Central pontine myelinolysis and the osmotic demyelination syndromes: an open and shut case?

Central pontine myelinolysis and extrapontine myelinolysis are collectively called the osmotic demyelination syndromes. Despite being described in 1959, there are several aspects of the disorder that remain an enigma. Animal models and neuroimaging techniques have allowed us to understand the condition better. From being a universally fatal disorder that was diagnosed post mortem, increased awareness, neuroimaging techniques and supportive care have enabled us to make the diagnosis ante-mortem. This has also led to a significant drop in associated mortality. The aim of this review is to highlight the clinical spectrum, neuroimaging findings, and recent developments.

The migraine postdrome: Spontaneous and triggered phenotypes.

BACKGROUND: Non-painful symptoms in migraine following headache resolution can last up to days. Studying the postdrome is important to appreciate the morbidity associated with migraine. METHODS: Fifty-three subjects (n = 53) with migraine were studied in an experimental setting, collecting historical phenotypic information on the postdrome in their spontaneous attacks, and also associated with nitroglycerin-triggered attacks, while being observed prospectively. In a separate headache clinic-based cohort of migraineurs (n = 42), who were age and sex-matched to the experimental group, the same phenotypic data were extracted from their clinic records. Spontaneous and nitroglycerin-triggered attack phenotypes, and experimental and clinical cohort phenotypes were compared using agreement analysis. RESULTS: In the experimental group, 100% had a postdrome with their triggered attack, while 98% reported a postdrome in their spontaneous attacks. In the clinical group, 79% had reported a postdrome. In the experimental group, there was good agreement between spontaneous and nitroglycerin-triggered tiredness, hunger, mood change, sensory sensitivities and vertigo and with similarity in premonitory and postdrome phenotypes experienced in the same individual. CONCLUSIONS: The migraine postdrome is common and symptomatically similar to the premonitory phase. The nitroglycerin model and migraine abortive agents can be used to study the postdrome experimentally. Systematic questioning of symptoms, as well as collateral histories from direct observers of migraine attacks, are likely to enhance symptomatic capture of the migraine postdrome, and aid understanding of attack mediation, abortion and neurobiology.

Are some patient-perceived migraine triggers simply early manifestations of the attack?

OBJECTIVE: To study the agreement between self-reported trigger factors and early premonitory symptoms amongst a group of migraineurs in both spontaneous and pharmacologically provoked attacks. METHODS: Fifty-three subjects with migraine with and without aura, with ≤ 22 headache days/month, with spontaneous premonitory symptoms associated with migraine attacks were recruited nationally. A detailed history was taken by a study investigator to confirm diagnosis and extended phenotyping was performed to identify patient-reported triggers for migraine attacks, premonitory symptom phenotype and headache characteristics, using a standardised physician-administered questionnaire. The same subjects were exposed to a 0.5 mcg/kg/min nitroglycerin infusion over 20 min, to determine if similar migraine symptoms could be triggered. The triggered attacks were phenotyped in the same way as spontaneous ones. Percentage agreement and Cohen's kappa measure of agreement were used to identify concordance between patient-reported triggers and the corresponding spontaneous and triggered premonitory symptoms. Percentage agreement of > 60% and/or a kappa value > 0.3 with P < 0.05 were considered significant. RESULTS: There was statistically significant agreement between perception of light as a migraine trigger and spontaneous premonitory photophobia; perception of sound as a trigger and triggered premonitory phonophobia; skipping meals as a trigger and spontaneous premonitory food cravings; and food triggers and spontaneous premonitory food cravings. There was good agreement between stress and premonitory triggered mood change. CONCLUSIONS: At least some patient-reported triggers, such as light, sound, foods and skipping meals, may represent early brain manifestations of the premonitory phase of the migraine attack.

Therapeutic targeting of nitroglycerin-mediated trigeminovascular neuronal hypersensitivity predicts clinical outcomes of migraine abortives.

ABSTRACT: Cranial hypersensitivity is a prominent symptom of migraine, exhibited as migraine headache exacerbated with physical activity, and cutaneous facial allodynia and hyperalgesia. The underlying mechanism is believed to be, in part, activation and sensitization of dural-responsive trigeminocervical neurons. Validated preclinical models that exhibit this phenotype have great utility for understanding putative mechanisms and as a tool to screen therapeutics. We have previously shown that nitroglycerin triggers cranial allodynia in association with migraine-like headache, and this translates to neuronal cranial hypersensitivity in rats. Furthermore, responses in both humans and rats are aborted by triptan administration, similar to responses in spontaneous migraine. Here, our objective was to study the nitroglycerin model examining the effects on therapeutic targets with newly approved treatments, specifically gepants and ditans, for the acute treatment of migraine. Using electrophysiological methods, we determined changes to ongoing firing and somatosensory-evoked cranial sensitivity, in response to nitroglycerin, followed by treatment with a calcitonin gene-related peptide receptor antagonist, gepant (olcegepant), a 5-HT1F receptor agonist, ditan (LY344864), and an NK1 receptor antagonist (GR205171). Nitroglycerin induced activation of migraine-like central trigeminocervical neurons, and intracranial and extracranial neuronal hypersensitivity. These responses were aborted by olcegepant and LY344864. However, GR205171, which failed in clinical trial for both abortive and preventive treatment of migraine, had no effect. These data support the nitroglycerin model as a valid approach to study cranial hypersensitivity and putative mechanisms involved in migraine and as a screen to dissect potentially efficacious migraine therapeutic targets.

Alterations in Functional Connectivity During Different Phases of the Triggered Migraine Attack.

OBJECTIVE: To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack. BACKGROUND: Migraine is a symptomatically heterogeneous disorder. Understanding the possible changes in brain function and, therefore, neurobiology during different phases of the migraine attack is important in developing disease biomarkers and advancing therapeutics. DESIGN: Randomized, double-blind, placebo-controlled, multi-visit experimental study. METHODS: Subjects aged 18-50 years with migraine with and without aura (≤22 headache days per month) were recruited from across the UK using advertising, from both population and hospital clinic samples (n = 53). Consented subjects were randomized to a 0.5 µg/kg/min nitroglycerin infusion or to placebo over 20 minutes across different study visits, during the period February 2015-July 2017.* All subjects were exposed to a nitroglycerin infusion at least on 1 occasion at screening.** For those subjects who consented to participate in imaging visits (n = 25), structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependant contrast (rsBOLD) time series, using a multiecho EPI sequence, were conducted over 30-40 minutes at baseline and rsBOLD during premonitory symptoms and migraine headache on a 3T General Electric MR750 MRI scanner. For the placebo visit, the imaging was conducted at the same times following infusion in the absence of symptoms. RESULTS: Montreal Neurological Institute (MNI) coordinates were used to characterize identified brain areas of connectivity change. Using repeated measures ANOVA models with time (visit number) and trigger substance (nitroglycerin/placebo) as factors, significant positive functional coupling was found between the thalami bilaterally and the right precuneus and cuneus regions during the nitroglycerin-triggered premonitory phase (T = 3.23, peak connectivity change at [-6, -68, 40] for left thalamus, P = 0.012 and [-4, -68, 40] for right thalamus, P = 0.019). The nitroglycerin-triggered premonitory phase was associated with a change in the direction of connectivity from positive to negative between the pons and the limbic lobe (T = 3.47, peak connectivity change at [2, 8, 50], P < 0.001). The headache phase of the nitroglycerin-triggered migraine attack was associated with ongoing negative functional coupling between the pons and the cingulate and frontal cortices, and positive functional coupling between the pons and the cerebellar tonsils and medulla (T = 3.47, peak connectivity change at [-8, -52, -58], P = 0.007). CONCLUSIONS: Understanding the functional reorganization between subcortical and cortical brain areas in different phases of the migraine attack provides novel insights into the abnormal sensory processing and integration during migraine, as well as functional correlation with clinical symptoms displayed during each phase. [*Correction added on July 22, 2020 after first online publication: This sentence was revised from, "Consented subjects had a 0.5 µg/kg/min nitroglycerin infusion…".] [**Correction added on July 22, 2020 after first online publication: This sentence was revised from, "… at least on 1 occasion at screening."].

Headache and non-headache symptoms provoked by nitroglycerin in migraineurs: A human pharmacological triggering study.

BACKGROUND: Studying a spontaneous migraine attack is challenging, particularly the earliest components. Nitroglycerin is a potent, reliable and reproducible migraine trigger of the entirety of the migraine attack, making its use experimentally attractive. METHODS: Fifty-three subjects with migraine with a history of spontaneous premonitory symptoms were exposed to a 0.5 mcg/kg/min nitroglycerin infusion. Eighty-three percent (n = 44) developed typical premonitory and headache symptomatology. Fifty-seven percent (n = 25) were invited back to further study visits, during which they were re-exposed to nitroglycerin or placebo infusion in a double-blind randomised design. The phenotype of premonitory symptoms and headache was captured and compared to spontaneous attacks and between triggered attacks using agreement analysis. RESULTS: More premonitory symptoms were triggered with nitroglycerin than placebo (mean symptom difference = 4, t20 = 7.06, p < 0.001). The agreement in triggering for the most commonly reported premonitory symptoms (concentration difficulty and tiredness) was >66%. The retriggering agreement for all but one premonitory symptom was >60%. The agreement in timing to onset of premonitory symptoms was reliable across two triggered attacks. The agreement with spontaneous attacks and between attacks for headache and its associated symptoms, including laterality, was less reliable. CONCLUSIONS: Nitroglycerin can reliably and reproducibly provoke premonitory symptomatology associated with migraine. This forms an ideal model to study the earliest manifestations of migraine attacks.

Nitroglycerine triggers triptan-responsive cranial allodynia and trigeminal neuronal hypersensitivity.

Cranial allodynia associated with spontaneous migraine is reported as either responsive to triptan treatment or to be predictive of lack of triptan efficacy. These conflicting results suggest that a single mechanism mediating the underlying neurophysiology of migraine symptoms is unlikely. The lack of a translational approach to study cranial allodynia reported in migraine patients is a limitation in dissecting potential mechanisms. Our objective was to study triptan-responsive cranial allodynia in migraine patients, and to develop an approach to studying its neural basis in the laboratory. Using nitroglycerine to trigger migraine attacks, we investigated whether cranial allodynia could be triggered experimentally, observing its response to treatment. Preclinically, we examined the cephalic response properties of central trigeminocervical neurons using extracellular recording techniques, determining changes to ongoing firing and somatosensory cranial-evoked sensitivity, in response to nitroglycerine followed by triptan treatment. Cranial allodynia was triggered alongside migraine-like headache in nearly half of subjects. Those who reported cranial allodynia accompanying their spontaneous migraine attacks were significantly more likely to have symptoms triggered than those that did not. Patients responded to treatment with aspirin or sumatriptan. Preclinically, nitroglycerine caused an increase in ongoing firing and hypersensitivity to intracranial-dural and extracranial-cutaneous (noxious and innocuous) somatosensory stimulation, reflecting signatures of central sensitization potentially mediating throbbing headache and cranial allodynia. These responses were aborted by a triptan. These data suggest that nitroglycerine can be used as an effective and reliable method to trigger cranial allodynia in subjects during evoked migraine, and the symptom is responsive to abortive triptan treatments. Preclinically, nitroglycerine activates the underlying neural mechanism of cephalic migraine symptoms, central sensitization, also predicting the clinical outcome to triptans. This supports a biological rationale that several mechanisms can mediate the underlying neurophysiology of migraine symptoms, with nitrergic-induced changes reflecting one that is relevant to spontaneous migraine in many migraineurs, whose symptoms of cranial allodynia are responsive to triptan treatment. This approach translates directly to responses in animals and is therefore a relevant platform to study migraine pathophysiology, and for use in migraine drug discovery.

The Migraine Premonitory Phase.

PURPOSE OF REVIEW: The premonitory phase of migraine is defined as the presence of nonpainful symptomatology occurring hours to days before the onset of headache. Symptoms can include neck stiffness, yawning, thirst, and increased frequency of micturition. Clinical recognition of these symptoms is important to ensure early and effective attack management. Further understanding of the clinical phenotype and neurobiological mediation of these symptoms is important in the advancement of therapeutics research in both acute and preventive treatments of migraine. RECENT FINDINGS: Since 2014, functional imaging studies have been conducted during the premonitory stage of migraine and have provided novel insights into the early neurobiology and anatomy of the earliest stage of the migraine attack. These studies have shown early involvement of subcortical brain areas including the hypothalamus, substantia nigra, dorsal pons, and various limbic cortical areas, including the anterior cingulate cortex during the premonitory phase. More recent work has revealed altered hypothalamic-brainstem functional connectivity during migraine, which starts before the onset of pain. These exciting findings have provided functional correlation of the symptoms experienced by patients and changes seen on functional brain imaging. SUMMARY: This article focuses on the prevalence, phenotype, and proposed neurobiology of premonitory symptomatology in migraineurs as well as the scope of future research.

The Migraine Postdrome.

PURPOSE OF REVIEW: The migraine postdrome is the least studied and least understood phase of migraine. This article covers the salient features of the migraine postdrome and provides insight into the history, clinical symptoms, and future implications of this phase of migraine. RECENT FINDINGS: Prospective electronic diary studies have shown that patients are left disabled with various nonheadache symptoms in the migraine postdrome, and 81% of patients report at least one nonheadache symptom in the postdrome. Hence, it is important to understand this phase better and ensure that more effective treatments become available in the future to lessen the morbidity associated with this phase. Functional imaging shows widespread reduction in brain-blood flow in the postdrome, which explains the multitudes of symptoms experienced by patients. SUMMARY: The disability related to migraine is not exclusive to the headache phase but extends into the postdrome phase and is associated with several nonheadache symptoms that prolong the symptoms experienced by patients with migraine. Further research into the postdrome is crucial to improve our overall understanding of migraine mechanisms. This knowledge may also help to treat the concurrent nonheadache symptoms better in the future. Novel neuroimaging techniques provide a valuable noninvasive tool to push the frontiers in the understanding of migraine pathophysiology. These methods may help shed further light onto the possible links between key brain structures and networks that could be implicated in the pathophysiology of the various migraine phases.

The migraine postdrome.

PURPOSE OF REVIEW: Migraine is a common, disabling neurological disorder that affects up to 12% of the world population. Its pathophysiology is incompletely described. Of the various phases of migraine, the migraine postdrome is the least studied and hence the least understood. RECENT FINDINGS: Electronic diary studies show patients are left disabled with non-headache symptoms in the migraine postdrome. Hence, the importance of understanding the phase better and ensuring that more effective treatments become available in the future to cut down the morbidity associated with this phase. SUMMARY: The disability related to migraine is not limited to the headache phase and pans out to include the postdrome phase. The migraine postdrome needs to be studied more as this may improve our overall understanding of migraine mechanisms and also treat the concurrent symptoms better.