Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments-a consensus article.

AIM: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. FINDINGS: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. CONCLUSION: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache.

Alcohol use among NTNU students 2007-19. / Alkoholvaner blant NTNU-studenter 2007­19.

BACKGROUND: Alcohol consumption is widespread in student environments. The objective of the study was to examine alcohol use among students at the Norwegian University of Science and Technology (NTNU) in a twelve-year perspective. MATERIAL AND METHOD: The study is cross-sectional, based on two questionnaire surveys conducted in lecture breaks at NTNU in 2007 and 2019. Participation was voluntary and anonymous. The questionnaire surveyed background variables and alcohol use, and included questions from the Alcohol Use Disorders Identification Test (AUDIT). The respondents were categorised into risk profiles based on their results. An AUDIT score of ≥ 8 was used as the threshold value for risky/potentially harmful alcohol use. RESULTS: The study included 2,247 students: 857 from 2007 and 1,390 from 2019. The proportion of women was 42.3 % in 2007 and 54.9 % in 2019. The average age was 21.5 years (2007) and 22.5 years (2019). The average AUDIT score was 10.7 in 2007 and 8.5 in 2019. A total of 937 students (67.6 %) consumed alcohol two to four times per month or more in 2019, a reduction of 9.8 % from 2007. Altogether 885 students (67.8 %) consumed five or more alcohol units on a typical drinking day in 2019, a reduction of 12.8 % from 2007. INTERPRETATION: A considerable one-fifth reduction in the proportion of students with risky alcohol use occurred from 2007 to 2019. However, the alcohol use of more than half of the students may still pose a long-term risk.

A young man with convulsive laughter. / En ung mann med krampaktig latter.

BACKGROUND: Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) can manifest with a wide range of neurological and psychiatric symptoms. CASE PRESENTATION: A previously healthy man in his late twenties was admitted several times over the course of half a year. He had acute episodes of reduced consciousness, involuntary movements and psychotic symptoms (e.g. hallucinations and delusions). Initial examinations were normal except for a positive urine drug screen (tetrahydrocannabinol), and the patient was diagnosed with cannabinoid intoxication. During the next admission cerebrospinal fluid analysis showed mild pleocytosis. Screening for anti-neuronal antibodies was negative, but anti-thyroid peroxidase antibodies were detected in serum and cerebrospinal fluid. He was successfully given steroid treatment on a tentative diagnosis of SREAT, but relapsed when the steroids were discontinued. After receiving a prolonged steroid treatment with gradual dose reduction over a year, he remains symptom-free 18 months after treatment discontinuation. INTERPRETATION: The diagnostic delay might have been mitigated with an earlier inclusion of neuroimmunological disorders in the differential diagnosis. Unexplained pleocytosis in the cerebrospinal fluid in the presence of paroxysmal neuropsychiatric symptoms should trigger an investigation that includes autoimmune encephalopathies.

Modification of Astrocyte Metabolism as an Approach to the Treatment of Epilepsy: Triheptanoin and Acetyl-L-Carnitine.

Epilepsy is a severe neurological disorder characterized by altered electrical activity in the brain. Important pathophysiological mechanisms include disturbed metabolism and homeostasis of major excitatory and inhibitory neurotransmitters, glutamate and GABA. Current drug treatments are largely aimed at decreasing neuronal excitability and thereby preventing the occurrence of seizures. However, many patients are refractory to treatment and side effects are frequent. Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults. In rodents, the pilocarpine-status epilepticus model reflects the pathology and chronic spontaneous seizures of TLE and the pentylenetetrazole kindling model exhibits chronic induced limbic seizures. Accumulating evidence from studies on TLE points to alterations in astrocytes and neurons as key metabolic changes. The present review describes interventions which alleviate these disturbances in astrocyte-neuronal interactions by supporting mitochondrial metabolism. The compounds discussed are the endogenous transport molecule acetyl-L-carnitine and the triglyceride of heptanoate, triheptanoin. Both provide acetyl moieties for oxidation in the tricarboxylic acid cycle whereas heptanoate is also provides propionyl-CoA, which after carboxylation can produce succinyl-CoA, resulting in anaplerosis-the refilling of the tricarboxylic acid cycle.

Erratum to "The Assistive Device Situation for ALS Patients in Norway".

[This corrects the article DOI: 10.1155/2021/5563343.].

Sleep restriction alters cortical inhibition in migraine: A transcranial magnetic stimulation study.

OBJECTIVE: Migraine is a primary headache disorder with a well-known association with insufficient sleep. However, both the underlying pathophysiology of the disease and the relationship with sleep is still unexplained. In this study, we apply transcranial magnetic stimulation to investigate possible mechanisms of insufficient sleep in migraine. METHODS: We used a randomised, blinded crossover design to examine 46 subjects with migraine during the interictal period and 29 healthy controls. Each subject underwent recordings of cortical silent period, short- and long-interval intracortical inhibition, intracortical facilitation and short-latency afferent inhibition after both two nights of habitual eight-hour sleep and two nights of restricted four-hour sleep. RESULTS: We found reduced cortical silent period duration after sleep restriction in interictal migraineurs compared to controls (p = 0.046). This effect was more pronounced for non-sleep related migraine (p = 0.002) and migraine with aura (p = 0.017). The sleep restriction effect was associated with ictal symptoms of hypersensitivity such as photophobia (p = 0.017) and overall silent period was associated with premonitory dopaminergic symptoms such as yawning (p = 0.034). CONCLUSIONS: Sleep restriction reduces GABAergic cortical inhibition during the interictal period in individuals with migraine. SIGNIFICANCE: Sleep related mechanisms appear to affect the pathophysiology of migraine and may differentiate between migraine subgroups.

The Assistive Device Situation for ALS Patients in Norway.

AIMS: There are limited analytical descriptions of the assistive device situation in Norway for patients with ALS and other motor neuron diseases. This study is aimed at investigating how patients, caregivers, and healthcare professionals (occupational therapists and physiotherapists) experience the assistive device situation. METHODS: Twenty-four interviews were conducted with patients with motor neuron disease, caregivers, and healthcare professionals involved in procurement and adaptation of assistive devices. Systematic text condensation was used to analyse the interviews. RESULTS: The majority of patients and caregivers had positive experiences of follow-up by the specialist healthcare service. Several found follow-up by the primary health service to be deficient owing to inadequate expertise, continuity, and resources. Healthcare professionals reported having a proactive approach to identifying needs for assistive devices, but for various reasons, application processes were often delayed. Several patients indicated a reluctance to use assistive devices and were ambivalent regarding proactivity. The availability of assistive devices for some functional impairments was described as inadequate. Some patients felt there was too little focus on sexuality in the follow-up. The respondents had a number of suggestions for improving the assistive device situation. CONCLUSIONS: Multidisciplinary ALS teams are found to ensure follow-up expertise and continuity. Healthcare professionals wish to take a proactive approach to assistive devices, but a number of bureaucratic obstacles occur. The study findings are preliminary and should be validated through a prospective national quality registry for motor neuron diseases.

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.

Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.

Alteration of glial-neuronal metabolic interactions in a mouse model of Alexander disease.

Alexander disease is a rare and usually fatal neurological disorder characterized by the abundant presence of protein aggregates in astrocytes. Most cases result from dominant missense de novo mutations in the gene encoding glial fibrillary acidic protein (GFAP), but how these mutations lead to aggregate formation and compromise function is not known. A transgenic mouse line (Tg73.7) over-expressing human GFAP produces astrocytic aggregates indistinguishable from those seen in the human disease, making them a model of this disorder. To investigate possible metabolic changes associated with Alexander disease Tg73.7 mice and controls were injected simultaneously with [1-(13)C]glucose to analyze neuronal metabolism and [1,2-(13)C]acetate to monitor astrocytic metabolism. Brain extracts were analyzed by (1)H magnetic resonance spectroscopy (MRS) to quantify amounts of several key metabolites, and by (13)C MRS to analyze amino acid neurotransmitter metabolism. In the cerebral cortex, reduced utilization of [1,2-(13)C]acetate was observed for synthesis of glutamine, glutamate, and GABA, and the concentration of the marker for neuronal mitochondrial metabolism, N-acetylaspartate (NAA) was decreased. This indicates impaired astrocytic and neuronal metabolism and decreased transfer of glutamine from astrocytes to neurons compared with control mice. In the cerebellum, glutamine and GABA content and labeling from [1-(13)C]glucose were increased. Evidence for brain edema was found in the increased amount of water and of the osmoregulators myo-inositol and taurine. It can be concluded that astrocyte-neuronal interactions were altered differently in distinct regions.

Region- and age-dependent alterations of glial-neuronal metabolic interactions correlate with CNS pathology in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) or Krabbe disease is a lysosomal storage disorder caused by genetic defects in the expression and activity of galactosylceramidase, a key enzyme in the catabolism of myelin-enriched sphingolipids. While there are several histologic, biochemical, and functional studies on GLD, correlations between morphologic and biochemical alterations in central nervous system (CNS) tissues during disease progression are lacking. Here, we combined immunohistochemistry and metabolic analysis using (1)H and (13)C magnetic resonance (MR) spectra of spinal cord, cerebellum, and forebrain to investigate glial-neuronal metabolic interactions and dysfunction in a GLD murine model that recapitulates the human pathology. In order to assess the temporal- and region-dependent disease progression and the potential metabolic correlates, we investigated CNS tissues at mildly symptomatic and fully symptomatic stages of the disease. When compared with age-matched controls, GLD mice showed glucose hypometabolism, alterations in neurotransmitter content, N-acetylaspartate, N-acetylaspartylglutamate, and osmolytes levels. Notably, age- and region-dependent patterns of metabolic disturbances were in close agreement with the progression of astrogliosis, microglia activation, apoptosis, and neurodegeneration. We suggest that MR spectroscopy could be used in vivo to monitor disease progression, as well as ex vivo and in vivo to provide criteria for the outcome of experimental therapies.

Metabolic aspects of neuron-oligodendrocyte-astrocyte interactions.

Whereas astrocytes have been in the limelight of scientific interest in brain energy metabolism for a while, oligodendrocytes are still waiting for a place on the metabolic stage. We propose to term the interaction of oligodendrocytes with astrocytes and neurons: NOA (neuron-oligodendrocyte-astrocyte) interactions. One of the reasons to find out more about metabolic interactions between oligodendrocytes, neurons, and astrocytes is to establish markers of healthy oligodendrocyte metabolism that could be used for the diagnosis and assessment of white matter disease. The vesicular release of glutamate in the white matter has received considerable attention in the past. Oligodendrocyte lineage cells express glutamate receptors and glutamate toxicity has been implicated in diseases affecting oligodendrocytes such as hypoxic-ischaemic encephalopathy, inflammatory diseases and trauma. As oligodendrocyte precursor cells vividly react to injury it is also important to establish whether cells recruited into damaged areas are able to regenerate lost myelin sheaths or whether astrocytic scarring occurs. It is therefore important to consider metabolic aspects of astrocytes and oligodendrocytes separately. The present review summarizes the limited evidence available on metabolic cycles in oligodendrocytes and so hopes to stimulate further research interests in this important field.

Dietary supplementation with acetyl-l-carnitine in seizure treatment of pentylenetetrazole kindled mice.

In spite of the availability of new antiepileptic drugs a considerable number of epilepsy patients still have pharmacoresistant seizures, and thus there is a need for novel approaches. Acetyl-l-carnitine (ALCAR), which delivers acetyl units to mitochondria for acetyl-CoA production, has been shown to improve brain energy homeostasis and protects against various neurotoxic insults. To our knowledge, this is the first study of ALCAR's effect on metabolism in pentylenetetrazole (PTZ) kindled mice. ALCAR or the commonly used antiepileptic drug valproate, was added to the drinking water of mice for 25days, and animals were injected with PTZ or saline three times a week during the last 21 days. In order to investigate ALCAR's effects on glucose metabolism, mice were injected with [1-(13)C]glucose 15 min prior to microwave fixation. Brain extracts from cortex and the hippocampal formation (HF) were studied using (1)H and (13)C NMR spectroscopy and HPLC. PTZ kindling caused glucose hypometabolism, evidenced by a reduction in both glycolysis and TCA cycle turnover in both brain regions investigated. Glutamatergic and GABAergic neurons were affected in cortex and HF, but the amount of glutamate was only reduced in HF. Slight astrocytic involvement could be detected in the cortex. Interestingly, the dopamine content was increased in the HF. ALCAR attenuated the PTZ induced reduction in [3-(13)C]alanine and the increase in dopamine in the HF. However, TCA cycle metabolism was not different from that seen in PTZ kindled animals. In conclusion, even though ALCAR did not delay the kindling process, it did show some promising ameliorative effects, worthy of further investigation.

Chronic acetyl-L-carnitine alters brain energy metabolism and increases noradrenaline and serotonin content in healthy mice.

Acetyl-L-carnitine (ALCAR), the short-chain ester of carnitine, is a common dietary supplement readily available in health food stores, claimed to improve energy levels and muscle strength. ALCAR has numerous effects on brain and muscle metabolism, protects against neurotoxic insults and may be an effective treatment for certain forms of depression. However, little is known about the effect of chronic ALCAR supplementation on the brain metabolism of healthy mice. Here, we investigated ALCAR's effect on cerebral energy and neurotransmitter metabolism after supplementing the drinking water of mice with ALCAR for 25 days, providing a daily dose of about 0.5 g/kg. Thereafter the animals were injected with [1-(13)C]glucose, and (13)C incorporation into and levels of various metabolites were quantified in extracts of the hippocampal formation (HF) and cortex using (1)H- and (13)C-nuclear magnetic resonance (NMR) spectroscopy and high performance liquid chromatography (HPLC). Increased glucose levels were detected in both regions together with a decreased amount of [3-(13)C]lactate, but no alterations in incorporation of (13)C derived from [1-(13)C]glucose into the amino acids glutamate, GABA and glutamine. These findings are consistent with decreased metabolism of glucose to lactate but not via the TCA cycle. Higher amounts of the sum of adenosine nucleotides, phosphocreatine and the phosphocreatine/creatine ratio found in the cortex of ALCAR-treated mice are indicative of increased energy levels. Furthermore, ALCAR supplementation increased the levels of the neurotransmitters noradrenaline in the HF and serotonin in cortex, consistent with ALCAR's potential efficacy for depressive symptoms. Other ALCAR-induced changes observed included reduced amounts of GABA in the HF and increased myo-inositol. In conclusion, chronic ALCAR supplementation decreased glucose metabolism to lactate, resulted in increased energy metabolite and altered monoamine neurotransmitter levels in the mouse brain.