Insomnia and sleep-disordered breathing in FKRP-related limb-girdle muscular dystrophy R9. The Norwegian LGMDR9 cohort study (2020).

Limb-girdle muscular dystrophy R9 (LGMDR9) is a progressive and disabling genetic muscle disease. Sleep is relevant in the patient care as it impacts on health, functioning, and well-being. LGMDR9 may potentially affect sleep by physical or emotional symptoms, myalgia, or sleep-disordered breathing (SDB) through cardiorespiratory involvement. The objective was to investigate the occurrence of insomnia and unrecognized or untreated SDB in LGMDR9, associated factors, and relationships with fatigue and health-related quality of life (HRQoL). All 90 adults in a Norwegian LGMDR9 cohort received questionnaires on sleep, fatigue, and HRQoL. Forty-nine of them underwent clinical assessments and 26 without mask-based therapy for respiration disorders additionally underwent polysomnography (PSG) and capnometry. Among 77 questionnaire respondents, 31% received mask-based therapy. The prevalence of insomnia was 32% of both those with and without such therapy but was significantly increased in fatigued respondents (54% vs 21%). Insomnia levels correlated inversely with mental HRQoL. Among 26 PSG candidates, an apnea-hypopnea index (AHI) ≥ 5/h was observed in 16/26 subjects (≥ 15/h in 8/26) with median 6.8 obstructive apneas and 0.2 central apneas per hour of sleep. The AHI was related to advancing age and an ejection fraction < 50%. Sleep-related hypoventilation was detected in one subject. Fatigue severity did not correlate with motor function or nocturnal metrics of respiration or sleep but with Maximal Inspiratory Pressure (r = - 0.46). The results indicate that insomnia and SDB are underrecognized comorbidities in LGMDR9 and associated with HRQoL impairment and heart failure, respectively. We propose an increased attention to insomnia and SDB in the interdisciplinary care of LGMDR9. Insomnia and pulmonary function should be examined in fatigued patients.

Health-Related Quality of Life in FKRP-Related Limb-Girdle Muscular Dystrophy R9.

BACKGROUND: Limb-girdle muscular dystrophy R9 (LGMDR9) is a chronic progressive hereditary muscle disease, related to the Fukutin Related Protein (FKRP) gene, that may cause major disabilities, cardiomyopathy, and ventilatory failure. Knowledge of how LGMDR9 affects health-related quality of life (HRQoL) is relevant in treatment and care. OBJECTIVE: To investigate HRQoL in the Norwegian LGMDR9 population over 14 months and relation to fatigue and sleep quality. METHODS: Participants (16+ years) of the Norwegian LGMDR9 cohort study completed two HRQoL measures, i.e., Individualized Neuromuscular Quality of Life questionnaire (INQoL) and the 36-item Short Form (SF-36) at baseline, 8, and 14 months and measures of fatigue and sleep quality at 9 months. RESULTS: HRQoL response rate was 84/90 (75 c.826 C > A homozygotes and nine c.826 C > A compound heterozygotes). Compared to Norwegian normative data, all SF-36 domain scores were impaired (p≤0.006) except mental health in males (p = 0.05) and pain scores. During 14 months, perceived muscle weakness and the INQoL index (disease burden) worsened in c.826 C > A homozygotes. Compound heterozygotes reported more dysphagia and physical difficulties than homozygotes and showed a tendency towards worsening in weakness over time but some improvement on the INQoL index. Homozygous females reported generally poorer HRQoL and a higher burden than males. The INQoL index was related to perceived muscle weakness and fatigue, and fatigue to myalgia and mental distress. The prevalence of fatigue and poor sleep was 40% and 49%, respectively. CONCLUSIONS: The 14-month follow-up period shows a worsening of perceived weakness and burden in c.826 C > A homozygotes, which can then be expected. The prevalence and impact of fatigue indicate a need for awareness and treatment of fatigue. Myalgia and mental distress are potential targets in the treatment of fatigue, which future studies need to establish. Sleep issues and gender-specific care needs also require attention in LGMDR9.

Continuous positive airway pressure in cluster headache: A randomized, placebo-controlled, triple-blind, crossover study.

BACKGROUND: Oxygen inhalation aborts cluster headache attacks, and case reports show the effect of continuous positive airway pressure. The aim of this study was to investigate the prophylactic effect of continuous positive airway pressure in chronic cluster headache. METHODS: This was a randomized placebo-controlled triple-blind crossover study using active and sham continuous positive airway pressure treatment for chronic cluster headache. Patients entered a one month's baseline period before randomly being assigned to two months' active continuous positive airway pressure treatment followed by a four weeks' washout period and two months' sham continuous positive airway pressure or vice versa. Primary outcome measure was number of cluster headache attacks/week. RESULTS: Of the 30 included participants (12 males, median age 49.5 years, min-max 20-66 years), 25 completed both treatment/sham cycles (two discontinued, three lost to follow-up). The median number of cluster headache attacks per week was reduced from 8.25 (0.75-89.75) attacks to 6.25 (0-56.00) attacks for active continuous positive airway pressure and to 7.50 (0.50-43.75) attacks for sham continuous positive airway pressure, but there was no difference in active versus sham (p = 0.904). One patient had a serious adverse event during active treatment, none occurred during sham treatment. CONCLUSIONS: Continuous positive airway pressure treatment did not reduce the number of cluster headache attacks compared to sham treatment in chronic cluster headache patients. TRIAL REGISTRATION CLINICALTRIALS.GOV: NCT03397563.

Epidemiology and natural history in 101 subjects with FKRP-related limb-girdle muscular dystrophy R9. The Norwegian LGMDR9 cohort study (2020).

We aimed to investigate the epidemiology and natural history of FKRP-related limb-girdle muscular dystrophy R9 (LGMDR9) in Norway. We identified 153 genetically confirmed subjects making the overall prevalence 2.84/100,000, the highest reported figure worldwide. Of the 153 subjects, 134 (88 %) were homozygous for FKRP c.826C>A giving a carrier frequency for this variant of 1/101 in Norway. Clinical questionnaires and patient notes from 101 subjects, including 88 c.826C>A homozygotes, were reviewed, and 43/101 subjects examined clinically. Age of onset in c.826C>A homozygotes demonstrated a bimodal distribution. Female subjects showed an increased cumulative probability of wheelchair dependency and need for ventilatory support. Across the cohort, the need for ventilatory support preceded wheelchair dependency in one third of the cases, usually due to sleep apnea. In c.826C>A homozygotes, occurrence of cardiomyopathy correlated positively with male gender but not with age or disease stage. This study highlights novel gender differences in both loss of ambulation, need for ventilatory support and the development of cardiomyopathy. Our results confirm the need for vigilance in order to detect respiratory insufficiency and cardiac involvement, but indicate that these events affect males and females differently.

Telemedicine in headache care: A systematic review.

OBJECTIVE: Telemedicine is defined as video-based consultations with synchronous video and sound. This systematic review investigated the use of telemedicine for headache patients. The primary outcomes of interest were treatment efficacy, feasibility, safety, convenience, compliance, and patient satisfaction. METHODS: A systematic literature search was performed using PubMed and Embase. Thirteen articles met the eligibility criteria and were included in the review. A systematic review protocol was registered on the International Prospective Register of Systematic Reviews, registration number CRD42021265875. RESULTS: There were no significant differences in treatment efficacy, patient satisfaction, compliance or safety using telemedicine when compared to traditional consultations. Telemedicine was found to be convenient due to being less time-consuming and expensive, especially for patients with limited access to health care. Despite the frequent occurrence of technical errors, telemedicine was found to be feasible. CONCLUSION: Telemedicine consultations are similar in quality to traditional in-office headache consultations and can be a more convenient solution for eligible headache patients.

Kennedy disease in two sisters with biallelic CAG expansions of the androgen receptor gene.

We present a retrospective 21-year follow-up of two sisters with X-linked biallelic CAG expansions in the androgen receptor (AR) gene causing Kennedy disease. Two sisters inherited CAG expansions from their mother who was a carrier and their father who had Kennedy disease. Genetic testing revealed alleles comprising 43/45, and 43/43 CAG repeats in the younger and older sister, respectively. They were referred to a neurologist for further evaluation. Both reported similar symptoms with chronic backache, pain and cramps in upper- and lower extremities, and fasciculations in their faces and extremities. Neurological examination demonstrated postural hand tremor in both and EMG revealed chronic neurogenic changes. Reevaluation of the patients at ages 74 and 83 showed slight progression of clinical manifestations. As opposed to male patients, these two females showed minimal disease progression and have maintained normal level of function into old age.

One-Year Remission Rate of Chronic Headache Comparing Video and Face-to-Face Consultations by Neurologist: Randomized Controlled Trial.

BACKGROUND: Chronic headache causing severe headache-related disability for those affected by the disease is under- or misdiagnosed in many cases and therefore requires easy access to a specialist for optimal health care management. OBJECTIVE: The goal of the research is to determine whether video consultations are noninferior to face-to-face consultations in treating chronic headache patients referred to a specialist in Northern Norway. METHODS: Patients included in the study were recruited from general practice referrals to a specialist at a neurological department in Northern Norway (Tromsø) and diagnosed according to the International Headache Society classification system. In a randomized controlled design, the 1-year remission rate of chronic headache (change from ≥15 to <15 headache days per month during the last 3 months), patient satisfaction with a specialist consultation, and need for follow-up consultations by general practitioners were compared between groups consulted by video and face-to-face in a post hoc analysis. Data were collected by interview (baseline) and questionnaire (follow-up). RESULTS: From a baseline cohort of 402 headache patients consecutively referred from general practice to a specialist over 2.5 years, 58.0% (233/402) were classified as chronic headache and included in this study. Response rates were 71.7% (86/120) in the video group and 67.3% (76/113) in the face-to-face group. One-year remission from chronic headache was achieved in 43.0% (37/86) in the video group and 39.5% (30/76) in the face-to-face group (P=.38). Patient satisfaction with consultations were 86.5% (32/37; video) and 93.3% (28/30; face-to-face; P=.25). A total of 30% (11/37) in the video group and 53% (16/30) in the face-to-face group consulted general practitioners during the follow-up period (P=.03), and median number of consultations was 1 (IQR 0-13) and 1.5 (IQR 0-15), respectively (P=.19). CONCLUSIONS: One-year remission rate from chronic headache was about 40% regardless of consultation form. Likewise, patient satisfaction with consultation and need for follow-up visits in general practice post consultation was similar. Treating chronic headache patients by using video consultations is not inferior to face-to-face consultations and may be used in clinical neurological practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT02270177; https://clinicaltrials.gov/ct2/show/NCT02270177.

The prevalence of hereditary neuromuscular disorders in Northern Norway.

AIM: To investigate the point prevalence of hereditary neuromuscular disorders on January 1, 2020 in Northern Norway. METHODS: From January 1, 1999, until January 1, 2020, we screened medical and genetic hospital records in Northern Norway for hereditary neuromuscular disorders. RESULTS: We identified 542 patients with a hereditary neuromuscular disorder living in Northern Norway, giving a point prevalence of 111.9/100,000 on January 1, 2020. The prevalence of children (<18 years old) and adults (≥18 years old) were 57.8/100,000 and 125.1/100,000, respectively. Inherited neuropathies had a prevalence of 38.8/100,000. Charcot-Marie-Tooth and hereditary neuropathy with liability to pressure palsies had a prevalence of 29.9/100,000 and 8.3/100,000, respectively. We calculated a prevalence of 3.7/100,000 for spinal muscular atrophies and 2.4/100,000 for Kennedy disease. Inherited myopathies were found in 67.7/100,000. Among these, we registered 13.4/100,000 myotonic dystrophy type 1, 6.8/100,000 myotonic dystrophy type 2, 7.3/100,000 Duchenne muscular dystrophy, 1.6/100,000 Becker muscular dystrophy, 3.7/100,000 facioscapulohumeral muscular dystrophy, 12.8/100,000 limb-girdle muscular dystrophy, 2.5/100,000 hypokalemic periodic paralysis and 11.4/100,000 myotonia congenita. CONCLUSION: Our total prevalence was higher than previously hypothesized in European population-based studies. The prevalence was especially high for myotonia congenita and limb-girdle muscular dystrophy. The prevalence of Charcot-Marie-Tooth polyneuropathy was higher than in most European studies, but lower than previously reported in epidemiological studies in other regions of Norway.

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.

ABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9.

Mutations in genes encoding KATP channel subunits have been reported for pancreatic disorders and Cantú syndrome. Here, we report a syndrome in six patients from two families with a consistent phenotype of mild intellectual disability, similar facies, myopathy, and cerebral white matter hyperintensities, with cardiac systolic dysfunction present in the two oldest patients. Patients are homozygous for a splice-site mutation in ABCC9 (c.1320 + 1 G > A), which encodes the sulfonylurea receptor 2 (SUR2) subunit of KATP channels. This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function.

Detecting At-Risk Alzheimer's Disease Cases.

While APOEɛ4 is the major genetic risk factor for Alzheimer's disease (AD), amyloid dysmetabolism is an initial or early event predicting clinical disease and is an important focus for secondary intervention trials. To improve identification of cases with increased AD risk, we evaluated recruitment procedures using pathological CSF concentrations of Aß42 (pAß) and APOEɛ4 as risk markers in a multi-center study in Norway. In total, 490 subjects aged 40-80 y were included after response to advertisements and media coverage or memory clinics referrals. Controls (n = 164) were classified as normal controls without first-degree relatives with dementia (NC), normal controls with first-degree relatives with dementia (NCFD), or controls scoring below norms on cognitive screening. Patients (n = 301) were classified as subjective cognitive decline or mild cognitive impairment. Subjects underwent a clinical and cognitive examination and MRI according to standardized protocols. Core biomarkers in CSF from 411 and APOE genotype from 445 subjects were obtained. Cases (both self-referrals (n = 180) and memory clinics referrals (n = 87)) had increased fractions of pAß and APOEɛ4 frequency compared to NC. Also, NCFD had higher APOEɛ4 frequencies without increased fraction of pAß compared to NC, and cases recruited from memory clinics had higher fractions of pAß and APOEɛ4 frequency than self-referred. This study shows that memory clinic referrals are pAß enriched, whereas self-referred and NCFD cases more frequently are pAß negative but at risk (APOEɛ4 positive), suitable for primary intervention.

Acceptability, Feasibility, and Cost of Telemedicine for Nonacute Headaches: A Randomized Study Comparing Video and Traditional Consultations.

BACKGROUND: The feasibility of telemedicine in diagnosing and treating nonacute headaches, such as primary headaches (migraine and tension-type) and medication-overuse headaches has not been previously investigated. By eliminating the need of travel to specialists, telemedicine may offer significant time and money savings. OBJECTIVES: Our objective was to estimate the acceptance of telemedicine and investigate the feasibility and cost savings of telemedicine consultations in diagnosing and treating nonacute headaches. METHODS: From September 2012 to March 2015, nonacute headache patients from Northern Norway who were referred to neurologists through an electronic application system were consecutively screened and randomized to participate in either telemedicine or traditional specialist visits. All patients were consulted by two neurologists at the neurological department in Tromsø University Hospital. Feasibility outcomes were compared between telemedicine and traditional groups. Baseline characteristics and costs were then compared between rural and urban patients. Travel costs were calculated by using the probabilistic method of the Norwegian traveling agency: the cheapest means of public transport for each study participant. Loss of pay was calculated based on the Norwegian full-time employee's average salary: < 3.5 hours=a half day's salary, > 3.5 hours spent on travel and consultation=one day's salary. Distance and time spent on travel were estimated by using Google Maps. RESULTS: Of 557 headache patients screened, 479 were found eligible and 402 accepted telemedicine participation (83.9%, 402/479) and were included in the final analyses. Of these, 202 received traditional specialist consultations and 200 received telemedicine. All patients in the telemedicine group were satisfied with the video quality, and 198 (99%, 198/200) were satisfied with the sound quality. The baseline characteristics as well as headache diagnostics and follow-up appointments, and the investigation, advice, and prescription practices were not statistically different between the two randomized groups. In addition, telemedicine consultations were shorter than traditional visits (38.8 vs 43.7 min, P<.001). The travel cost per rural individual (292/402, 73%) was €249, and estimated lost income was €234 per visit. The travel cost in the urban area (110/402, 27%) was €6, and estimated lost income was €117 per visit. The median traveling distance for rural patients was 526 km (range 1892 km), and the median traveling time was 7.8 hours (range 27.3 hours). Rural patients had a longer waiting time than urban patients (64 vs 47 days, P=.001), and fewer women were referred from rural areas (P=.04). Rural women reported higher pain scores than urban women (P=.005). CONCLUSION: Our study shows that telemedicine is an accepted, feasible, time-saving, and cost-saving alternative to traditional specialist consultations for nonacute headaches. TRIAL REGISTRATION: Clinicaltrials.gov NCT02270177; http://clinicaltrials.gov/ct2/show/NCT02270177 (Archived by WebCite at http://www.webcitation.org/6hmoHGo9Q).

Visual impairment and posterior cortical atrophy preceding rapid progressive dementia.

Posterior cortical atrophy (PCA), also known as Benson's disease, has been previously reported as a variant of Alzheimer's disease (AD). We present a clinical picture and MRI findings of a patient with PCA who developed early right-sided homonymous haemianopia and marked atrophy of parieto-occipital regions of the brain before a cognitive decline appeared. This case demonstrates that PCA may appear with advanced brain atrophy at the onset of focal visual deficits before the development of progressive dementia, and adds to the knowledge of dementias with rapid progression.

Thrombolysis in anterior spinal artery syndrome.

Anterior spinal artery syndrome (ASAS) is often a devastating spinal stroke occurring when the anterior spinal artery or one of its supplying anterior medullary arteries are occluded. The most common causes are arteriosclerosis, dissection of the abdominal aorta, cardiac embolism and degenerative spine disease, and the major risk factors are smoking, hypertension, diabetes and hypercholesterolaemia. The treatment has generally been supportive. We believe thrombolysis should be considered in the acute phase of this condition, and present a case with ASAS who experienced partial recovery after treatment given 4.5 h after symptom onset.

[A woman with unilateral headache]. / En kvinne med ensidig hodepine.

A woman in her fifties, with a long history of side-locked unilateral headache, was hospitalized for left-sided side-locked paroxysmal headache (attacks with 10-20 min duration). Clinical and neurological examinations, and brain MRI revealed normal findings. She responded well to indomethacin (50 mg three times daily). Due to non-compliance because of dyspepsia, which delayed the final diagnosis of chronic paroxysmal hemicrania (CPH) for 16, months indomethacin was administered both rectally and orally. A retrospective review of her medical history showed 15 years of unsuccessfully treated unilateral headache, until she responded completely to rofecoxib. Ipsilateral cranial autonomic symptoms also supported the diagnosis of hemicrania continua, although these symptoms presented before indomethacin was tried. Diagnostic delay and misdiagnoses of unilateral headaches, as illustrated by this case, shows the clinical controversies and difficulties in diagnosing and treating this condition.

Hemicrania continua changed to chronic paroxysmal hemicrania after treatment with cyclooxygenase-2 inhibitor.

Remission of hemicrania continua (HC) and transformation from HC to chronic paroxysmal hemicrania (CPH) are unusual. We report a patient with left-sided HC who, after a period of remission, presented as CPH. The continuous HC headache disappeared completely after initiating treatment with cyclooxygenase (COX)-2 inhibitor, but reappeared on the same side after 14 months remission with paroxysmal, frequent, intense and short-lasting headache attacks accompanied by ipsilateral cranial autonomic symptoms. This happened shortly after the treatment was discontinued because of withdrawal of the COX-2 inhibitor from the market. The response to indomethacin was prompt, and the patient became completely free from her paroxysmal headache with a dose of 50 mg 2 times daily. This case questions a possible modification effect on the course of HC by use of COX-2 inhibitor, as well as further supporting that some aspects of the pathophysiology of HC may resemble those of CPH, and may argue for common biological mechanisms in HC and CPH.

Epilepsy in a patient with ataxia caused by vitamin E deficiency.

Ataxia due to vitamin E deficiency is important because disease progression can be stopped by supplementary therapy. A limited number of studies and case series suggest that the disease is mainly confined to the cerebellum and spinal cord tract and seems to be more common in North African countries. We report a patient from North Norway with progressive ataxia from the age of 5, bilateral dropfoot, Babinski's sign, dysarthria and early epilepsy. Two mutations, 513insTT and p.Arg134x, were detected. When treatment was initiated 25 years after onset of symptoms, the patient was bound to the wheel chair. No further progression of pareses, ataxia or epileptic seizures has been observed in a 3-year follow-up period. This case indicates that cerebral involvement may be present in patients with a lack of vitamin E. If this observation is confirmed, a further exploration of clinical presentation, anatomic involvement and geographic distribution of the disease is warranted.