5 more weeks. Results: The study was terminated due to low recruitment. Ten subjects with a mean age of 46.3 ± 9.9 years, BMI of 24.9 ± 3.7, and a mean blood pressure of 134/83 ± 17/12 mmHg were enrolled. The average consumption of caffeine per day was 539 ± 196.3 mg. The average monthly headache days and migraine attack frequency at baseline was 11.5 ± 4.9 and 5.2 ± 1.2, respectively. At baseline Pittsburgh Sleep Quality Index was 5.8 ± 2.5 and HIT-6 was 62.8 ± 3.9. There were no differences in these or in parameters from actigraphy during the caffeine period compared with the placebo period. One subject withdrew just after entering the study. In the remaining nine, withdrawal triggered severe migraine attacks in seven, causing one more drop-out, and a typical caffeine withdrawal syndrome in two. Caffeine continuation did not trigger migraines, but one attack occurred in the wake of caffeine reintroduction. Conclusions: The study failed to answer how caffeine withdrawal affects migraineurs over time, but showed that abrupt withdrawal of caffeine is a potent trigger for migraine attacks.

Caffeine and Primary (Migraine) Headaches-Friend or Foe?

Background: The actions of caffeine as an antagonist of adenosine receptors have been extensively studied, and there is no doubt that both daily and sporadic dietary consumption of caffeine has substantial biological effects on the nervous system. Caffeine influences headaches, the migraine syndrome in particular, but how is unclear. Materials and Methods: This is a narrative review based on selected articles from an extensive literature search. The aim of this study is to elucidate and discuss how caffeine may affect the migraine syndrome and discuss the potential pathophysiological pathways involved. Results: Whether caffeine has any significant analgesic and/or prophylactic effect in migraine remains elusive. Neither is it clear whether caffeine withdrawal is an important trigger for migraine. However, withdrawal after chronic exposure of caffeine may cause migraine-like headache and a syndrome similar to that experienced in the prodromal phase of migraine. Sensory hypersensitivity however, does not seem to be a part of the caffeine withdrawal syndrome. Whether it is among migraineurs is unknown. From a modern viewpoint, the traditional vascular explanation of the withdrawal headache is too simplistic and partly not conceivable. Peripheral mechanisms can hardly explain prodromal symptoms and non-headache withdrawal symptoms. Several lines of evidence point at the hypothalamus as a locus where pivotal actions take place. Conclusion: In general, chronic consumption of caffeine seems to increase the burden of migraine, but a protective effect as an acute treatment or in severely affected patients cannot be excluded. Future clinical trials should explore the relationship between caffeine withdrawal and migraine, and investigate the effects of long-term elimination.

Amyotrophic lateral sclerosis in Nordland county, Norway, 2000-2015: prevalence, incidence, and clinical features.

OBJECTIVE: There are some indications of increasing incidence of amyotrophic lateral sclerosis (ALS). Awareness of cognitive impairment in ALS has increased in recent years. We describe the epidemiology and clinical features of ALS in a county in northern Norway over a period of 15 years. METHODS: All patients with motor neuron disease (MND) living in Nordland County in the period 2000-2015 were identified and the medical records were scrutinized. The average annual incidence was calculated for the whole period and for five-year periods. Prevalence point was 1 January 2015. RESULTS: We identified 74 cases with MND. The crude point prevalence was 4.1 per 100,000. The average annual incidence was 2.1 per 100,000 for the whole period, 2.0 in the period 2000-2004, 2.3 in 2005-2009, and 2.0 in 2010-2014. All except one of the 22 patients with other forms of MND developed ALS during the course of the disease. The mean survival time was 38 months, patients with bulbar symptoms at diagnosis had a mean survival time of 29 months and those with solely spinal symptoms had a mean survival time of 50 months. Seven patients were diagnosed with frontotemporal dementia (FTD). CONCLUSION: The incidence was stable during the study period. Other forms of MND converts to clinical ALS given time. Survival time is almost two years shorter in patients with bulbar symptoms at the first examination, compared to those with solely symptoms from spinal muscles. FTD was found in 9% of the patients.

The prevalence and characteristics of epilepsy in patients with multiple sclerosis in Nordland county, Norway.

PURPOSE: The prevalence of epilepsy among patients with multiple sclerosis (MS) has been found higher than in the general population. Although cortical pathology may be involved, the causal link between MS and epileptic seizures is still unclear. We aimed to identify and describe the patients with active epilepsy in a previously described population based MS-cohort. METHODS: Medical records of all patients with MS in Nordland County on January 1, 2010, were scrutinizing for evidence of comorbid seizures and epilepsy. RESULTS: Among 431 patients with MS, we identified 19 (4.4%) with a history of seizures or epilepsy. Fourteen (3.2%) of these had active epilepsy defined as use of antiepileptic drugs or seizures within the last 5 years. One patient got epilepsy before other signs of MS. In patients with relapsing-remitting MS (RRMS) at onset and active epilepsy (n=10), 70% had converted to secondary progressive (SPMS) at prevalence date, compared to only 35% of those without active epilepsy (p=0.02). 43% had converted to SPMS before they got epilepsy. Attack semiology or electroencephalogram recordings indicated a focal onset of seizures in 12 of 14 (86%) with active epilepsy. CONCLUSION: The frequency of active epilepsy among MS patients in Nordland was 3.2%, approximately 4.5 times higher than in the general Norwegian population. RRMS patients with active epilepsy had more likely converted to SPMS than patients without active epilepsy. With a high frequency of focal epilepsy, the study supports that focal MS brain pathology is the cause of the comorbid epilepsy.

A randomized trial of telemedicine efficacy and safety for nonacute headaches.

OBJECTIVE: To evaluate long-term treatment efficacy and safety of one-time telemedicine consultations for nonacute headaches. METHODS: We randomized, allocated, and consulted nonacute headache patients via telemedicine (n = 200) or in a traditional manner (n = 202) in a noninferiority trial. Efficacy endpoints, assessed by questionnaires at 3 and 12 months, included change from baseline in Headache Impact Test-6 (HIT-6) (primary endpoint) and pain intensity (visual analogue scale [VAS]) (secondary endpoint). The primary safety endpoint, assessed via patient records, was presence of secondary headache within 12 months after consultation. RESULTS: We found no differences between telemedicine and traditional consultations in HIT-6 (p = 0.84) or VAS (p = 0.64) over 3 periods. The absolute difference in HIT-6 from baseline was 0.3 (95% confidence interval [CI] -1.26 to 1.82, p = 0.72) at 3 months and 0.2 (95% CI -1.98 to 1.58, p = 0.83) at 12 months. The absolute change in VAS was 0.4 (95% CI -0.93 to 0.22, p = 0.23) after 3 months and 0.3 (95% CI -0.94 to 0.29, p = 0.30) at 12 months. We found one secondary headache in each group at 12 months. The estimated number of consultations needed to miss one secondary headache with the use of telemedicine was 20,200. CONCLUSION: Telemedicine consultation for nonacute headache is as efficient and safe as a traditional consultation. CLINICALTRIALSGOV IDENTIFIER: NCT02270177. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a one-time telemedicine consultation for nonacute headache is noninferior to a one-time traditional consultation regarding long-term treatment outcome and safety.

Photophobia and Seasonal Variation of Migraine in a Subarctic Population.

OBJECTIVE: To investigate associations between photophobia and seasonal variation of migraine. METHODS: In this cross-sectional study, migraineurs consecutively recruited were referred to a specialist center located above the Arctic Circle at 68-71 degrees North during a 2.5-year period. Data were obtained through a structured interview. RESULTS: In total, 302 migraineurs with a mean (±SD) age of 35.5 (±12.6) years were included. Patients who reported seasonal variation of migraine (n = 90; 29.8%) also reported more often interictal photophobia than the others (61/90, 67.8% vs 92/212, 43.4%, P < .0001). Patients reported sunlight or other bright light to trigger migraine attacks in 74.4% with seasonal migraine (SM) compared with 40.6% in patients with non-seasonal migraine (NSM) (P < .0001), but there were similar frequencies of attacks reported to be triggered by sleep, menstruation, and other precipitating factors. After adjusting for migraine with aura, migraine disability, chronic migraine, interictal photophobia, and insomnia, sunlight or other bright light, photophobia was still associated with SM (OR; 3.47, CI [95%]; 1.83-6.59, P < .0001). CONCLUSIONS: Migraineurs in a subarctic area reporting seasonal variation of attack frequency also report increased interictal photophobia independent of other clinical factors. Chronobiological mechanisms and/or increased activity in the visual system may be responsible for this phenomenon.

Progressive multifocal leukoencephalopathy in a patient with systemic mastocytosis treated with cladribine.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic brain infection caused by the human polyomavirus JC (JCPyV). A particular problem with the drug cladribine seems to be prolonged suppression of the CD4+ T-cells, a well-known risk factor for PML. CASE DESCRIPTION: A 67-year-old male presented with a 3-weeks history of unsteady gait, dysarthria and a dysfunctional right arm. Seven years earlier, he had been diagnosed with urticaria pigmentosa, and 2 years later aggressive systemic mastocytosis. Cladribine treatment was initiated and regarded effective, but the course was complicated with bouts of severe anemia and recurrent episodes of salmonella associated gastroenteritis. His lymphocyte count fell to 0.1×109/L at its lowest level, but gradually rose. Despite this, in the 6 month wake of the last dose of cladribine given, the patient experienced herpetic stomatitis, had CMV present in blood, and ultimately developed the neurological symptoms. An MRI scan revealed a lesion in the right cerebellar hemisphere compatible with PML, and PCR analysis of the CSF showed positive for JCPyV DNA with a load of 323 950 copies/ml. No pathological cells were seen on CSF flow cytometry. The CD4/CD8-ratio was 0.45 (160 CD4+ cells/mm3 and 360 CD8+ cells/mm3). The patient passed away 3 weeks later. CONCLUSION: PML may be the consequence of prolonged lymphopenia due to the use of cladribine.

Telemedicine in the management of non-acute headaches: A prospective, open-labelled non-inferiority, randomised clinical trial.

Objectives We determined headache patients' satisfaction with telemedicine and assessed how telemedicine influenced headache burden, compliance with diagnosis and treatment, and need for follow-up consultations. Methods During 2.5 years, patients from Northern Norway referred with non-acute headaches for a specialist consultation at Tromsø University Hospital were consecutively randomised to either telemedicine or traditional visits. Baseline data were recorded and compared to data from a three-month follow-up questionnaire (see Supplementary material). The following were evaluated: (1) satisfaction with the consultation; (2) headache status; subjective improvement, average pain intensity, treatment, headache days per month, and Headache Impact Test (HIT-6); and (3) treatment compliance and follow-up visits. Results Out of 402 consultations, 348 (86.6%) answered the questionnaire. Satisfaction was similar in the telemedicine and the traditional group (88.8% vs. 92.3%; p = 0.35). Subgroup analyses were not prespecified, but there were no differences in satisfaction among females, migraineurs, rural patients and urban patients. Improvement from baseline after three months was reported equally in the telemedicine and the traditional groups. There were also no differences in treatment compliance, but rural telemedicine patients had less-frequent headache visits at three months' follow-up (28.9% vs. 48.7%, p = 0.002). Conclusion Telemedicine is non-inferior to traditional consultations in patient satisfaction, specialist evaluation, and treatment of non-acute headaches. ClinicalTrials.gov ID: NCT02270177.

Preventing and treating medication overuse headache.

Medication overuse headache is a secondary headache-a worsening of a pre-existing headache (usually a primary headache) owing to overuse of one or more attack-aborting or pain-relieving medications.

A case of relapsing-remitting facial palsy and ipsilateral brachial plexopathy caused by HSV-1.

The etiologies of Bell's palsy and brachial neuritis remain uncertain, and the conditions rarely co-occur or reoccur. Here we present a woman in her twenties who had several relapsing-remitting episodes with left-sided facial palsy and brachial neuropathy. The episodes always started with painful left-sided oral blisters. Repeat PCRs HSV-1 DNA from oral vesicular lesions were positive. Extensive screening did not reveal any other underlying cause. Findings on MRI T2-weighted brachial plexus STIR images, using a 3.0-Tesla scanner during an episode, were compatible with brachial plexus neuritis. Except a mannose-binding lectin deficiency, a congenital complement deficiency that is frequently found in the general Caucasian population, no other immunodeficiency was demonstrated in our patient. In vitro resistance to acyclovir was tested negative, but despite prophylactic treatment with the drug in high doses, relapses recurred. To our knowledge, this is the first ever reported documentation of relapsing-remitting facial and brachial plexus neuritis caused by HSV-1.

Lack of association between cluster headache and PER3 clock gene polymorphism.

BACKGROUND: Cluster headache (CH) is regarded as a chronobiological disorder. The hypothalamic biological clock may thus be involved in the pathophysiology, but few studies have actually investigated this in CH patients. A variable number tandem repeat (VNTR) polymorphism of the PER3 clock gene has been associated to preferred daily rhythm (chronotype) in several studies. We aimed to study the distribution of PER3 VNTR polymorphisms and chronotypes in a CH population. METHODS: We used blood samples from a biobank of CH patients for genetic tests, and invited all tested patients to complete the Horne-Ostberg Morningness-eveningness Questionnaire (MEQ), the Pittsburgh sleep quality Index (PSQI) and the Shift Work Index. Genotypes were compared to a previously tested population of 432 healthy students. RESULTS: One hundred forty nine patients were genotyped, and we found no difference in PER3 VNTR polymorphisms between patients and controls. Seventy-four patients completed the MEQ (54 men, 20 women, mean age 52.3 years ± 13.4), and chronotypes were as follows: 12 % morning-, 37 % intermediate-, and 51 % evening types. Compared with a previous Danish study of CH patients and controls, there were no difference in chronotype distribution. Sixty percent of patients were defined as bad sleepers (PSQI >5), and 51 % of patients currently employed were shift workers. CONCLUSIONS: No association between CH, PER3 VNTR polymorphism and chronotype was found in this study.

Reduced cranial parasympathetic tone during the remission phase of cluster headache.

BACKGROUND: Cluster headache (CH) attacks are accompanied by cranial autonomic symptoms indicative of parasympathetic hyperactivity and sympathetic dysfunction ipsilateral to the pain. We aimed to assess cranial autonomic function in CH patients during the remission phase of cluster headache. MATERIALS AND METHODS: During a remission phase, 38 episodic CH patients underwent the following: dynamic pupillometry, measurement of the superficial temporal artery diameter by ultrasound, and measurement of the retinal vessel diameters from digital retinal photographs. Pupillometry was also performed on 30 age- and sex-matched healthy controls. RESULTS: Thirty patients were included (27 men, three women, mean age 50.2 years ± 12.6). Seven patients reported occasional side shift of their headache, but with a clear predominating side. Significantly reduced average pupillary constriction velocity and retinal venular diameter on the CH pain side were found. There was no asymmetry of the superficial temporal artery diameters. Compared to healthy controls, cluster patients displayed bilaterally reduced pupillary average and maximum constriction velocities, reduced constriction in percentage and increased latency of the light reflex. CONCLUSIONS: The present findings indicate a bilaterally reduced cranial parasympathetic tone in CH patients in remission phase, with significant lateralization to the CH pain side. This implies a central origin, and a central pathophysiological model of CH is discussed.