Ultra-late response (> 24 weeks) to anti-CGRP monoclonal antibodies in migraine: a multicenter, prospective, observational study.

OBJECTIVE: Nearly 60% of migraine patients treated with monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway experience a ≥ 50% reduction in monthly migraine days (MMD) at 12 weeks compared to baseline (responders). However, approximately half of the patients not responding to anti-CGRP mAbs ≤ 12 weeks do respond ≤ 24 weeks (late responders). We assessed frequency and characteristics of patients responding to anti-CGRP mAbs only > 24 weeks (ultra-late responders). METHODS: In this multicenter (n = 16), prospective, observational, real-life study, we enrolled all consecutive adults affected by high-frequency episodic migraine (HFEM: ≥ 8 days/month) or chronic migraine (CM), with ≥ 3 prior therapeutic failures, treated with any anti-CGRP mAbs for ≥ 48 weeks. We defined responders patients with a ≥ 50% response rate ≤ 12 weeks, late responders those with a ≥ 50% response rate ≤ 24 weeks, and ultra-late responders those achieving a ≥ 50% response only > 24 weeks. RESULTS: A total of 572 migraine patients completed ≥ 48 weeks of anti-CGRP mAbs treatment. Responders accounted for 60.5% (346/572), late responders for 15% (86/572), and ultra-late responders for 15.7% (90/572). Among ultra-late responders, 7.3% (42/572) maintained the ≥ 50% response rate across all subsequent time intervals (weeks 28, 32, 36, 40, 44, and 48) and were considered persistent ultra-late responders, while 8.4% (48/572) missed the ≥ 50% response rate at ≥ 1 subsequent time interval and were classified as fluctuating ultra-late responders. Fifty patients (8.7%) did not respond at any time interval ≤ 48 weeks. Ultra-late responders differed from responders for higher BMI (p = 0.033), longer duration of medication overuse (p < 0.001), lower NRS (p = 0.017) and HIT-6 scores (p = 0.002), higher frequency of dopaminergic symptoms (p = 0.002), less common unilateral pain-either alone (p = 0.010) or in combination with UAS (p = 0.023), allodynia (p = 0.043), or UAS and allodynia (p = 0.012)-a higher number of comorbidities (p = 0.012), psychiatric comorbidities (p = 0.010) and a higher proportion of patients with ≥ 1 comorbidity (p = 0.020). CONCLUSION: Two-thirds of patients not responding to anti-CGRP mAbs ≤ 24 weeks do respond later, while non-responders ≤ 48 weeks are quite rare (8.7%). These findings suggest to rethink the duration of migraine prophylaxis and the definition of resistant and refractory migraine, currently based on the response after 2-3 months of treatment.

External trigeminal neurostimulation in patients with chronic migraine.

Aim: To assess the safety and efficacy of external trigeminal neurostimulation (e-TNS) as an add-on treatment in chronic migraine (CM) prophylaxis. Materials & methods: A prospective observational open-label study was conducted on CM patients observed at baseline and 3 months after starting daily sessions of 20 min with e-TNS (Cefaly®). Results: A total of 24 volunteers affected by CM according to the ICHD-3 were included. At the 3 month follow-up, a >30% reduction of headache days was observed in four (16.5%) of 24 patients; a marginal headache improvement was observed in ten (42%) patients, with no or minor adverse effects (four of 24 patients). Conclusion: e-TNS may constitute a safe preventive treatment in CM, its limited efficacy is not statistically significant.

Migraine is one of the most prevalent and disabling diseases in the world. In chronic migraine cases, patients have headache ≥15 days/month, of which at least eight are migraines, for >3 months and often develop a medication overuse headache because of the excessive intake of drugs. Preventive therapies include, among others, peripheral nerve stimulation. In our study, 24 patients affected by chronic migraine were asked to use a peripheral nerve stimulation device (Cefaly^®) for 20 min daily for 3 months. During this period, we evaluated the efficacy and safety of the treatment using specific headache diaries in which patients collect information about their symptoms and disability. Our results show a limited and not statistically significant reduction in headache days in a group of patients ('responders') without serious adverse reactions.

Acute confusional state in HaNDL syndrome.

OBJECTIVE: To assess epidemiological, clinical and neuroimaging features of acute confusional state in the Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) syndrome. BACKGROUND: HaNDL is an increasingly recognized syndrome in which migraine-like headache episodes accompanied by hemiparaesthesia and/or hemiparesis and/or dysphasia are associated to CSF lymphocytic pleocytosis. The International Classification of Headache Disorders (ICHD-3) includes HaNDL syndrome in group 7 "headache attributed to non-vascular intracranial disorder" code 7.3.5, and lists the HaNDL-associated signs/symptoms that may be found less frequently. Confusional state is not mentioned in the 7.3.5-ICHD-3 "notes" or "comments" section as part of the HaNDL neurological spectrum. Moreover, the acute confusional state pathogenesis in HaNDL syndrome remains still uncertain and debated. METHODS: Here, we report a 32-year-old male who complained episodes of migraine-like headache and left hemiparaesthesia complicated by confusional state which led to discovering CSF lymphocytosis. Since other workup to determine the cause of his symptoms was otherwise negative, he was diagnosed as having HaNDL syndrome. We also ascertained and reviewed all available reports of HaNDL to assess the significance of confusional state in this syndrome. RESULTS: The search yielded 159 HaNDL cases among single reports and small/large series. Out of 159 patients who fulfilled the inclusion criteria for HaNDL according to the current ICHD at the time of diagnosis, 41 (25.7%) presented with acute confusional state. Among 41 HaNDL patients with confusional state, 16 (66.6%) out of 24 who underwent spinal tap had increased opening pressure. CONCLUSION: We propose that a mention of acute confusional state may be included in the "comments" section of "7.3.5-syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL)," when ICHD-3 diagnostic criteria will be updated. Moreover, we speculate that intracranial hypertension may play a role in the pathogenesis of the acute confusional state associated to HaNDL syndrome. Larger case series are needed to evaluate this hypothesis.

Acute confusional migraine in CADASIL: A case report and literature review.

BACKGROUND: Acute confusional state associated with migraine in adults is an infrequent entity. Around 30-60% of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients get affected by migraine attacks-the majority with aura-often as the first symptom of the disease. Acute confusional state during migraine has been rarely described in CADASIL patients and a complete neuropsychological assessment during the acute phase has never been conducted so far. CASE SUMMARY: We here describe the clinical and neuropsychological features of two distinct episodes of ACM in a 54-year-old female with CADASIL. EEG recording during acute confusional migraine and after attack resolution and neuroimaging has been reported. DISCUSSION AND LITERATURE REVIEW: This paper also reports a literature review on the topic of ACM in CADASIL highlighting a lack of adequate knowledge about this entity among clinicians and prompting further larger studies to explore its incidence and characteristics.

Cerebral venous thrombosis in spontaneous intracranial hypotension: A report of 8 cases and review of the literature.

BACKGROUND: The occurrence of cerebral venous thrombosis (CVT) in patients with spontaneous intracranial hypotension (SIH) raises difficult practical questions regarding the management of the two conditions. The first-line therapy for CVT is anticoagulation (AC); however, its potential benefit in SIH/CVT patients, especially if complicated by subdural haematoma, must be carefully evaluated taking account of the intracranial haemorrhage risk. Venous system recanalization and good prognosis in SIH/CVT patients treated with epidural blood patch (EBP), the main treatment option for SIH, have been already described. METHODS: We reviewed our cases of SIH complicated by CVT among a cohort of 445 SIH patients observed and treated during the last years. All published case reports and case series reporting patients with SIH and CVT were also ascertained and reviewed. RESULTS: Eight (2%) out of 445 patients suffering with SIH, were also diagnosed with CVT. All patients observed had orthostatic headache, three of them experienced a change in their headache pattern over the SIH course. Six out of eight patients received both AC and EBP treatments. Two patients were treated using only AC or EBP. A bilateral subdural haematoma enlargement after 1 month of AC was observed in one case. Complete CVT recanalization after treatment was obtained in three patients, including two with multiple CVT at baseline; partial CVT recanalization was achieved in two patients. Three patients experienced no CVT recanalization. After 6-48 months' follow-up all patients were still asymptomatic. CONCLUSIONS: The use of AC therapy should be weighed against the intracranial haemorrage risk and should be monitored carefully if initiated. Effective and prompt EBP, even without AC therapy, might lead to a good prognosis in selected cases.

Facemask headache: a new nosographic entity among healthcare providers in COVID-19 era.

BACKGROUND: SARS-CoV-2 is a novel infectious agent causing coronavirus disease 2019, which has been declared as pandemic in March 2020. Personal protective equipment has been mandatory for healthcare workers in order to contain the outbreak of pandemic disease. Mild neurological disturbances such as headache have been related to the extensive utilization of facemask. This study aims to examine headache variations related to the intensive utilization of facemask among a cohort of healthcare professionals in a setting of low-medium risk of exposure to SARS-CoV-2. METHODS: This is a cross-sectional study among healthcare providers from different hospital and clinics in Italy. Each participant completed a specifically designed self-administered questionnaire. Headache features and outcome measures' change from baseline were evaluated over a 4-month period, in which wearing facemask has become mandatory for Italian healthcare workers. RESULTS: A total of 400 healthcare providers completed the questionnaire, 383 of them met the inclusion criteria. The majority were doctors, with a mean age of 33.4 ± 9.2 years old. Among 166/383 subjects, who were headache free at baseline, 44 (26.5%) developed de novo headache. Furthermore, 217/383 reported a previous diagnosis of primary headache disorder: 137 were affected by migraine and 80 had tension-type headache. A proportion (31.3%) of these primary headache sufferers experienced worsening of their pre-existing headache disorder, mainly for migraine frequency and attack mean duration. CONCLUSIONS: Our data showed the appearance of de novo associated facemask headache in previous headache-free subjects and an exacerbation of pre-existing primary headache disorders, mostly experienced by people with migraine disease.

Late-Onset Ictal Asystole and Falls Related to Severe Coronary Artery Stenosis: A Case Report.

Introduction: Ictal asystole (IA) is a rare, underestimated, and life-threatening cause of transient loss of consciousness and fall. Current treatment options for seizures associated with IA usually include cardiac pacemaker implantation. We report, for the first time, a case of IA that is related to coronary stenosis, which was resolved after coronary angioplasty. Case Presentation: A 73-year-old man had a 2-year history of focal seizures with impaired awareness. Three months before our observation, he started to have sudden falls resulting in injury on several occasions. General and neurological examinations, as well as brain MRI, were unremarkable. Interictal electroencephalography (EEG) showed bitemporal spiking. Ictal video-polygraphy revealed a diffuse electrodecrement, followed by a buildup of rhythmic 4-6 Hz sharp activity, which was more evident in the left temporal region. After the seizure onset, the ECG showed sinus bradycardia, followed by sinus arrest that was associated with the patient's fall from the standing position. Afterwards, sinus rhythm returned spontaneously. A diagnosis of IA was made. A comprehensive cardiologic evaluation revealed a sub-occlusive stenosis of the left anterior descending artery. Successful coronary angioplasty resolved IA, levetiracetam was added, and no seizure or fall has occurred in the following 20 months. Moreover, he underwent a 7-day Holter ECG monitoring, and no asystole was depicted. Conclusion: The present case was unique as it shows the potential association between IA and coronary stenosis, also suggesting a possible therapeutic role for coronary angioplasty. It also highlights the importance of carefully investigating epilepsy patients with falls, especially in the elderly, since IA-related falls can be easily misdiagnosed in older age. Thus, if IA is identified, a deeper cardiac evaluation should be considered. As seen in our patient, non-invasive diagnostic examination including routine, prolonged, and exercise ECG, as well as echocardiogram, were readily available and were informative in diagnosing cardiac abnormalities that are amenable to specific treatment.

Objective bilateral tinnitus from palatal nystagmus. Audio and video features of a rare case of palatal myoclonus.

Tinnitus is one of the most represented otological symptom, affecting 15% of adults, worldwide. Literature describes subjective tinnitus when it's perceived by the patient only, and objective tinnitus when it's heard both, by patient and examiner. An objective tinnitus can be caused by a large variety of anomalies and diseases; one of them is Palatal Myoclonus, characterized by rhytmic movements of soft palatal muscles and, only occasionally, involving other near districts. Case presentation. We observed a rare case of essential palatal myoclonus in a 54 y.o. female, suffering from chronic objective bilateral tinnitus, since 35 years, who underwent a wide number of clinical evaluations over the years, without receiving any conclusive diagnosis. In this video, we illustrate all the districts involved in clonic movements: soft palate, larynx and nasal wings. At the same time, we report the spectrographic analysis of tinnitus, recorded in esternal ear canal, taken together with the muscle movements. Palatal Myoclonus has to be considered in the etiological diagnosis of each objective tinnitus and should always be investigated properly.

Management of Spontaneous Intracranial Hypotension During Pregnancy: A Case Series.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is a rare condition resulting from cerebrospinal fluid (CSF) volume depletion, nearly always from spontaneous CSF leaks. CSF pressure in SIH is usually normal; low CSF pressure is found in a substantial minority of patients. SIH is uncommonly described in pregnancy. CASE SERIES: Five women with SIH during pregnancy have been conservatively treated adopting bed rest and overhydration. After prolonged conservative treatment, only 1 patient showed complete symptoms resolution. A rare SIH complication as cerebral venous thrombosis has been reported in 1 case. All 4 remaining patients had lumbar epidural blood patch (EBP) with symptoms disappearance. CONCLUSIONS: EBP might be proposed to SIH patients also during pregnancy and after a brief period (~10 days) of ineffective conservative treatment, because it could allow faster symptoms improvement and complete recovery. Furthermore, EBP would avoid prolonged bed rest with the risk of SIH severe complications.

Looking for indicative magnetic resonance imaging signs of hippocampal developmental abnormalities in patients with mesial temporal lobe epilepsy and healthy controls.

OBJECTIVE: To evaluate the frequency of qualitative features for hippocampal developmental abnormalities (HiDeA) definition on magnetic resonance imaging (MRI) in mesial temporal lobe epilepsy (MTLE) patients and healthy controls, highlighting which were more sensitive and specific to the epileptic syndrome. METHODS: We enrolled 93 healthy controls and 187 MTLE patients. Among patients, 133 were MRI-negative and 54 had hippocampal sclerosis (HS). Two blinded, trained investigators defined HiDeA if three signs were present, including at least one of the following: (1) globular hippocampal shape (HCS), (2) verticalized collateral sulcus, and (3) medial positioning of hippocampus (HCP). After evaluating the prevalence of HiDeA in MTLE and controls, we assessed the frequency of each sign. Then, we classified differences in type or number of HiDeA diagnostic features, calculating their sensitivity and specificity. Fisher exact test was used to assess statistical significance. RESULTS: HiDeA was detected in 36 of 187 MTLE cases (19.25%) and in eight of 93 (8.6%) controls. In particular, HiDeA was present in 25 of 133 (18.8%) patients with MRI-negative MTLE. Among all visual criteria here considered, HCS showed higher sensitivity both in the MRI-negative MTLE group (88%) and in the HS-MTLE group (91%). HCP, thickened subiculum, and reduction of the upper horizontal portion of the parahippocampal gyrus (HCTH) signs demonstrated a 100% specificity in both groups. In healthy controls, HCS was confirmed to have the highest sensitivity (100%), whereas HCP showed the highest specificity (98.8%). All these criteria were statistically associated with HiDeA. Electroencephalographic focus was concordant with the HiDeA side in 52.2% of MTLE patients. An association was not found among signs of HiDeA and treatment responsiveness. SIGNIFICANCE: We identified characteristic signs of HiDeA, such as HCTH or HCP, differentiating HiDeA features between MTLE and healthy controls. The identification of sensitive and, more importantly, specific criteria of HiDeA could be helpful to make a more confident visual diagnosis.

Spontaneous intracranial hypotension: review and expert opinion.

Spontaneous intracranial hypotension (SIH) results from spinal cerebrospinal fluid (CSF) leaking. An underlying connective tissue disorder that predisposes to weakness of the dura is implicated in spontaneous spinal CSF leaks. During the last decades, a much larger number of spontaneous cases are identified and a far broader clinical SIH spectrum is recognized. Orthostatic headache is the main presentation symptom of SIH; some patients also have other manifestations, mainly cochlear-vestibular signs and symptoms. Differential diagnosis with other syndromes presenting with orthostatic headache is crucial. Brain CT, brain MR, spine MRI, and MRI myelography are the imaging modalities of first choice for SIH diagnosis. Invasive imaging techniques, such as myelography, CT myelography, and radioisotopic cisternography, are progressively being abandoned. No randomized clinical trials have assessed the treatment of SIH. In a minority of cases, SIH resolved spontaneously or with only conservative treatment. If orthostatic headache persists after conservative treatment, a lumbar epidural blood patch (EBP) without previous leak identification (so-called "blind" EBP) is a widely used initial intervention and may be repeated several times. If EBPs fail, after the CSF leak sites identification using invasive imaging techniques, other therapeutic approaches include: a targeted epidural patch, surgical reduction of dural sac volume, or direct surgical closure. The prognosis is generally good after intervention, but serious complications may occur. More research is needed to better understand SIH pathophysiology to refine imaging modalities and treatment approaches and to evaluate clinical outcomes.