Reinaldo Teixeira Ribeiro

Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man

Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs(∗)17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.

Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention

Introduction Melatonin has been studied in headache disorders. Amitriptyline is efficacious for migraine prevention, but its unfavourable side effect profile limits its use. Methods A randomised, double-blind, placebo-controlled study was carried out. Men and women, aged 18–65 years, with migraine with or without aura, experiencing 2–8 attacks per month, were enrolled. After a 4-week baseline phase, 196 participants were randomised to placebo, amitriptyline 25 mg or melatonin 3 mg, and 178 took a study medication and were followed for 3 months (12 weeks). The primary outcome was the number of migraine headache days per month at baseline versus last month. Secondary end points were responder rate, migraine intensity, duration and analgesic use. Tolerability was also compared between groups. Results Mean headache frequency reduction was 2.7 migraine headache days in the melatonin group, 2.2 for amitriptyline and 1.1 for placebo. Melatonin significantly reduced headache frequency compared with placebo (p=0.009), but not to amitriptyline (p=0.19). Melatonin was superior to amitriptyline in the percentage of patients with a greater than 50% reduction in migraine frequency. Melatonin was better tolerated than amitriptyline. Weight loss was found in the melatonin group, a slight weight gain in placebo and significantly for amitriptyline users. Conclusions Melatonin 3 mg is better than placebo for migraine prevention, more tolerable than amitriptyline and as effective as amitriptyline 25 mg.

Trigeminal sensory neuropathy associated with systemic sclerosis: report of three Brazilian cases

Dr. Reinaldo Teixeira Ribeiro – Rua Borges Lagoa 71 / 93 04038-030 São Paulo SP Brasil. E-mail: reinaldo_ribeiro@yahoo.com.br Systemic sclerosis (SSc) is a connective tissue disease manifest by fibrotic tissue changes, microvascular disease, and autoimmune abnormalities. The prevalence of different neurological manifestations in SSc has ranged from 0.8% to 18.5% according to the adopted criteria. Trigeminal sensory neuropathy (TSN) causes numbness in the mandibular or maxillary divisions of the nerve in about 2/3 of the cases, and in the distribution of all divisions in the remaining cases. The sensory abnormalities evolve slowly and usually spread contralaterally in an asymmetric pattern. The numbness may be accompanied by burning dysesthesia that is distinct from trigeminal neuralgia. TSN is an infrequent complication of SSc. Although epidemiological studies are scarce, the prevalence of TSN associated with SSc in the largest series available was 4%. A fairly diligent review of the literature revealed no previous report of TSN as a complication of SSc in Brazil. We present three cases of such association.

Glossopharyngeal neuralgia with syncope as a sign of neck cancer recurrence

Glossopharyngeal neuralgia with syncope as a sign of neck cancer is a very rare condition. A review of the literature revealed only 29 cases formerly reported. We present the first Brazilian case of such association. A 68-year-old man presented with paroxysmal excruciating pain over the right side of the neck, sometimes followed by syncope. Given the suspicion of recurrent tumor from a previously treated neck malignancy, a computed tomography scan was performed and a right parapharyngeal tumor was shown. Pain and syncope were successfully controlled with carbamazepine and the patient underwent palliative radiotherapy.

Unbalanced plasma TNF-α and IL-12/IL-10 profile in women with migraine is associated with psychological and physiological outcomes

Increased plasma pro-inflammatory and decreased anti-inflammatory cytokines have been implicated in physiological and behavioural aspects of mood- and pain-related disorders, including migraine. In this case-control study, we assessed mood scores, cardiorespiratory fitness (VO2Peak), and plasma concentrations of TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-12p70 interictally in women with episodic migraine with/without aura (ICHD-II), taking no preventive medicine, and in healthy women recruited from São Paulo Hospital and local community, respectively. Thirty-seven participants (mean±SD age=34±10 and BMI=26.5±4.9) were assessed. Groups (Control, n=17; Migraine, n=20) showed no differences in age, BMI, and VO2Peak. Migraine patients showed higher tension (p=0.019) and anxiety scores (p=0.046), TNF-α (p<0.01), and IL-12p70 (p=0.01), while IL-6 (p<0.01), IL-8 (p<0.01), and IL-10 (p<0.01) were decreased compared to control group. Multiple linear regression models showed that migraine was positively associated with TNF-α and IL-12p70, and negatively associated with IL-6, IL-8, and IL-10. Anxiety scores were positively associated with IL-12p70, and VO2Peak was negatively associated with TNF-α. In conclusion, an exaggeratedly skewed cytokine profile, in particular the TNF-α and 12p70/IL-10 balance may be related to migraine pathomechanisms, and its psychiatric comorbidities and functional capacity. Additional studies are needed to confirm these results.

The first inborn error of manganese metabolism caused by mutations in SLC30A10, a newly identified manganese transporter

Abstract Background We have identified an autosomal recessively inherited disorder of manganese metabolism that causes manganese accumulation in liver and brain with characteristic MRI brain appearances of hyperintense basal ganglia on T1-weighted sequences. Most affected individuals present in childhood with difficulties walking and fine motor impairment due to dystonia. Movement disorder is accompanied by liver cirrhosis, and some patients have died at a young age following complications of cirrhosis. An adult-onset form of parkinsonism associated with hepatomegaly and hypermanganesaemia has also been described. Further characteristics of both phenotypes include polycythaemia and features of iron depletion. Methods Homozygosity mapping was performed using an Illumina CytoSNP-12. The candidate gene was sequenced on an ABI sequencer. Functional studies in the manganese-sensitive yeast strain Δpmr1 were performed using Gateway technology (Invitrogen). Findings Homozygosity mapping identified SLC30A10 as the affected gene, and homozygous sequence changes were found in all affected individuals. SLC30A10 had previously been presumed to belong to a class of zinc transporters. However, expression of human wildtype SLC30A10 in Δpmr1 rescued growth in high manganese conditions confirming its role in manganese transport. The presence of missense and nonsense mutations in SLC30A10 failed to restore manganese resistance. Interpretation Evidently, evolutionary changes in the aminoacid sequence have altered the substrate specificity of this transporter from zinc in yeast to manganese in mammalian cells. SLC30A10 is the first recognised human manganese transporter that, when defective, causes two distinct phenotypes—childhood onset dystonia and adult onset parkinsonism—that are associated with hepatic cirrhosis and polycythaemia. Present treatment strategies, including chelation therapy with disodium calcium edetate and iron supplementation, lead to significant improvement of clinical symptoms and blood manganese levels. Funding Action Medical Research.

Fatores associados ao uso excessivo de medicação sintomática em pacientes com enxaqueca crônica

OBJECTIVE To evaluate the prevalence of psychiatric disorders in patients diagnosed with chronic migraine with and without acute medication overuse. METHODS Seventy-two volunteers were recruited from a Family Health Program of the Paraisópolis community in São Paulo (SP), Brazil. These patients were submitted to a detailed headache questionnaire. All participants were submitted to physical and neurological examinations. The following variables were analyzed: age, gender, education level, body mass index, type of overused medication, headache characteristics, and caffeine consumption, lifetime anxiety and mood disorders. RESULTS Out of 72 patients, 50 (69%) had chronic migraine with medication overuse, and 22 (31%) had chronic migraine without medication overuse. Factors such as age, gender, education level, body mass index, type of overused medication, headache characteristics, and caffeine consumption were not significantly different between the two studied groups. Lifetime anxiety and mood disorders were more common in patients with acute medication overuse (p=0.003 and p=0.045, respectively). CONCLUSION This study has shown a significant association among chronic migraine and medication overuse with lifetime mood and anxiety disorders in patients of the studied population. No association was found for other researched psychiatric disorders.

Migrainous infarction as a complication of sporadic hemiplegic migraine in childhood

, migrain-ous infarction (MI) is a complication of migraine with aura. MI is diagnosed when one or more aura symptoms last longer than 60 minutes, and neuroradiological stud-ies demonstrate ischemic stroke that potentially explains the symptoms. Stroke should not be attributed to anoth-er disorder. The ICHD-II also defines sporadic hemiplegic migraine (SHM) as a subtype of migraine with aura asso-ciated with fully reversible motor weakness in association to the typical aura symptoms (visual, sensory or dyspha-sic aura). Unlike familial hemiplegic migraine (FHM), fa-milial history of migraine with motor weakness in first- or second-degree relatives is absent. MI in childhood is very rare and epidemiological studies are scarce

Prednisone in withdrawal therapy following medication overuse headache

Dear Sir We have read the article ‘Prednisone vs. placebo in withdrawal therapy following medication overuse headache’ by Pageler et al. in the February issue of Cephalalgia and found it extremely interesting (1). The basis of medication overuse headache treatment continues to be the interruption of all overused medications. The high prevalence of this condition in headache clinics results in many patients suffering from withdrawal symptoms and headache intensification (2). Due to this remarkably uncomfortable process, many patients fail to complete withdrawal therapy (3). Any method that enables patients to tolerate this therapy will be welcome. We would like to comment on some aspects of the article in order to assist and simplify future studies. Although intended to be a pilot study, the study population and protocol should have been described in more detail, in order to allow the precise reproduction of the study and to avoid dispute. Exclusion criteria should include the presence of active peptic ulcer and other severe disorders, subsequently increasing safety prior to the use of such a high dose of prednisone in a larger population. These additional criteria were used in two previous studies that included a high dose of prednisone in withdrawal therapy, but in a lower and tapering dose (4, 5). We are not considering the hypothesis of peptic ulceration caused by steroids, whose evidence is fogged by conflicting data (6). Rather, we have in mind that a supraphysiological dose of steroids may inhibit the healing of preexistent lesions, which can be caused by the overused medication (2). Besides, it is tempting to speculate that nine patients do not constitute a meaningful sample size to demonstrate adverse events and to prove the safety of the therapy of choice. Moreover, the article should have clearly described the method used to record headache characteristics before withdrawal therapy. Retrospective reports on chronic pain patients indicate a tendency to present inaccurate information and suggest that reliance on medication increases the divergence between reported and actual pain severity (7). Studies in children and adults imply that a combination of clinical interviews and the use of diagnostic headache diaries provides a more precise diagnosis (both quantitatively and qualitatively) than a clinical interview alone (8, 9). Our experience with children and adolescents, comparing chronic daily headache severity prior to and following the use of a headache diary, has confirmed the superior diagnostic potential of the combination of the two methods (especially in a population such as this, prone to recall bias, placebo effect and previous overestimation) (10). A reliable baseline headache severity should have been documented in a diary or calendar in order to reduce bias and to increase the accuracy of description, which would strengthen the comparison after withdrawal therapy (11). Furthermore, if patients 6 and 10 (shown in Table 1 of Pageler et al.) (1) had been asked to complete a baseline headache diary, they would probably not have been included in the study or submitted to withdrawal therapy at all. In conclusion, we are optimistic about this approach (with a high dose of prednisone) to the treatment of withdrawal symptoms and headache intensification. There is still the need for a doubleblind, randomized, placebo-controlled study with the use of prednisone, which takes the abovementioned suggestions into consideration. A larger, multicentre, Phase III study has been initiated in various European centres (1), and these results are eagerly expected by patients who previously failed to complete withdrawal therapy and by their doctors.

Exercise-Induced Change in Plasma IL-12p70 Is Linked to Migraine Prevention and Anxiolytic Effects in Treatment-Naive Women: A Randomized Controlled Trial

Objective: To conduct a randomized controlled trial to evaluate the effect of a 12-week aerobic exercise program for migraine prevention, plasma cytokines concentrations (TNF-α, interleukin [IL]-1β, IL-6, IL-8, IL-10, and IL-12p70), and anxiety in women with migraine. Methods: Women with episodic migraine (ICHD-II), aged between 20 and 50 years, who had never taken any prophylactic medication, and were physically inactive in the past 12 months were recruited from the university’s hospital and a tertiary headache clinic between March 2012 and March 2015. Migraine attacks were recorded in headache diaries, cytokines were quantified by flow cytometry, and anxiety was assessed by the 7-item General Anxiety Disorder (GAD-7) scale. Blood sampling and psychometric interviews were undertaken on headache-free days. Results: Twenty participants ([mean ± SD] age 33.8 ± 10.5; BMI 26 ± 5.2) were randomly assigned and received intervention (“trained”: n = 10) or entered on a waitlist (“inactive”: n = 10). There were no differences between groups regarding patients’ characteristics and baseline data. Days with migraine (p = 0.001), IL-12p70 levels (p = 0.036), and GAD-7 score (p = 0.034) were significantly reduced in the trained group after the intervention period, but there were no significant changes in these variables in the inactive group. There was no change in the levels of the other cytokines in either group. There were positive correlations between a reduction in IL-12p70 level and a reduction in the number of days with migraine (R2 = 0.19, p = 0.045), and GAD-7 score (R2 = 0.53, p < 0.001). Conclusion: The clinical and psychological therapeutic effects of aerobic exercise in treatment-naïve women with migraine may involve the downregulation of IL-12p70.