Beta-thalassemia major patients are treated with repeated blood transfusions, which may cause iron overload, which in turn may induce immune aberrations, and show an increased risk of depression. The aim of the present study is to examine whether repeated blood transfusions, iron overload, and immune-inflammatory responses are associated with depression in children (6–12 years) with transfusion-dependent thalassemia (TDT). The Children’s Depression Inventory (CDI), iron status (serum iron, ferritin, transferrin, TS%), and serum levels of CCL11, IL-1β, IL-10, and TNF-α were measured in TDT with (n = 54) and without (n = 57) a major depression-like episode (MDLE) and in healthy children (n = 55). The results show that MDLE due to TDT is associated with a greater number of blood transfusions and increased iron overload and IL-1β levels. Partial least squares path analysis shows that 68.8% of the variance in the CDI score is explained by the number of blood transfusions, iron overload, and increased levels of IL-1β and TNF-α. The latter two cytokines partly mediate the effects of iron overload on the CDI score, while the effects of blood transfusions on the CDI score are partly mediated by iron overload and the path from iron overload to immune activation. Iron overload is also associated with increased IL-10 and lower CCL11 levels, but these alterations are not significantly associated with depression. In conclusion, blood transfusions may be causally related to MDLE in TDT children and their effects are in part mediated by increased iron overload and the consequent immune-inflammatory response. The results suggest that effects of iron overload and its consequences including inflammation and oxidative stress toxicity may cause MDLE. Current treatment modalities with folic acid and vitamin C are insufficient to attenuate iron overload and immune-inflammatory responses and to prevent MDLE in children with TDT.

Major Depression in Children with Transfusion-Dependent Thalassemia Is Strongly Associated with the Combined Effects of Blood Transfusion Rate, Iron Overload, and Increased Pro-inflammatory Cytokines.

Purpose of review Cluster headache is a neurological disorder that patients consider the most severe pain they experience. Recognizing new treatments provides opportunities to advance current management. Recent findings In contrast to the classic treatments, new options narrow in on the therapeutic target and are better tolerated. Calcitonin gene-related peptide (CGRP) pathway blockade with monoclonal antibodies (MABs), specifically the CGRP MAB galcanezumab, represents an important advance for episodic cluster headache, reducing the number of attacks during a bout. Neuromodulation strategies aimed at anatomical structures involved in the pathophysiology of cluster headache, such as the sphenopalatine ganglion and the vagus nerve, have proved effective in reducing the pain intensity and the number of attacks, and also to be safe and well tolerated. Summary Our understanding of the pathophysiology of cluster headache and its management continues to grow. Novel treatments have appeared from research, such as neuromodulation and CGRP monoclonal antibodies. Nonetheless, chronic cluster headache and designing trials that select the correct sham in evaluating devices remain challenging.

Evolving options for the treatment of cluster headache.

Among the spectrum of pain conditions, cluster headache represents one of the most severe. Targeted therapies for cluster headache are evolving thus improving the available therapeutic armamentarium. A better understanding of the currently available therapies, as well as new and emerging options, may aide physicians to manage affected sufferers better by evolving treatment guidance. While classic first-line medications are useful in some patients with cluster headache, they are often accompanied by significant side effects that limit their use. Recently, novel treatments with better tolerability and decreased medication interactions have proven to be effective. A remarkable example of this is the blockage of the calcitonin gene-related peptide pathway with monoclonal antibodies, which may be a key element in the future treatment of cluster headache. The sphenopalatine ganglion and vagus nerve perform a critical role in the regulation of pain and the trigeminal autonomic reflex. Neuromodulation therapies targeting these structures have shown excellent tolerability and few significant adverse events, constituting a promising form of treatment. Finally, several potential therapeutic targets are examined in this review, such as small molecule CGRP receptor antagonists, known as gepants, and serotonin receptor 5-HT1F receptor agonists: ditans. In summary, a deepening of the understanding of cluster headache mechanisms in recent years has driven the evolution of sophisticated therapeutic approaches that could allow a new era in the treatment of this difficult condition.

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Recent Advances in the Management of Cluster Headache

No information is currently available regarding the natural history of asymptomatic intracranial aneurysms in beta-thalassemia, raising several concerns about their proper management. We performed a prospective longitudinal three-year-long MR-angiography study on nine beta-thalassemia patients (mean-age 40.3 ± 7.5, six females, 8 transfusion dependent) harboring ten asymptomatic intracranial aneurysms. In addition, we analyzed the clinical files of all adult beta-thalassemia patients (160 patients including those followed with MR-angiography, 121 transfusion dependent) referring to our Centers between 2014 and 2019 searching for history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms. At the end of the three-year-long follow-up, no patient showed any change in the size and shape of the aneurysms, none presented new intracranial aneurysms or artery stenoses, none showed new brain vascular-like parenchymal lesions or enlargement of the preexisting ones. Besides, in our database of all adult beta-thalassemia patients, no one had history of subarachnoid hemorrhage or history of symptomatic intracranial aneurysms. Incidental asymptomatic intracranial aneurysms do not seem to be associated, in beta-thalassemia, with an increased risk of complications (enlargement or rupture) at least in the short term period, helping to optimize human and economic resources and patient compliance during their complex long-lasting management.

/pdf/asymptomatic-intracranial-aneurysms-in-beta-thalassemia-a-4a59ic9pit.pdf

Asymptomatic intracranial aneurysms in beta-thalassemia: a three-year follow-up report

REFERENCES 1. U.S. Food & Drug Administration. Information about immune globulin (human) product shortage. 2018. https://www.fda.gov/vaccines-bloodbiologics/safety-availability-biologics/information-about-immune-globulinhuman-product-shortage. Accessed November 21, 2019. 2. Ciszewski TS, Ralston S, Acteson D, Wasi S, Strong SJ. Protein levels and plasmapheresis intensity. Transfus Med. 1993;3:59-65. 3. Schulzki T, Seidel K, Storch H, et al. A prospective multicentre study on the safety of long-term intensive plasmapheresis in donors (SIPLA). Vox Sang. 2006;91:162-173. 4. Food and Drug Administration HHS. Volume Limits Automated Collection of Source Plasma. https://www.fda.gov/media/70951/ download. Accessed July 22, 2019. 5. Gustafson M. Source Plasma Donor Hemovigilance Activities and Results. 2017. https://www.pptaglobal.org/images/presentations/2017/Gustafson_ PlasmaVigilance100817.pdf. Accessed July 22, 2019. 6. Buffaloe GW, Heineken FG. Plasma volume nomograms for use in therapeutic plasma exchange. Transfusion. 1983;23:355-357. 7. Lemmens HJ, Bernstein DP, Brodsky JB. Estimating blood volume in obese and morbidly obese patients. Obes Surg. 2006;16:773-776.

White matter volume changes in adult beta-thalassemia: Negligible and unrelated to anemia and cognitive performances.

Neurological manifestations are reported only occasionally in patients with thalassaemia and are given much less prominence than the complications related to anaemia and iron overload. White matter changes (WMCs) on magnetic resonance imaging (MRI) in patients with thalassaemia were first reported two decades ago but the significance of these lesions remains unclear. We studied the neurological and cognitive manifestations in 82 older patients with thalssaemia [25 Thalassaemia major (TM), 24 thalassaemia intermedia (TI) and 33 haemaglobin E β thalassaemia (EBT)] and 80 controls, and found that headaches were more common in thalassaemia patients (50/82, 61%) than in controls (18/80, 22·5%: P < 0·001). WMCs on MRI were found in 20/82 (24·3%) patients and 2/29 (6·9%) controls had (P = 0·078). WMC were more common among those with headaches (17/50: 34%) than in those without headache (3/32; 9·3%) (P = 0·023). WMCs were not associated with reduction of cognition. Nevertheless, cognition was lower in the TI and EBT groups compared with those with TM (P = 0·002). The association of headache with WMC in thalassaemia has not been reported before and warrants further study.

Headache: an important symptom possibly linked to white matter lesions in thalassaemia

Purpose: Primary headache disorders are common, but many patients are refractory to medical treatment. Percutaneous electrical nerve stimulation (PENS) therapy involves the stimulation of one or mo...

Percutaneous electrical nerve stimulation (PENS) therapy for refractory primary headache disorders: a pilot study.

Ajovy (fremanezumab, Teva Pharmaceuticals, Israel) is a fully humanized monoclonal antibody that selectively binds both isoforms of the calcitonin gene-related peptide. Calcitonin gene-related pept...

Mark W Weatherall

Papers

Headache: an important symptom possibly linked to white matter lesions in thalassaemia

Percutaneous electrical nerve stimulation (PENS) therapy for refractory primary headache disorders: a pilot study.

Fremanezumab autoinjector pen for the prevention of migraine.