Osmophobia in allodynic migraineurs: cause or consequence of central sensitization?

Migraine is a primary headache characterized by recurrent attacks of head pain associated with nausea or vomit, photophobia, phonophobia and osmophobia. The presence of osmophobia during migraine attacks seems to be a very specific complaint. Cutaneous allodynia (CA) is very common in migraineurs, and it is the most evident clinical manifestation of central sensitization, a mechanism involved in migraine chronification. This study was aimed at identifying the possible correlation between osmophobia and CA in migraineurs. 673 migraineurs were studied (492 episodic, 181 chronic). The prevalence of both CA and osmophobia was higher in chronic than in episodic migraineurs. The association between these two symptoms was significant in chronic migraineurs at Chi square test. The highlighted relationship between CA and osmophobia may be interpreted in different ways: central sensitization induced by recurrent pain stimulation may in parallel induce a distortion of both cutaneous sensitivity (CA) and olfaction (osmophobia); alternatively, the recurrent olfactory stimulation in subjects with a hypersensitivity to olfactory stimuli may co-work with repetitive pain stimulation to induce the central sensitization process.

Prevalence and profile of obsessive-compulsive trait in patients with chronic migraine and medication overuse.

Patients with chronic migraine (CM) and medication overuse headache (MOH) have high frequency of psychiatric comorbidity or psychopathological traits, the presence of which can influence the clinical course. The presence of subclinical obsessive compulsive disorder (OCD) is underestimated in migraine patients. The aim of this study was to estimate the prevalence and profile of obsessive-compulsive (OBS) trait in a sample of CM patients with MOH using the OBS questionnaire of Spectrum Collaborative Project. According to the new international classification of headache disorders (ICHD-III beta) criteria, 106 patients (15 M, 91 F, mean age 47.3 years) were selected in a consecutive clinical series. Our results showed that 36 % of patients with CM and MOH were positive at OBS-questionnaire. As far as the profile of OBS trait, we performed an evaluation of prevalence of items separating the first part of the questionnaire (childhood/adolescence and doubts in lifetime) from the other five domains: 21 % of the patients showed prevalence of items in childhood/adolescence domain; 79 % in doubts in lifetime domain; as for other five domains, 10.5 % of patients had prevalence of pathological answers among hypercontrol, 5.2 % in spending time, 23.7 % in perfectionism, 29 % in repetition and automation, and 31.5 % in specific themes (obsessive thoughts). The presence of subclinical OCD in migraine patients, and the link between progression to CM, particularly through MO, and OBS trait is still not well defined. The use of specific tools to assess this possible comorbidity should be encouraged in clinical and research settings.

Is the brain of migraineurs "different" even in dreams?

Migraineurs brain is hyper-excitable and hypo-metabolic. Dreaming is a mental state characterized by hallucinatory features in which imagery, emotion, motor skills and memory are created de novo. To evaluate dreams in different kinds of headache. We included 219 controls; 148 migraineurs (66 with aura-MA, 82 without aura-MO); 45 tension type headache (TTH) patients. ICHD-II diagnostic criteria were used. Ad hoc questionnaire was used to evaluate oneiric activity. The Generalized Anxiety Disorder Questionnaire, and the Patient Health Questionnaire were administered to evaluate anxiety and mood. The prevalence of dreamers was similar in different groups. Frequency of visual and auditory dreams was not different between groups. Migraineurs, particularly MA, had an increased frequency of taste dreams (present in 19.6 % of controls, 40.9 % of MA, 23.2 % of MO, 11.1 % of TTH, p < 0.01), and of olfactory dreams (present in 20 % of controls, 36 % of MA, 35 % of MO and 20 % of TTH, p < 0.01). Anxiety and mood did not influence these results. The increased frequency of taste and olfactory dreams among migraineurs seems to be specific, possibly reflecting a particular sensitivity of gustative and olfactory brain structures, as suggested by osmofobia and nausea, typical of migraine. This may suggest the role of some cerebral structures, such as amygdala and hypothalamus, which are known to be involved in migraine mechanisms as well in the biology of sleep and dreaming.

Blood pressure during nocturnal sleep in headache.

AIM: Interactions between blood pressure control, sleep and headache have been largely studied, although not well understood. We designed a study trying to simultaneously evaluate all three aspects in the same subjects. We particularly concentrated on the observation of physiological blood pressure circadian rhythm, and the presence of cutaneous allodynia correlated to headache. Objective of the study was to investigate blood pressure during nocturnal sleep in patients that underwent a blood pressure 24 hours monitoring, and at the same time the presence of headache and of sleep behavioural alterations. METHODS: Blood pressure 24 hours monitoring was performed by an ambulatory blood pressure (ABP) monitor (Space Labs) with its ad hoc software. Headache diagnosis was made according to ICHD-II criteria. Presence of allodynia and sleep behavior were evaluated through semi-structured ad hoc questionnaires. RESULTS: A total of 195 subjects were included, of which 122 without headache (mean age 60.4±11.6 years, 78 men and 44 women) and 73 with history of headache, (mean age 54.2±12.5 years, 18 men and 55 women). Fifty-one headache patients had migraine (mean age 52.6±11.7 years, 11 men and 40 women) and 22 tension type headache (TTH - mean age 58.0±13.5 years, 7 men and 15 women). Allodynia was found in 30 out of 73 headache patients: 23 out of 51 in the migraine group and in 7 out of 22 in the tension-type one. The physiological reduction of blood pressure during night (dipping) was more conserved among headache patients (34 dippers out of 73 subjects, 46,6%) with respect to subjects without headache (40 dippers out of 122, 32,8%) and that this border-line difference was more strongly significant comparing allodynic subjects (19 dippers out of 30, 63.3%) with both non-headache (40 dippers out of 122, 32.8%, P<0.001) and non-allodynic (15 out of 43, 34.9%, P<0.05) ones. No significant difference was observed between headache patients and subjects without headache in terms of mean systolic and diastolic pressure, neither between migraine and TTH. CONCLUSION: Allodynic headache patients seem to maintain a more physiologic pressure circadian rhythm. While considering the possibility of selection bias, the hypothesis of an allostatic function of headache and allodynia in patients with unbalanced blood pressure could be made.

Possible correlations between blood pressure, primary headaches and cutaneous allodynia.

Following an allostatic perspective, episodic migraine (M) may be considered as an adaptive behavioural response to endogenous or exogenous stressors, while its progression to a daily or nearly daily form (chronic migraine) may represent the failure of adaptive strategies. Multiple factors may enhance the progression/chronification of M, and among these the presence of cutaneous allodynia (CA) as well as alterations in blood pressure and in sleep. The working hypothesis of the study was that subjects with M, and particularly those with CA, could show a tendency towards high blood pressure levels and/or to alterations in the circadian rhythm of blood pressure. We studied 235 subjects consecutively attending a centre for blood pressure control for a blood pressure 24 h monitoring. Headache diagnosis was made according to the ICHD-II criteria. The presence of CA was evaluated through a semi-structured ad hoc questionnaire. Blood pressure 24 h monitoring was performed by an ambulatory blood pressure monitor (Space Labs) with its ad hoc software. Seventy-eight subjects had a history of headache (mean age 54.0 ± 12.4 years, 18 men and 60 women); 56 of them had M, 22 had tension-type headache; among them, CA was found in 24/56 subjects with M, and in 6/22 with tension-type headache; 157 subjects did not suffer from headache (mean age 60.5 ± 11.5 years, 99 men and 58 women). No significant difference was observed between headache subjects and subjects without headache in terms of mean systolic and diastolic pressure, neither in the M nor in tension-type subgroups. With regard to the circadian rhythm of blood pressure, the physiological reduction during night (dipping) was more evident among headache subjects than in subjects without headache; this border-line difference was more strongly significant in subjects with CA than both non-headache (p = 0.003) and non-CA (p = 0.05) ones. The difference between allodynic and non-allodynic subjects was present also in the M sub-group (7 dippers out of 32 non-allodynic migraineurs vs. 12 dippers out of 24 allodynic migraineurs, p = 0.03) notwithstanding the reduction of the sample size. Despite the initial hypothesis, subjects with primary headaches did not show differences in terms of mean blood pressure values and they showed a more physiologic blood pressure daily rhythm than those without headaches. Also the presence of CA, a marker of progression to chronic headache forms, was associated neither with hypertension nor with increased frequency of loss of dipping. M, particularly when associated with allodynia, may improve breathing during nocturnal sleep and consequently counteract possible blood pressure alterations, suggesting an allostatic function of allodynic headache.

Chilblain-like lesions (COVID-19 toes) have the same impact on family members than psoriasis systemically treated: insights from a case-control study targeting the pediatric population.

OBJECTIVE: COVID-19 toes represent the main dermatological COVID-19 cutaneous manifestation in pediatric patients. Its diagnosis exposes the whole family to social stigma and this aspect was not previously evaluated. PATIENTS AND METHODS: This was a multicenter, case-control, observational study that compared the family impact of COVID-19 toes vs. psoriasis (PsO). We enrolled 46 pediatric patients (23 with psoriasis and 23 with COVID-19 toes, age and gender matched) and their parents/caregivers that had to fill the Dermatitis Family Impact (DFI) questionnaire. RESULTS: DFI index did not differ significantly between both subgroups (p=0.48), and in psoriatic patients did not correlate with both Psoriasis Area Severity Index (PASI) (p=0.59) and itch-VAS (p=0.16). CONCLUSIONS: COVID-19 toes, a transitory dermatosis, exerted a similar impact/perturbation on family dynamics than PsO, a well-known stigmatizing, chronic inflammatory dermatosis.

Possible relationships between headache-allodynia and nocturnal sleep breathing.

Sleep and headache are linked in a bidirectional way. Breathing quality during sleep may be a possible link between them. The objective of this study were to evaluate the prevalence of headache--and of allodynia--in a population of subjects who underwent cardiopulmonary monitoring during sleep for presumed respiratory problems; to evaluate the possible relationships between the presence of headaches--and of allodynia--and respiratory parameters. We studied 181 subjects, 112 without headache (mean age 59.4 ± 13.1 years, 97 men and 15 women); 69 with history of headache (42 men and 27 women; 41 migraineurs and 28 with tension type headache). Headache diagnosis was made according to ICHD-II criteria. A semi-structured ad hoc questionnaire was used to evaluate the presence of allodynia. Full cardiopulmonary monitoring was performed by SOMNO check(®) effort (WEINMANN) with SaO(2), T90 and AHI determination. Headache and headache-associated allodynia were particularly frequent in this population, suggesting a positive correlation between breathing problems during sleep and head pain, and allodynia. The observation that better respiratory parameters were found among headache sufferers with respect to those without headache, even in allodynic subjects, seems to reverse this point of view: headache and allodynia may possibly have an allostatic function preventing deep sleep and, in turn, avoiding prolonged apneas.

Undertreatment in patients with primary headaches attending headache centres.

Undertreatment in patients with primary headaches was evaluated in 600 patients attending 7 headache centres in Lombardy by assessing the rates of acute and prophylactic treatments used before the first visit and the rates of prescription of acute and prophylactic treatments after the visit at the headache centre. Our results clearly showed that most headache patients are likely to receive suboptimal treatments, confirming the utility of headache centres as well as the need for promoting education of GPs and the development of appropriate networks to reduce undertreatment rates, in order to highlight the negative impact caused by primary headache on individuals and on the society.

Correlation between presence of allodynia and sleep quality in migraineurs.

Cutaneous allodynia is a frequent complaint in migraine patients, possibly induced by central sensitisation of trigeminal nucleus. The objective of this study is to investigate if sleep quality is related to the presence of migraine-associated allodynia. A total of 175 consecutive migraineurs were included, 124 with episodic and 51 with chronic forms. As control group, 73 subjects free from any kind of headache were included (HC). The presence of allodynia and sleep disturbances was assessed by a set of semi-structured questions. Chi-square test was applied to compare frequencies among groups. Sleep quality was worse among migraineurs with respect to controls for each sleep item analysed. This difference was significant for all items but one (i.e. frequency in drug use to induce sleep). The frequency of sleep disturbances was higher than in controls in both allodynic and non-allodynic migraineurs, although statistical analysis showed that all these differences were still significant in allodynic migraineurs (also in this case for all the sleep items but one, i.e. frequency in drug use to induce sleep), whilst non-allodynic migraineurs were significantly different from controls only for one item (frequency of initial insomnia). These results suggest that allodynia is strongly related to sleep quality, in a bi-directional way: sleep disturbances may favour central sensitisation, and, in turn, allodynia may impair sleep.

Underdiagnosis of primary headaches: results of a survey on patients attending headache centres.

Underdiagnosis of primary headaches was evaluated in 504 patients attending six Headache Centres in Lombardy. We found high figures of missed diagnoses (no diagnosis of a specific headache form), and of misdiagnosis (non-concordance between previous diagnoses made by the GP and the final diagnoses given by the headache specialist). We note that underdiagnosis in headache patients may have negative consequences, enhancing the risk of progressive worsening of primary headache syndromes, increasing their impact on individuals and on society, and favouring medication overuse.

Neuronal nitric oxide synthase C276T polymorphism increases the risk for frontotemporal lobar degeneration.

The neuronal nitric oxide synthase (nNOS) is abundantly expressed in the brain and its transcripts have been found in the frontal cerebral cortex. Eighty-nine patients with different neurodegenerative tau-related disorders, including 71 patients with frontotemporal lobar degeneration (FTLD), 12 with progressive supranuclear palsy (PSP) and 6 with corticobasal degeneration (CBD), were genotyped for the C276T single nucleotide polymorphism (SNP) in exon 29 of the nNOS gene and compared with 190 age-matched controls (CON). A significantly increased allelic frequency of the T allele was observed in patients compared with CON (40.4% vs. 29.7%, P = 0.014, OR: 1.94, CI: 1.15-3.27). Considering each disorder separately, significance was reached for FTLD only (39.4%, P = 0.0248 versus controls, OR: 1.96, CI: 1.11-3.47). However, the frequency of the T allele was elevated also in patients with PSP (45.8%) and CBD (41.7%). No differences were observed stratifying according to gender or apolipoprotein E status. The C276T SNP acts as risk factor for sporadic FTLD, possibly influencing NOS1 transcription. Studies in larger populations are needed to confirm its role in PSP and CBD.

CXCL10 haplotypes and multiple sclerosis: association and correlation with clinical course.

CXCL10 (interferon-gamma-inducible protein-10) levels are increased in cerebrospinal fluid of multiple sclerosis (MS) patients with symptomatic attacks of inflammatory demyelination, supporting a role for this molecule in MS pathogenesis. Two hundred and twenty-six patients with MS and 235 controls were genotyped for G --> C and T --> C single nucleotide polymorphisms (SNPs) in exon 4 of CXCL10 gene. Haplotypes were tested for association and correlated with clinical variables. The two SNPs studied were in complete linkage disequilibrium. None of the determined haplotypes was associated with MS. However, carriers of the GGTT haplotype (defined as wild type, according to the sequence in National Centre for Biotechnology Information (NCBI) database) had a significantly lower progression index than non-carriers (P = 0.016). Furthermore, amongst patients who had an initial relapsing remitting (RR) course of the disease, the time between onset and second episode was significantly longer in GGTT carriers (P = 0.021). Considering secondary progressive (SP)-MS patients, the time between the initial RR form and the subsequent worsening to SP was longer in this group (P = 0.08). Therefore, the GGTT haplotype of the CXCL10 gene is not a susceptibility factor for the development of MS, but is probably to influence the course of MS, possibly contributing to slow down the progression of the disease.

[Hexadactylism of the four limbs: a case report]. / Esadattilia dei quattro arti: un insolito caso.

An unusual case of postaxial hexadactylism of the hands and feet in one female Caucasian neonate is described. The clinical picture was characterized by symmetrical duplication of the 5th finger in both hands and of the 4th finger in both feet. Malformations of the extremities both in the paternal and in the maternal family were reported. No other associated malformations have been found in the baby and her karyotype was normal. The performed analysis of the literature confirmed the peculiarity of the associated features of this case.

Episodes of flushing, dyspnea and hypertension after carotid stenting for severe carotid stenosis.

INTRODUCTION: Carotid angioplasty and stenting (CAS) is a treatment option for carotid stenosis in high surgical risk patients. As it implies instrumentation of the carotid bulb, baroreceptors dysfunction may be provoked with consequent hemodynamic instability. REPORT: An 83-year-old woman treated by CAS presented with episodes of flushing, dyspnea and palpitations accompanied by transitory desaturation, hypertension, agitation and anxiety. Symptoms started 12h after the procedure. Each episode lasted 10 min. Five episodes in 3 days were observed. DISCUSSION: A dysfunction of the carotid baroreceptors and chemoreceptors was hypothesized.

Childhood rhabdomyosarcoma with meningeal extension: results of combined therapy including central nervous system prophylaxis.

Results achieved in two consecutive series of children with rhabdomyosarcoma (RMSA) of the head and neck area, presenting with meningeal involvement, are compared. The first series consisted of 12 children treated with local radiotherapy and with (mostly) polidrug systemic chemotherapy from 1969 to 1977. The second series consisted of 11 children who, besides local radiotherapy and polichemotherapy, received brain radiotherapy (30 Gy) and intrathecal (I.T.) methotrexate (MTX) as central nervous system (CNS) prophylaxis from 1978 to 1980. In the first group, 50% of patients achieved a complete remission and only one child (8%) is surviving relapse-free. In the second group, 91% of patients achieved a complete remission and seven (64%) are surviving relapse-free after a median follow-up of 32 months. The most important reason for failure in the first series was represented by the inability to achieve a persistent local control of the primary tumor. This observation and the higher doses of radiotherapy delivered to the primary tumor in the second series prevent the conclusion that the improved results are attributable entirely to the addition of CNS prophylaxis.

Negative emotions in migraineurs dreams: the increased prevalence of oneiric fear and anguish, unrelated to mood disorders.

BACKGROUND: Migraineurs brain has shown some functional peculiarities that reflect not only in phonophobia, and photophobia, but also in mood and sleep. Dreaming is a universal mental state characterized by hallucinatory features in which imagery, emotion, motor skills, and memory are created de novo. We evaluated dream contents and associated emotions in migraineurs. MATERIALS AND METHODS: 412 subjects: 219 controls; and 148 migraineurs (66 with aura, MA; 82 without aura, MO), and 45 tension type headache patients (TTH). A semistructured retrospective self-reported questionnaire was used to evaluate dreams. The Generalized Anxiety Disorder Questionnaire (GAD-7), and the Patient Health Questionnaire (PHQ-9) were administered to evaluate anxiety and depression. RESULTS: Migraineurs showed increased levels of anxiety (P = 0.0002 for MA versus controls, P = 0.004 for MO versus controls). Fear and anguish during dreaming were more frequently reported by migraine patients compared to controls, independently by anxiety and depression scores. DISCUSSION: The brain of migraineurs seems to dream with some peculiar features, all with a negative connotation, as fear and anguish. It may be due to the recorded negative sensations induced by recurrent migraine pain, but it may just reflect a peculiar attitude of the mesolimbic structures of migraineurs brain, activated in both dreaming and migraine attacks.

Novel and recurrent spastin mutations in a large series of SPG4 Italian families.

BACKGROUND: Hereditary spastic paraplegias (HSP) are heterogeneous neurodegenerative disorders, genetically classified according to the identified disease gene or locus. Clinically, HSP are distinguished in pure and complicated forms. Mutations in the spastin gene (SPAST) are responsible for SPG4 and account approximately for 50% of the dominantly inherited paraplegias with a pure HSP phenotype. METHODS: Molecular screening of the SPAST gene allowed the identification of 31 Italian mutation carriers, from 19 unrelated families. Genetic testing was performed by direct sequencing and multiplex ligation-dependent probe amplification. Subjects carrying SPAST mutations were retrospectively evaluated for clinical phenotype and disability score assessment. RESULTS: We found 12 recurrent mutations, and 7 novel SPAST mutations. Twenty-eight patients exhibited a pure spastic paraplegia phenotype, while 3 subjects were asymptomatic mutation carriers. Four patients were sporadic cases. Age at onset ranged from 10 to 61 years. Disability score increased with age at examination and disease duration. Patients with onset >38 years presented a faster disease progression, and a higher disability functional index, than the patients with earlier onset (p<0.04). CONCLUSIONS: Our study enlarges the number of pathogenic SPAST mutations, and confirms the association with a pure spastic paraplegia phenotype. Age at onset was highly variable and correlates with the rate of disease progression. Future longitudinal clinical studies are needed to confirm these observations.