The Evolution of Medication Overuse Headache: History, Pathophysiology and Clinical Update.

Medication overuse headache (MOH), the development or worsening of chronic headache resulting from frequent and excessive intake of medications used for acute treatment of headache, is a common secondary headache disorder and is associated with significant personal and societal burdens. The plausible physiologic mechanism is that chronic exposure to acute care migraine treatment leads to suppression of endogenous antinociceptive systems, consequently facilitating the trigeminal nociceptive process via up-regulation of the calcitonin gene-related peptide (CGRP) system. Recognizing and preventing its development is an integral aspect of migraine management, as medication overuse is a modifiable risk factor in the progression from episodic to chronic migraine. Over the years, MOH has been difficult to treat and has generated much controversy. Ongoing debates exist over the diagnostic criteria and treatment strategies, particularly regarding the roles of formal detoxification and preventive treatment. The arrival of the anti-CGRP monoclonal antibodies has also challenged our views of MOH and its treatment. This review outlines the evolution of MOH diagnostic criteria, presents the current understanding of MOH pathogenesis and discusses the debates over its development and treatment. Data on the efficacy of anti-CGRP monoclonal antibodies in the setting of medication overuse is also presented. These results indicate that patients with medication overuse, who are treated with these new medications, may not need to be detoxified in order to treat MOH. In light of these developments, it is likely that in the future MOH will be more readily diagnosed and treatment will result in better outcomes.

Secondary stabbing headache associated with intracranial tumors, aneurysms, and arteriovenous malformation: An alarming warning sign.

BACKGROUND: Stabbing headache (SH) is considered as a pure primary headache, but according to a few clinical observations it could also be secondary. Over the past decades, we have been observing the complaint of SH in patients with intracranial vascular and neoplastic lesions. OBJECTIVE: To describe a series of patients with intracranial lesions who experienced SH. METHODS: This is a cross-sectional, retrospective study of 34 patients with intracranial lesions associated with SH, admitted at Hospital das Clínicas, Federal University of Pernambuco, Brazil. RESULTS: In this series of 34 patients [29 women, 44 ± 12 years (mean ± SD)] with secondary SH, the causes were intracranial neoplasms (n = 31), cerebral aneurysms (n = 2), or arteriovenous malformation (n = 1). Pituitary tumor (n = 18), meningioma (n = 6), and vestibular schwannomas (n = 4) were the most prevalent types of intracranial neoplasms. All these lesions had intimate contact with the dura mater, including an oligodendroglioma, the only intra-axial tumor in the series. A characteristic in the secondary SH is the crescendo pattern (12/34, 35%), progressing from infrequent attacks to recurrent crises occurring several times a day. The SH lasted from 5 days to 60 months (15 ± 18 months, mean ± SD) until the correct diagnosis [16/34 (47%) of the patients ≤6 months]. The SH was triggered by the movement of the head (5/34, 15%) or Valsalva maneuver (1/34). After surgery, suppression of the SH was observed. In a few of the patients to whom dexamethasone was prescribed, the SH subsided within a few days. CONCLUSION: This study was able to identify clinical red flags associated with intracranial lesions and secondary SH, for example, recent onset of SH, exclusively unilateral (ipsilateral) at the same location, crescendo pattern, triggered by head movements, or Valsalva maneuver.

Headache characteristics and burden from chronic migraine with medication overuse headache: Cross-sectional observations from the Medication Overuse Treatment Strategy trial.

OBJECTIVE: To describe headache characteristics, medication use, disability, and quality of life in a large patient cohort from the United States who have chronic migraine (CM) and medication overuse headache (MOH). METHODS: In all, 610 adult patients were enrolled into the Medication Overuse Treatment Strategy trial from 34 healthcare clinics, including headache specialty, general neurology, and primary care clinics. Descriptive statistics characterize baseline demographics, headache characteristics, medication use, disability (Headache Impact Test 6 [HIT-6] and Migraine Functional Impact Questionnaire [MFIQ]), pain interference (PROMIS Pain Interference), and quality of life (EQ-5D-5L). Relationships with headache frequency were assessed. RESULTS: Mean age was 45 years (SD 13) and 531/608 (87.3%) were females. Mean headache days per 30 was 24.3 (SD 5.5), including 13.6 (SD 7.1) with moderate to severe headache. Daily headaches were reported by 36.1% (219/607) of patients. Acute headache medications were used on 21.5 (SD 7.5) per 30 days. The most commonly overused medications were simple analgesics (378/607, 62% of patients), combination analgesics (246/607, 41%), and triptans (128/607, 21%). HIT-6, MFIQ, PROMIS Pain Interference, and EQ-5D-5L scores demonstrated substantial negative impact from CM with MOH on patient functioning and quality of life. Higher headache frequency was associated with more moderate-severe headache days, more frequent acute headache medication use, greater headache-related disability, and lower quality of life. Only 272/606 (44.9%) were taking migraine preventive medication. CONCLUSIONS: CM with MOH is associated with a large burden on patients in the United States. Higher headache frequency is associated with greater impact on functioning, pain interference, and quality of life.

Anodal transcranial direct current stimulation in chronic migraine and medication overuse headache: A pilot double-blind randomized sham-controlled trial.

OBJECTIVES: Little evidence is available on the role of transcranial direct current stimulation (tDCS) in patients affected by chronic migraine (CM) and medication overuse headache (MOH). We aim to investigate the effects of tDCS in patients with CM and MOH as well as its role on brain activity. METHODS: Twenty patients with CM and MOH were hospitalized for a 7-day detoxification treatment. Upon admission, patients were randomly assigned to anodal tDCS or sham stimulation delivered over the primary motor cortex contralateral to the prevalent migraine pain side every day for 5 days. Clinical data were recorded at baseline (T0), after 1 month (T2) and 6 months (T3). EEG recording was performed at T0, at the end of the tDCS/Sham treatment, and at T2. RESULTS: At T2 and T3, we found a significant reduction in monthly migraine days (p = 0.001), which were more pronounced in the tDCS group when compared to the sham group (p = 0.016). At T2, we found a significant increase of alpha rhythm in occipital leads, which was significantly higher in tDCS group when compared to sham group. CONCLUSIONS: tDCS showed adjuvant effects to detoxification in the management of patients with CM and MOH. The EEG recording showed a significant potentiation of alpha rhythm, which may represent a correlate of the underlying changes in cortico-thalamic connections. SIGNIFICANCE: This study suggests a possible role for tDCS in the treatment of CM and MOH. The observed clinical improvement is coupled with a potentiation of EEG alpha rhythm.

Clinical and biobehavioral perspectives: Is medication overuse headache a behavior of dependence?

Medication overuse headache (MOH), previously known as analgesic abuse headache or medication misuse headaches, is a common form of chronic headache disorder that has a detrimental impact on health and society. Although it has been widely accepted that overusing abortive medications is paradoxically the cause of MOH and drug discontinuation is the treatment of choice, ongoing debates exist as to whether drug consumption per se is the cause or consequence of headache chronification. Certain features in MOH such as their compulsive drug-seeking behavior, withdrawal headaches and high relapse rates share similarities with drug dependence, suggesting that there might be common underlying biological and psychobehavioral mechanisms. In this regard, this article will discuss the updated evidence and current debates on the possible biobehavioral overlap between MOH and drug dependence. To begin with, we will discuss whether MOH has characteristics of substance dependence based on standard psychiatry diagnostic criteria and other widely used dependence scales. Recent epidemiological studies underscoring common psychiatric comorbidities between the two disorders will also be presented. Although both demonstrate seemingly distinct personality traits, recent studies revealed similar decision-making impairment from a cognitive perspective, indicating the presence of a maladaptive reward system in both disorders. In addition, emerging imaging studies also support this notion by showing reversible morphological and functional brain changes related to the mesocorticolimbic reward circuitry in MOH, with a strong resemblance to those in addiction. Finally, an increased familial risk for drug dependence and genetic association with dopaminergic and drug dependence molecular pathways in MOH also support a possible link between MOH and addiction. Understanding the role of dependence in MOH will have a great impact on disease management as this will provide the missing piece of the puzzle in current therapeutic strategies.

COVID-19 and Headache: A Primer for Trainees.

OBJECTIVE: To summarize for the trainee audience the possible mechanisms of headache in patients with COVID-19 as well as to outline the impact of the pandemic on patients with headache disorders and headache medicine in clinical practice. BACKGROUND: COVID-19 is a global pandemic caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2, of which a large subset of patients features neurological symptoms, commonly headache. The virus is highly contagious and is, therefore, changing clinical practice by forcing limitations on in-person visits and procedural treatments, more quickly shifting toward the widespread adaptation of telemedicine services. DESIGN/RESULTS: We review what is currently known about the pathophysiology of COVID-19 and how it relates to possible mechanisms of headache, including indirect, potential direct, and secondary causes. Alternative options for the treatment of patients with headache disorders and the use of telemedicine are also explored. CONCLUSIONS: Limited information exists regarding the mechanisms and timing of headache in patients with COVID-19, though causes relate to plausible direct viral invasion of the nervous system as well as the cytokine release syndrome. Though headache care in the COVID-19 era requires alterations, the improved preventive treatment options now available and evidence for feasibility and safety of telemedicine well positions clinicians to take care of such patients, especially in the COVID-19 epicenter of New York City.

Medication overuse headache: an overview of clinical aspects, mechanisms, and treatments.

INTRODUCTION: Medication-overuse headache (MOH) is a common debilitating neurological disorder, with a prevalence of 1% to 7% in general population. It affects more than 60 million people worldwide and provokes substantial burden. Despite that, most practitioners don't know MOH. This review aims at presenting MOH clinical features, pathophysiology insights, and recent knowledge and guidance regarding treatments. AREAS COVERED: A literature search in the major medical databases including the terms 'medication overuse headache,' 'chronic daily headache,' 'chronic migraine,' 'symptomatic medication overuse' and others, published between 1990 and 2020, was carried out. EXPERT COMMENTARY: Primary headache sufferers such as migraineurs and tension-type headache patients may increase the headache frequency and induce the transition from episodic to chronic forms, as well as develop MOH, in the presence of medication overuse. There is evidence of structural and functional changes in some areas of the brain, which may identify those likely to respond or not to treatments. Despite the geographical differences and lack of consensus regarding approaches, to educate the patients about reducing medication intake, to withdraw overused medications and to start prophylaxis in some sufferers are crucial steps. Emerging treatments as monoclonal antibodies to migraine may result in better adherence and tolerability profiles as well as outcomes.

Other primary headaches-thunderclap-, cough-, exertional-, and sexual headache.

This article reviews the disorders of thunderclap, cough, exertional and sexual headache. These are a group of paroxysmal and precipitated headaches, which often occur in bouts with prolonged remissions. Indometacin seems to be the most effective preventative. Each can occur in primary and secondary form. Thunderclap headache is the most frequently reported headache syndrome associated with a secondary pathology. Discussed are the complexities of whether all patients with thunderclap headache should have further investigation if timely computerised tomography is normal and, the relevance of abnormal imaging in these disorders, differentiating what is deemed to be secondary and managing the pain.

Multisensorial Perception in Chronic Migraine and the Role of Medication Overuse.

Multisensory processing can be assessed by measuring susceptibility to crossmodal illusions such as the Sound-Induced Flash Illusion (SIFI). When a single flash is accompanied by 2 or more beeps, it is perceived as multiple flashes (fission illusion); conversely, a fusion illusion is experienced when more flashes are matched with a single beep, leading to the perception of a single flash. Such illusory perceptions are associated to crossmodal changes in visual cortical excitability. Indeed, increasing occipital cortical excitability, by means of transcranial electrical currents, disrupts the SIFI (ie, fission illusion). Similarly, a reduced fission illusion was shown in patients with episodic migraine, especially during the attack, in agreement with the pathophysiological model of cortical hyperexcitability of this disease. If episodic migraine patients present with reduced SIFI especially during the attack, we hypothesize that chronic migraine (CM) patients should consistently report less illusory effects than healthy controls; drugs intake could also affect SIFI. On such a basis, we studied the proneness to SIFI in CM patients (n = 63), including 52 patients with Medication Overuse Headache (MOH), compared to 24 healthy controls. All migraine patients showed reduced fission phenomena than controls (P < .0001). Triptan MOH patients (n = 23) presented significantly less fission effects than other CM groups (P = .008). This exploratory study suggests that CM - both with and without medication overuse - is associated to a higher visual cortical responsiveness which causes deficit of multisensorial processing, as assessed by the SIFI. PERSPECTIVE: This observational study shows reduced susceptibility to the SIFI in CM, confirming and extending previous results in episodic migraine. MOH contributes to this phenomenon, especially in case of triptans.

The American Registry for Migraine Research: Research Methods and Baseline Data for an Initial Patient Cohort.

BACKGROUND: The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants. METHODS: Adults with any International Classification of Headache Disorders (ICHD) diagnosis were prospectively enrolled from one of the 8 participating headache specialty centers. At baseline, ARMR participants complete web-based questionnaires, clinicians enter the participant's ICHD diagnoses, an optional blood specimen is collected, and neuroimaging data are uploaded to the ARMR neuroimaging repository. Participants maintain the ARMR daily headache diary longitudinally and follow-up questionnaires are completed by participants every 3 months. EHR data are integrated into the ARMR database from a subset of ARMR sites. Herein, we describe the ARMR methodology and report the summary data from ARMR participants who had, from February 2016 to May 2019, completed at least 1 baseline questionnaire from which data are reported in this manuscript. Descriptive statistics are used to provide an overview of patient's sociodemographics, headache diagnoses, headache characteristics, most bothersome symptoms other than headache, headache-related disability, comorbidities, and treatments. RESULTS: Data were available from 996 ARMR participants, enrolled from Mayo Clinic Arizona, Dartmouth-Hitchcock Medical Center, University of Utah, University of Colorado, Thomas Jefferson University, University of Texas Health Science Center at Houston, Georgetown University Medical Center, and DENT Neurological Institute. Among ARMR participants, 86.7% (n = 864) were female and the mean age at the time of enrollment was 48.6 years (±13.9; range 18-84). The most common provider-reported diagnosis was chronic migraine (n = 622), followed by migraine without aura (n = 327), migraine with aura (n = 196), and medication overuse headache (n = 65). Average headache frequency was 19.1 ± 9.2 days per month (n = 751), with 68% reporting at least 15 headache days per month. Sensitivity to light was the most frequent (n = 222) most bothersome symptom overall, other than headache, but when present, cognitive dysfunction was most frequently (n = 157) the most bothersome symptom other than headache. Average migraine disability assessment (MIDAS) score was 52 ± 49 (n = 760), (very severe headache-related disability); however, 17% of the ARMR population had MIDAS scores suggesting "no" or "mild" disability. The most common non-headache health issues were allergies (n = 364), back pain (n = 296), neck pain (n = 296), depression (n = 292), and anxiety (n = 278). Nearly 85% (n = 695) of patients were using preventive medications and 24.7% were using non-medication preventive therapy (eg, vitamins and neuromodulation). The most common preventive medication classes were neurotoxins, anticonvulsants, antidepressants, vitamins/supplements, and anticalcitonin gene-related peptide ligand or receptor-targeted monoclonal antibodies. Nearly 90% (n = 734) of ARMR participants was taking medications to treat migraine attacks, with the most common classes being triptans, non-steroidal anti-inflammatory drugs, antiemetics, acetaminophen, and combination analgesics. CONCLUSIONS: ARMR is a source of real-world patient data, biospecimens, and brain neuroimaging data that provides comprehensive insight into patients with migraine and other headache types being seen in headache specialty clinics in the United States. ARMR data will allow for longitudinal and advanced analytics that are expected to lead to a better characterization of patient heterogeneity, healthcare resource utilization, identification of endophenotypes, factors that predict treatment outcomes and clinical course, and ultimately advance the field toward precision headache medicine.

Headache and Methemoglobinemia.

AIM: This basic review is intended to summarize the current knowledge of methemoglobinemia as an important cause of secondary headache with the hope of generating a growing interest in studying this phenomenon. BACKGROUND: We describe the pathological underpinnings of headaches generated by hypoxia. Possible mechanisms include cerebral vasodilation-associated stretching of the vessel nociceptors, sensitization of perivascular nociceptors mediated by nitric oxide, cerebral calcitonin gene-related peptide, activation of the cyclic adenosine monophosphate pathway, cortical spreading depression, disruption of the blood-brain barrier, and neurogenic inflammation. We review the clinical features, pathophysiology, and management of methemoglobinemia. We conducted a literature review of reports of symptomatic methemoglobinemia with headache. In addition, we describe a case report of a patient who presented with an acute onset of severe holocranial headache associated with rapidly progressive perioral paresthesia, cyanosis in lips and hands, nausea, and mild dyspnea on exertion. These features can be misinterpreted as an acute attack of migraine with pain-related hyperventilation syndrome and anxiety leading to clinically detrimental delay in the management of the progressive hypoxia. Her symptoms resolved following treatment with methylene blue. The complex relationship of migraine and hypoxia-related headaches is also reviewed. We propose that methemoglobinemia-associated headaches are possibly generated by stretching of the nociceptor nerve endings during cerebral vasodilation and hypoxia-mediated oxidative stress. CONCLUSIONS: The case highlights the need to broaden the formulated differential diagnosis of an acute onset severe holocranial headache and pay careful attention to other signs and symptoms that may provide hints on potential mechanism(s) for secondary headaches. We provide justification for the need to incorporate "Headache attributed to Methemoglobinemia" as a subtype under the section "Headache attributed to hypoxia and/or hypercapnia" of the International Classification of Headache Disorders to support clinical decision making.

Altered activity in the nucleus raphe magnus underlies cortical hyperexcitability and facilitates trigeminal nociception in a rat model of medication overuse headache.

BACKGROUND: The pathogenesis of medication overuse headache (MOH) involves hyperexcitability of cortical and trigeminal neurons. Derangement of the brainstem modulating system, especially raphe nuclei may contribute to this hyperexcitability. The present study aimed to investigate the involvement of the nucleus raphe magnus (NRM) in the development of cortical and trigeminal hyperexcitability in a rat model of MOH. RESULTS: Chronic treatment with acetaminophen increased the frequency of cortical spreading depression (CSD) and the number of c-Fos-immunoreactive (Fos-IR) neurons in the trigeminal nucleus caudalis (TNC). In the control group, muscimol microinjected into the NRM increased significantly the frequency of CSD-evoked direct current shift and Fos-IR neurons in the TNC. This facilitating effect was not found in rats with chronic acetaminophen exposure. In a model of migraine induced by intravenous systemic infusion of nitroglycerin (NTG), rats with chronic exposure to acetaminophen exhibited significantly more frequent neuronal firing in the TNC and greater Fos-IR than those without the acetaminophen treatment. Muscimol microinjection increased neuronal firing in the TNC in control rats, but not in acetaminophen-treated rats. The number of Fos-IR cells in TNC was not changed significantly. CONCLUSION: Chronic exposure to acetaminophen alters the function of the NRM contributing to cortical hyperexcitability and facilitating trigeminal nociception.

Pathophysiology, prevention, and treatment of medication overuse headache.

Regular or frequent use of analgesics and acute antimigraine drugs can increase the frequency of headache, and induce the transition from episodic to chronic headache or medication overuse headache. The 1-year prevalence of this condition in the general population is between 1% and 2%. Medication overuse headache is more common in women and in people with comorbid depression, anxiety, and other chronic pain conditions. Treatment of medication overuse headache has three components. First, patients need education and counselling to reduce the intake of medication for acute headache attacks. Second, some patients benefit from drug withdrawal (discontinuation of the overused medication). Finally, preventive drug therapy and non-medical prevention might be necessary in patients at onset of treatment or in patients who do not respond to the first two steps. The optimal therapeutic approach requires validation in controlled trials.

Withdrawal from acute medication normalises short-term cortical synaptic potentiation in medication overuse headache.

OBJECTIVES: To study the effects of a standard acute medication withdrawal program on short-term cortical plasticity mechanisms in patients with medication overuse headache (MOH). METHODS: Thirteen patients with MOH and 16 healthy volunteers underwent repetitive transcranial magnetic stimulation (rTMS) over the left motor cortex; in patients with MOH, recordings were performed before and after a 3-week medication withdrawal program. Ten trains of 10 stimuli each (120% resting motor threshold) were delivered at 1 Hz or 5 Hz in two separate sessions in a randomised order. Motor evoked potential (MEP) amplitudes were measured from the right first dorsal interosseous muscle and the slope of the linear regression line from the first to the tenth stimuli was calculated for each participant. RESULTS: All subjects exhibited MEP amplitude inhibition in response to 1 Hz rTMS. Alternatively, the 5-Hz trains of rTMS inhibited rather than potentiated MEP amplitudes in patients with MOH. The physiological potentiating effect of 5 Hz rTMS on MEP amplitudes was restored after drug withdrawal and in proportion with the percentage reduction in monthly headache days in patients with MOH. CONCLUSIONS: The results suggest that acute medication withdrawal normalises brain responses in patients with MOH. Clinical improvements after medication withdrawal may reflect the reversal of neurophysiological dysfunction. Accordingly, medication withdrawal should be offered to patients with MOH as early as possible in order to prevent the development of more pronounced alterations in brain plasticity.

Short-term cortical synaptic depression/potentiation mechanisms in chronic migraine patients with or without medication overuse.

OBJECTIVE: To study the effects of trains of repetitive transcranial magnetic stimulation (rTMS) over the motor cortex in patients with chronic migraine (CM) with or without medication overuse (MOH). SUBJECTS AND METHODS: Thirty-two patients (CM [n = 16]; MOH [n = 16]) and 16 healthy volunteers (HVs) underwent rTMS recording. Ten trains of 10 stimuli each (120% resting motor threshold) were applied over the left motor cortex at 1 Hz or 5 Hz in random order. The amplitude of motor evoked potential (MEP) was evaluated from electromyographic recording in the first dorsal interosseous muscle. The slope of the linear regression line for the 10 stimuli for each participant was calculated using normalized data. RESULTS: rTMS-1 Hz had a normal depressive effect on MEP amplitude in all groups. rTMS-5 Hz depressed instead of potentiating MEP amplitudes in MOH patients, with a significantly different response from that in HVs and CM patients. The slope of the linear regression of MEP amplitudes was negatively correlated with pain intensity in CM patients, and with the duration of overuse headache in MOH patients. CONCLUSIONS: This different plastic behaviour suggests that MOH and CM, despite exhibiting a similar clinical phenotype, have different neurophysiological learning processes, probably related to different pathophysiological mechanisms of migraine chronification.

Sustained exposure to acute migraine medications combined with repeated noxious stimulation dysregulates descending pain modulatory circuits: Relevance to medication overuse headache.

BACKGROUND: Loss of conditioned pain modulation/diffuse noxious inhibitory controls has been demonstrated in patients with migraine and medication overuse headache. We hypothesized that exposure to acute migraine medications may lead to dysregulation of central pain modulatory circuits that could be revealed by evaluating diffuse noxious inhibitory controls and that prior noxious stimulus is required for a loss of the diffuse noxious inhibitory control response in rats exposed to these medications. METHODS: Rats were "primed" by continuous infusion of morphine or one of two doses of sumatriptan. Diffuse noxious inhibitory control was evaluated at the end of drug-priming (day 7) and again after sensory thresholds returned to baseline (day 21). The Randall-Selitto hindpaw pressure test was used as the test stimulus and forepaw capsaicin injection served as the conditioning stimulus. RESULTS: Morphine-primed rats showed opioid-induced hyperalgesia accompanied by a loss of diffuse noxious inhibitory controls on day 7. Sumatriptan-primed rats did not develop hyperalgesia or loss of diffuse noxious inhibitory controls on day 7. Morphine-primed and high-dose sumatriptan-primed rats only had a loss of diffuse noxious inhibitory control on day 21 if they received a capsaicin injection on day 7. CONCLUSIONS: Prolonged exposure to migraine treatments followed by an acute nociceptive stimulation caused long-lasting alterations in descending pain modulation, shown by a loss of diffuse noxious inhibitory controls. Morphine was more detrimental than sumatriptan, consistent with clinical observations of higher medication overuse headache risk with opioids. These data suggest a mechanism of medication overuse headache by which migraine medications combined with repeated episodes of pain may amplify the consequences of nociceptor activation and increase the probability of future migraine attacks as well as risk of medication overuse headache.

Neurophysiological correlates of clinical improvement after greater occipital nerve (GON) block in chronic migraine: relevance for chronic migraine pathophysiology.

BACKGROUND: Therapeutic management of Chronic Migraine (CM), often associated with Medication Overuse Headache (MOH), is chiefly empirical, as no biomarker predicting or correlating with clinical efficacy is available to address therapeutic choices. The present study searched for neurophysiological correlates of Greater Occipital Nerve Block (GON-B) effects in CM. METHODS: We recruited 17 CM women, of whom 12 with MOH, and 19 healthy volunteers (HV). Patients had no preventive treatment since at least 3 months. After a 30-day baseline, they received a bilateral betamethasone-lidocaine GON-B of which the therapeutic effect was assessed 1 month later. Habituation of visual evoked potentials (VEP) and intensity dependence of auditory evoked potentials (IDAP) were recorded before and 1 week after the GON-B. RESULTS: At baseline, CM patients had a VEP habituation not different from HV, but a steeper IDAP value than HV (p = 0.01), suggestive of a lower serotonergic tone. GON-B significantly reduced the number of total headache days per month (- 34.9%; p = 0.003). Eight out 17CM patients reversed to episodic migraine and medication overuse resolved in 11 out of 12 patients. One week after the GON-B VEP habituation became lacking respect to baseline (p = 0.01) and to that of HV (p = 0.02) like in episodic migraine, while the IDAP slope significantly flattened (p < 0.0001). GON-B-induced reduction in headache days positively correlated with IDAP slope decrease (rho = 0.51, p = 0.03). CONCLUSIONS: GON-B may be effective in the treatment of CM, with or without MOH. The pre-treatment IDAP increase is compatible with a weak central serotonergic tone, which is strengthened after GON-B, suggesting that serotonergic mechanisms may play a role in CM and its reversion to episodic migraine. Since the degree of post-treatment IDAP decrease is correlated with clinical improvement, IDAP might be potentially useful as an early predictor of GON-B efficacy.

Secondary Headaches in Children and Adolescents: What Not to Miss.

INTRODUCTION: Headaches are a common occurrence in childhood and adolescence. Most children presenting with a chief complaint of headache have a self-limited infectious disorder or primary headache syndrome that should not require extensive workup. PURPOSE OF REVIEW: Differentiating these conditions from other more serious causes of headache in children can sometimes be difficult. This article aims to provide information regarding "red flags" that should indicate a need for concern for disorders that require more urgent evaluation. RECENT FINDINGS: Long-held beliefs about specific "red flags" that have been analyzed in recent years as to their validity and new criteria for the diagnosis of idiopathic intracranial hypertension have been elaborated based on study. These publications are reviewed in this article. Knowledge of past and current literature on secondary headache in children, combined with thorough history taking and examination, should help determine when there is concern for a serious secondary cause for headache in children and adolescents and direct workup.

Resting State Functional Connectivity After Sphenopalatine Ganglion Blocks in Chronic Migraine With Medication Overuse Headache: A Pilot Longitudinal fMRI Study.

OBJECTIVE: In this pilot study, the purpose is to investigate if a series of sphenopalatine ganglion (SPG) blockade treatments modulate the functional connectivity within the salience and central executive network (CEN) in chronic migraine with medication overuse headaches (CMw/MOH ). BACKGROUND: Using intranasal local anesthesia to block the SPG for the treatment of various headache disorders has been employed in clinical practice since the early 1900s. However, the exact mechanism of how SPG modulate resting state intrinsic functional brain networks connectivity remains to be elucidated. This pilot study seeks to understand the resting state connectivity changes in salience and CENs, with emphasis on the mesocorticolimbic systems, before and after a series of SPG block treatments. METHODS: Using fMRI, resting state connectivity was derived from predefined networks of nodes (regions of interests) for the salience (27 nodes, 351 connections) and CENs (17 nodes, 136 connections). After treatments, a paired samples t-test (with 10,000 permutations to correct for multiple comparison) was used to evaluate changes in the intranetwork resting state functional connectivity within the salience and executive networks, as well as the overall network connectivity strength. RESULTS: When comparing connectivity strength at baseline to that at the end of treatment in our cohort of 10 CMw/MOH participants, there were several connections within the salience (n = 9) and executive (n = 8) networks that were significantly improved. Within the salience network, improved connectivity was observed between the prefrontal cortex and various regions of the insula, basal ganglia, motor, and frontal cortex. Additionally, changes in connectivity were observed between regions of the temporal cortex with the basal ganglia and supramarginal gyrus. Within the CEN, improved connectivity was observed between the prefrontal cortex and regions of the anterior thalamus, caudate, and frontal cortex. After treatment, the overall CEN connectivity was significantly improved (Baseline 0.00 ± 0.08; 6 weeks 0.03 ± 0.09, P = .01); however, the overall salience network connectivity was not significantly improved (Baseline -0.01 ± 0.10; 6 weeks 0.01 ± 0.12, P = .26). Additionally, after treatment, there was a significant reduction in the number of moderate/severe headache days per month (Baseline 21.1 ± 6.6; 6 weeks 11.2 ± 6.5, P < .001), HIT-6 (Baseline 66.1 ± 2.6; 6 weeks 60.2 ± 3.6, P < .001), and PHQ-9 (Baseline 12.4 ± 5.7; 6 weeks 6.1 ± 3.6, P = .008) scores. CONCLUSION: In this longitudinal fMRI study, we observed improved functional connectivity within both networks, primarily involving connectivity between regions of the prefrontal cortex and limbic (cortical-limbic) structures, and between different cortical (cortical-cortical) regions after a series of repetitive SPG blockades. The overall CEN strength was also improved. Our results suggest that recurrent parasympathetic inhibition via SPG is associated with improved functional connectivity in brain regions critical to pain processing in CMw/MOH .