Australian Headache Epidemiology Data (AHEAD): a pilot study to assess sampling and engagement methodology for a nationwide population-based survey.

BACKGROUND: There are no robust population-based Australian data on prevalence and attributed burden of migraine and medication-overuse headache (MOH) data. In this pilot cross-sectional study, we aimed to capture the participation rate, preferred response method, and acceptability of self-report questionnaires to inform the conduct of a future nationwide migraine/MOH epidemiological study. METHODS: We developed a self-report questionnaire, available in hard-copy and online, including modules from the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, the Eq. 5D (quality of life), and enquiry into treatment gaps. Study invitations were mailed to 20,000 randomly selected households across Australia's two most populous states. The household member who most recently had a birthday and was aged ≥ 18 years was invited to participate, and could do so by returning a hard-copy questionnaire via reply-paid mail, or by entering responses directly into an online platform. RESULTS: The participation rate was 5.0% (N = 1,000). Participants' median age was 60 years (IQR 44-71 years), and 64.7% (n = 647) were female. Significantly more responses were received from areas with relatively older populations and middle-level socioeconomic status. Hard copy was the more commonly chosen response method (n = 736). Females and younger respondents were significantly more likely to respond online than via hard-copy. CONCLUSIONS: This pilot study indicates that alternative methodology is needed to achieve satisfactory engagement in a future nationwide migraine/MOH epidemiological study, for example through inclusion of migraine screening questions in well-resourced, interview-based national health surveys that are conducted regularly by government agencies. Meanwhile, additional future research directions include defining and addressing treatment gaps to improve migraine awareness, and minimise under-diagnosis and under-treatment.

Effects of somatostatin, a somatostatin agonist, and an antagonist, on a putative migraine trigger pathway.

OBJECTIVE: To determine whether somatostatin (SST) could be a cortico-brainstem neurotransmitter involved in producing the headache of migraine. BACKGROUND: There is evidence to support the idea that a cortico-brainstem-trigeminal nucleus neuraxis might be responsible for producing migraine headache; we have suggested that SST may be one of the neurotransmitters involved. METHODS: Rats were anesthetised and prepared for recording neurons in either the periaqueductal gray matter (PAG) or nucleus raphe magnus (NRM), as well as the trigeminal nucleus caudalis (TNC). The dura mater and facial skin were stimulated electrically or mechanically. SST, the SST agonist L054264 and the SST antagonist CYN54806 were injected intravenously, by microinjection, or by iontophoresis into the PAG or NRM. Cortical neuronal activity was provoked by cortical spreading depression (CSD) or light flash (LF) and was monitored by recording cortical blood flow (CBF). RESULTS: Intravenous injection of SST: (a) selectively decreased the responses of TNC neurons to stimulation of the dura, but not skin, for up to 5 h; (b) decreased the ongoing discharge rate of TNC neurons while simultaneously increasing the discharge rate of neurons in either brainstem nucleus and; (c) prevented, or reversed, the effect of CSD and LF on brainstem and trigeminal neuron discharge rates. CSD and LF decreased the discharge rate of neurons in both brainstem nuclei and increased the discharge rate of TNC neurons. These effects were reversed by L054264 and mimicked by CYN54806. Injections of L054264 into the PAG or NRM reduced the response of TNC neurons to dural stimulation and skin stimulation differentially, depending on the nucleus injected. Injections of CYN54806 into either brainstem nucleus potentiated the responses of TNC neurons to dural and skin stimulation, but without a marked differential effect. CONCLUSIONS: These results imply that SST could be a neurotransmitter in a pathway responsible for migraine pain.

Most endovascular thrombectomy patients have Target Mismatch despite absence of formal CT perfusion selection criteria.

Endovascular thrombectomy (EVT) is the standard of care for large vessel occlusion stroke. Use of Computed Tomographic Perfusion (CTP) to select EVT candidates is variable. The frequency of treatment and outcome in patients with unfavourable CTP patterns is unknown. A retrospective analysis of CTP utilisation prior to EVT was conducted. All CTP data were analysed centrally and a Target Mismatch was defined as an infarct core ≤70 ml, penumbral volume ≥15ml, and a total hypoperfused volume:core volume ratio >1.8. The primary outcome was good functional outcome at 90 days, defined as a modified Rankin Scale (mRS) score 0-2. follow-up infarct volume, core expansion and penumbral salvage volumes were secondary outcomes. Of 572 anterior circulation EVT patients, CTP source image data required to generate objective maps were available in 170, and a Target Mismatch was present in 151 (89%). The rate of 90-day good functional outcome was similar between Target Mismatch (53%) and Large Core Non-Mismatch groups (46%, p = 0.629). Median follow-up infarct volume in the Large Core Non-Mismatch group (104ml [IQR 25ml-189ml]) was larger than that in the Target Mismatch patients (16ml [8ml-47ml], p<0.001). Despite a lack of formal CTP selection criteria, the majority of patients treated at our centres had a Target Mismatch. Patients without Target Mismatch had larger follow-up infarct volumes, but the functional recovery rate was similar to that in Target Mismatch patients. Infarct volumes should be included as objective assessment criteria in the evaluation of the efficacy of EVT in non-Target Mismatch patients.

Specific Learning Disorders: Variation Analysis of 15 Candidate Genes in 9 Multiplex Families.

Background and Objectives: Specific Learning Disorder (SLD) is a complex neurobiological disorder characterized by a persistent difficult in reading (dyslexia), written expression (dysgraphia), and mathematics (dyscalculia). The hereditary and genetic component is one of the underlying causes of SLD, but the relationship between genes and the environment should be considered. Several genetic studies were performed in different populations to identify causative genes. Materials and Methods: Here, we show the analysis of 9 multiplex families with at least 2 individuals diagnosed with SLD per family, with a total of 37 persons, 21 of whom are young subjects with SLD, by means of Next-Generation Sequencing (NGS) to identify possible causative mutations in a panel of 15 candidate genes: CCPG1, CYP19A1, DCDC2, DGKI, DIP2A, DYM, GCFC2, KIAA0319, MC5R, MRPL19, NEDD4L, PCNT, PRMT2, ROBO1, and S100B. Results: We detected, in eight families out nine, SNP variants in the DGKI, DIP2A, KIAA0319, and PCNT genes, even if in silico analysis did not show any causative effect on this behavioral condition. In all cases, the mutation was transmitted by one of the two parents, thus excluding the case of de novo mutation. Moreover, the parent carrying the allelic variant transmitted to the children, in six out of seven families, reports language difficulties. Conclusions: Although the present results cannot be considered conclusive due to the limited sample size, the identification of genetic variants in the above genes can provide input for further research on the same, as well as on other genes/mutations, to better understand the genetic basis of this disorder, and from this perspective, to better understand also the neuropsychological and social aspects connected to this disorder, which affects an increasing number of young people.

The effect of blood pressure lowering medications on the prevention of episodic migraine: A systematic review and meta-analysis.

BACKGROUND: Currently, only a few specific blood pressure-lowering medications are recommended for migraine prevention. Whether benefits extend to other classes or drugs is uncertain. METHODS: Embase, MEDLINE, and the Cochrane Central Registry of Controlled Trials were searched for randomized control trials on the effect of blood pressure-lowering medications compared with placebo in participants with episodic migraine. Data were collected on four outcomes - monthly headache or migraine days, and monthly headache or migraine attacks, with a standardised mean difference calculated for overall. Random effect meta-analysis was performed. RESULTS: In total, 50 trials (70% of which were crossover) were included, comprising 60 comparisons. Overall mean age was 39 years, and 79% were female. Monthly headache days were fewer in all classes compared to placebo, and this was statistically significant for all but one class: alpha-blockers -0.7 (95% CI: -1.2, -0.1), angiotensin-converting enzyme inhibitors -1.3 (95% CI: -2.9, 0.2), angiotensin II receptor blockers -0.9 (-1.6, -0.1), beta-blocker -0.4 (-0.8, -0.0) and calcium channel blockers -1.8 (-3.4, -0.2). Standardised mean difference was significantly reduced for all drug classes and was separately significant for numerous specific drugs: clonidine, candesartan, atenolol, bisoprolol, metoprolol, propranolol, timolol, nicardipine and verapamil. CONCLUSION: Among people with episodic migraine, a broader number of blood pressure-lowering medication classes and drugs reduce headache frequency than those currently included in treatment guidelines.Trial Registration: The study was registered at PROSPERO (CRD42017079176).

A potential role for two brainstem nuclei in craniovascular nociception and the triggering of migraine headache.

AIM: To use an animal model of migraine to test whether migraine headache might arise from a brainstem-trigeminal nucleus pathway. METHODS: We measured evoked and spontaneous activity of second-order trigeminovascular neurons in rats to test whether the activity of these neurons increased following the induction of cortical spreading depression or the imposition of light flash - two potential migraine triggers, or headache provokers. We then tested whether drugs that could activate, or inactivate, neurons of the nucleus raphe magnus or the periaqueductal gray matter, would affect any such increases selectively for the dura mater. RESULTS: Injection of sodium glutamate (a neuronal excitant) into these two nuclei selectively inhibited the responses of trigeminovascular second-order neurons to dura mater, but not to facial skin, stimulation. Injection of lignocaine (a local anaesthetic) into these nuclei selectively potentiated the responses of these neurons to dura, but not to facial skin, stimulation. Furthermore, injections into either nucleus of glutamate inhibited the increase in the ongoing discharge rate of these neurons produced by cortical spreading depression and light flash. CONCLUSIONS: These results provide indirect evidence that trigeminovascular nociception may be tightly controlled by these two nuclei, whereas cutaneous trigeminal sensation may be less so. These nuclei may be relays of one possible brainstem-trigeminal pathway that could mediate migraine headache. Modification of neuronal activity in these two nuclei produced by migraine (headache) triggers may lie behind the pain of a migraine attack, at least in some cases.

Isolated painful trigeminal neuropathy as an unusual presentation of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids: A case report.

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder, typically presenting with subacute symptoms referable to brainstem and cerebellar pathology. This is the first report of CLIPPERS presenting with a painful trigeminal neuropathy. CASE REPORT: We report an unusual case of CLIPPERS presenting with facial pain and sensory symptoms, in the absence of other brainstem or cerebellar signs. Perivascular enhancement of peri-pontine structures on neuroimaging, lymphocytic infiltrate on histopathology and rapid clinical and radiological responsiveness to glucocorticosteroids were key to diagnosis. Extensive investigations excluded various differential aetiologies. CONCLUSION: The pathogenesis of CLIPPERS is poorly understood, and the diagnostic criteria are yet to be validated. In this case, facial pain was not associated with other brainstem or cerebellar signs, broadening current understanding of how CLIPPERS may present. This has clinical implications in guiding future investigations for patients presenting with painful trigeminal neuropathy.

Thrombectomy in stroke of unknown onset, wake up stroke and late presentations: Australian experience from 2 comprehensive stroke centres.

Two recent randomized controlled trials (RCTs) showed selected patients treated with endovascular thrombectomy (EVT) more than 6 h from acute ischemic stroke (AIS) onset had significant improvement in functional outcome at 90 days compared with standard care alone. Our aim is to determine the outcome and predictors of good outcome in AIS patients undergoing EVT with unknown-onset, or late presentation, stroke after 6 h from time last seen well, or witnessed stroke onset, at two Australian comprehensive stroke centres. A retrospective analysis of functional outcome and mortality at 90-days from a prospective cohort of 56 consecutive patients with unknown-onset, or late presentation, stroke with large vessel occlusion (LVO) in the anterior cerebral circulation undergoing EVT over a 15-month period (2016-2017). We evaluated factors which correlated with good functional outcome defined as a 90-day modified Rankin scale (mRS) 0-2. Recanalization times and symptomatic intracranial haemorrhage (sICH) rates were also examined. A good functional outcome was achieved in 35 patients (62%). Eight patients died (14%). Median time-to-recanalization was 7.6 h. SICH occurred in four patients (7%). Factors which predicted good 90-day functional outcome included baseline National Institutes of Health Stroke Scale (NIHSS) < 16, 24 h NIHSS < 10, baseline Alberta Stroke Program Early CT Score (ASPECTS) ≥ 8, pre-procedural CT perfusion imaging and LVO lesion location. This study shows good 'real world' outcomes, comparable to published RCTs, in patients with unknown-onset, or late presentation, stroke treated with EVT more than 6 h from stroke onset.

Endovascular Thrombectomy >24-hr From Stroke Symptom Onset.

Background: Trials have demonstrated efficacy for endovascular thrombectomy (EVT) for anterior circulation acute ischaemic stroke (AIS) up to 24-h from symptom onset. The magnitude of effect suggests benefit may exist beyond 24-h. Objectives: To perform a retrospective review of all patients undergoing EVT for anterior circulation LVO stroke beyond 24-h from symptom onset and assess safety and efficacy. Methods:A prospectively maintained database of EVT patients treated at two comprehensive stroke centers between January 2016 and December 2017 was retrospectively screened. Patients undergoing EVT for anterior circulation AIS >24-h from symptom onset were selected. Results: A total of 429 AIS patient underwent EVT in the study period. Five patients treated >24-h from symptom onset were identified. The median age was 72 (range 42-84); median ASPECTS 8 (range 6-8); median baseline-NIHSS 9 (range 4-17); and median time from symptom onset to groin puncture 44 h and 55 min (range 25:07-90:10). One patient underwent CT perfusion imaging. The remaining four patients were selected based on non-contrast CT brain and CT-angiography. Two patients had tandem cervical carotid lesions and underwent acute stenting. Modified thrombolysis in cerebral ischaemia (mTICI) 3 reperfusion was achieved in four patients. No hemorrhagic transformation occurred. All patients were alive at 90-day follow-up. Four patients achieved functional independence at 90-days (mRS 0-2). Conclusion: Endovascular thrombectomy for AIS patients beyond 24-h from symptom onset appears to be safe and effective in this limited study. There is a need for further evidence-based trials of benefit vs. risk in very prolonged time windows.

Does somatostatin have a role to play in migraine headache?

Migraine is a condition without apparent pathology. Its cardinal symptom is the prolonged excruciating headache. Theories about this pain have posited pathologies which run the gamut from neural to vascular to neurovascular, but no observations have detected a plausible pathology. We believe that no pathology can be found for migraine headache because none exists. Migraine is not driven by pathology - it is driven by neural events produced by triggers - or simply by neural noise- noise that has crossed a critical threshold. If these ideas are true, how does the pain arise? We hypothesise that migraine headache is a consequence of withdrawal of descending pain control, produced by "noise" in the cerebral cortex. Nevertheless, there has to be a neural circuit to transform cortical noise to withdrawal of pain control. In our hypothesis, this neural circuit extends from the cortex, synapses in two brainstem nuclei (the periaqueductal gray matter and the raphe magnus nucleus) and ultimately reaches the first synapse of the trigeminal sensory system. The second stage of this circuit uses serotonin (5HT) as a neurotransmitter, but the neuronal projection from the cortex to the brainstem seems to involve relatively uncommon neurotransmitters. We believe that one of these is somatostatin (SST). Temporal changes in levels of circulating SST mirror the temporal changes in the incidence of migraine, particularly in women. The SST2 receptor agonist octreotide has been used with some success in migraine and cluster headache. A cortical to PAG/NRM neural projection certainly exists and we briefly review the anatomical and neurophysiological evidence for it and provide preliminary evidence that SST may the critical neurotransmitter in this pathway. We therefore suggest that the withdrawal of descending tone in SST-containing neurons, might create a false pain signal and hence the headache of migraine.

Treatment of the Patient with Refractory Headache.

PURPOSE OF REVIEW: To review recent studies outlining the management of refractory primary headache patients, including emerging therapies such as neuromodulation. This includes both noninvasive and invasive neuromodulation techniques. Recent studies on the management of medication overuse headache were also reviewed. RECENT FINDINGS: There is no consensus as yet on the definitions of refractory chronic migraine and chronic cluster headache although there is broad agreement on some aspects of these terms. The importance of identifying medication overuse headache and dealing effectively with it has been highlighted in several studies although there is still not consensus on how best to achieve the cessation of medication overuse. Some recommend the use of preventative medication together with medication cessation, while others do not. Recent studies on neuromodulation have used both noninvasive vagal nerve stimulation as well invasive techniques. Recent studies using noninvasive vagal nerve stimulation for chronic migraine have been disappointing although the data in chronic cluster headache are more encouraging. Similarly, recent studies on occipital nerve stimulation have again been more positive in chronic cluster headache and generally negative in chronic migraine. In recent years, new forms of neuromodulation have emerged and long-term follow-up data from previous invasive neuromodulation techniques have become available. The sphenopalatine ganglion has been increasingly targeted by various interventions in several different headache types. Sphenopalatine ganglion stimulation is yielding encouraging data for the treatment of chronic cluster headache. New studies and long-term follow-up data from previous studies have provided further evidence for the benefit of deep brain stimulation for refractory chronic cluster headache although the exact target location is still debated. Data from phase 3 trials using CGRP monoclonal antibodies in chronic migraine and chronic cluster headache, if positive, may herald a long overdue, new and effective treatment for our refractory headache patients.

Stimulation of dural vessels excites the SI somatosensory cortex of the cat via a relay in the thalamus.

AIM: We carried out experiments in cats to determine the thalamo-cortical projection sites of trigeminovascular sensory neurons. METHODS: 1) We stimulated the middle meningeal artery (MMA) with C-fibre intensity electrical shocks and made field potential recordings over the somatosensory cortical surface. 2) We then recorded neurons in the ventroposteromedial (VPM) nucleus of the thalamus in search of neurons which could be activated from the skin, MMA and superior sagittal sinus. 3) Finally, we attempted to antidromically activate the neurons found in stage 2 by stimulating the responsive cortical areas revealed in stage 1. RESULTS: VPM neurons received trigeminovascular input, input from the V1 facial skin and could also be activated by electrical stimulation of the somatosensory cortex. VPM neurons activated from the cortex responded with short and invariant latencies (6.7 ± 7.7 msec mean and SD). They could follow high rates of stimulation and sometimes showed collision with orthodromic action potentials. CONCLUSIONS: We conclude that somatosensory (SI) cortical stimulation excites trigeminovascular VPM neurons antidromically. In consequence, these VPM neurons project to the somatosensory cortex. These findings may help to explain the ability of migraineurs with headache in the trigeminal distribution to localise their pain to a particular region in this distribution.

Pituitary adenylate cyclase activating polypeptide and migraine.

Pituitary adenylate cyclase activating peptide (PACAP) is found in human trigeminocervical complex and can trigger migraine. PACAP levels were measured using a sensitive radioimmunoassay. Stimulation of the superior sagittal sinus (SSS) in cat elevated PACAP levels in cranial blood. Patients with moderate or severe migraine headache had elevated PACAP in the external jugular vein during headache (n = 15), that was reduced 1 h after treatment with sumatriptan 6 mg (n = 11), and further reduced interictally (n = 9). The data suggest PACAP, or its receptors, are a promising target for migraine therapeutics.

An illustrative case of primary angiitis of the central nervous system.

Primary angiitis of the central nervous system is a rare idiopathic vasculitis affecting small- and medium-sized vessels, isolated to the brain, leptomeninges and spinal cord. We report a case of biopsy-proven primary angiitis of the central nervous system, displaying some atypical features. This case highlights several key diagnostic and management issues of the disorder as well as its potential heterogeneity.

Recurrent headaches with visual disturbance.

Headache, particularly migraine, is the commonest neurological problem with which patients present to general practitioners and neurologists. Episodic migraine affects up to 18% of women and 6% of men. Acute migraine attacks can be severely disabling and chronic migraine is even more disabling. Of the mental and neurological disorders, migraine ranks eighth worldwide in terms of disability. Migraine is one of the primary headaches and may occur with or without aura. Differentiation from other severe primary headaches, such as cluster headache, is important for management. The vast majority of patients with migraine can be satisfactorily helped and treated. This involves acute and prophylactic drug therapy and management of triggers. In patients with migraine, medication overuse headache and chronic migraine need to be identified and treated.