Giorgio Bono

The brain as a target for adrenocortical steroids: Cognitive implications

It is well established that a reciprocal control exists between the brain and glucocorticoid hormones. The brain regulates adrenocortical function via hypothalamic corticotrophin releasing hormone-41 (CRH-41), glucocorticoids act at specific receptors in the hippocampus, thus promoting negative feedback mechanisms. Because the hippocampus is a major site for memory processes, a role for excessive/long-lasting plasma glucocorticoid levels has been suggested in conditions of mental impairment. Major depression, Cushings disease, and dementia of the Alzheimer type are disorders which share hyperactivity of the hypothalamo-pituitary-adrenal axis, as well as symptoms of cognitive decline. Although the mechanisms leading to hypercortisolemia appear to be different in each case, the neuropsychological features of these three disorders accord with the hypothesis of glucocorticoid-associated brain damage. It therefore is important to find pharmacological strategies that will avert or reduce these potential consequences on brain function.

Cognitive and affective status in mild hypothyroidism and interactions with L-thyroxine treatment.

Objectives – While clinical hypothyroidism is associated with frank neuropsychological and affective alterations and is considered one of the causes of reversible dementia, the occurrence of these alterations and their treatment in mild hypothyroidism (MH) remains a controversial issue. Our aim was therefore to evaluate cognitive and psychological functions in a selected population of recently‐diagnosed MH patients with minor subjective symptoms.

Cervicogenic headache: evaluation of the original diagnostic criteria.

A variety of headaches are frequently associated with the occurrence of neck pain. The purpose of this paper was to describe the adherence to diagnostic criteria of a series of patients enrolled on the basis of two clinical criteria: (1) unilateral headache without side-shift, and (2) pain starting in the neck and spreading to the fronto-ocular area. One hundred and thirty-two patients (36 male and 96 female) entered the study. Sixty-two patients were assigned to Group A (patients fulfilling criteria 1 and 2), 40 to Group B (criterion 2 only) and 12 to Group C (criterion 1, only). Eighteen subjects were excluded because X-rays of the neck were not available. Patients were evaluated regardless of whether or not they fell into one or more of the following diagnostic categories: cervicogenic headache (CEH), migraine without aura (M) and headache associated with disorders of the neck (HN) (IHS definitions). Fulfilment of the diagnostic criteria for CEH was found to be particularly frequent in Group A. A higher frequency of CEH diagnosis was found when two criteria were used (Group A) than in Group B (P = 0.001); in the former group a higher mean number of diagnostic criteria for CEH were also present (P = 0.001). Group A patients more frequently presented pain episodes of varying duration or fluctuating, continuous pain and moderate, non-excruciating, non-throbbing pain than Group B patients (P = 0.04 and P = 0.08, respectively). In Group C patients, the frequency of these two criteria was relatively low (17%) especially of the first mentioned variable. The presence of at least five of the seven ‘pooled’ CEH criteria (present in ≥ 50% of the patients) might be deemed a reliable cut-off point, allowing the headache to be diagnosed as ‘probable’ CEH. If patients fulfilling M or HN criteria in addition to the CEH criteria are added to the ‘pure’ CEH group a total of 74% of Group A patients may have a CEH picture. The temporal pattern of pain and the quality of pain in Group A showed good sensitivity and specificity (≥ 75) when compared with Group B; therefore, the chances of diagnosing a definite CEH are significantly more frequent in patients presenting with unilateral pain that also begins as a neck pain. Head/neck trauma and radiological abnormalities in the cervical spine were not significantly associated with CEH, M or HN diagnoses. An improvement of the current diagnostic IHS criteria might make it possible to avoid the existing, partial overlap of CEH with HN and M. Extensive use should be made of the GON, and other, blockades in the routine work-up of CEH, both in the differential diagnosis and in the mixed forms (CEH + M, and CEH + HN), in order to improve the efficiency of the current diagnostic system.

Italian guidelines for primary headaches: 2012 revised version

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105–190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version.

Systemic thrombolysis in patients with acute ischemic stroke and Internal Carotid ARtery Occlusion: the ICARO study

Background and Purpose— The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients. Methods— ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0–2) or unfavorable (score of 3–6). Safety outcomes were death and any intracranial bleeding. Results— Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03–3.15; P=0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36–3.22; P=0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87–58.71; P=0.068) in the cases than in the controls. Conclusions— In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.

BDNF Val66Met polymorphism is associated with cognitive impairment in Italian patients with Parkinson's disease

Background and purpose:  A possible association between Parkinson’s disease (PD) and the polymorphism of Brain Derived Neurotrophic Factor (BDNF) G196A (Val66Met) has been suggested by different studies that nevertheless yielded‐contrasting result. The purpose of this study was to analyze such possible association in a cohort of Italian PD patients.

Brain volumes in healthy adults aged 40 years and over: a voxel-based morphometry study.

Background and aims: Gender and age effect on brain morphology have been extensively investigated. However, the great variety in methods applied to morphology partly explain the conflicting results of linear patterns of tissue changes and lateral asymmetry in men and women. The aim of the present study was to assess the effect of age, gender and laterality on the volumes of gray matter (GM) and white matter (WM) in a large group of healthy adults by means of voxel-based morphometry. This technique, based on observer-independent algorithms, automatically segments the 3 types of tissue and computes the amount of tissue in each single voxel. Methods: Subjects were 229 healthy subjects of 40 years of age or older, who underwent magnetic resonance (MR) for reasons other than cognitive impairment. MR images were reoriented following the AC-PC line and, after removing the voxels below the cerebellum, were processed by Statistical Parametric Mapping (SPM99). GM and WM volumes were normalized for intracranial volume. Results: Women had more fractional GM and WM volumes than men. Age was negatively correlated with both fractional GM and WM, and a gender × age interaction effect was found for WM, men having greater WM loss with advancing age. Pairwise differences between left and right GM were negative (greater GM in right hemisphere) in men, and positive (greater GM in left hemisphere) in women (−0.56±4.2 vs 0.99±4.8; p=0.019). Conclusions: These results support side-specific accelerated WM loss in men, and may help our better understanding of changes in regional brain structures associated with pathological aging.

Early Recurrence and Cerebral Bleeding in Patients With Acute Ischemic Stroke and Atrial Fibrillation Effect of Anticoagulation and Its Timing: The RAF Study

Background and Purpose— The best time for administering anticoagulation therapy in acute cardioembolic stroke remains unclear. This prospective cohort study of patients with acute stroke and atrial fibrillation, evaluated (1) the risk of recurrent ischemic event and severe bleeding; (2) the risk factors for recurrence and bleeding; and (3) the risks of recurrence and bleeding associated with anticoagulant therapy and its starting time after the acute stroke. Methods— The primary outcome of this multicenter study was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding within 90 days from acute stroke. Results— Of the 1029 patients enrolled, 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or transient ischemic attack or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding, and 14 (1.4%) major extracranial bleeding. At 90 days, 50% of the patients were either deceased or disabled (modified Rankin score ≥3), and 10.9% were deceased. High CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesion and type of anticoagulant were predictive factors for primary study outcome. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared with initiating treatment before 4 or after 14 days: hazard ratio 0.53 (95% confidence interval 0.30–0.93). About 7% of the patients treated with oral anticoagulants alone had an outcome event compared with 16.8% and 12.3% of the patients treated with low molecular weight heparins alone or followed by oral anticoagulants, respectively (P=0.003). Conclusions— Acute stroke in atrial fibrillation patients is associated with high rates of ischemic recurrence and major bleeding at 90 days. This study has observed that high CHA2DS2-VASc score, high National Institutes of Health Stroke Scale, large ischemic lesions, and type of anticoagulant administered each independently led to a greater risk of recurrence and bleedings. Also, data showed that the best time for initiating anticoagulation treatment for secondary stroke prevention is 4 to 14 days from stroke onset. Moreover, patients treated with oral anticoagulants alone had better outcomes compared with patients treated with low molecular weight heparins alone or before oral anticoagulants.

MMP9 Variation After Thrombolysis Is Associated With Hemorrhagic Transformation of Lesion and Death

Background and Purpose— Experimentally, matrix metalloproteinases (MMPs) play a detrimental role related to hemorrhagic transformation and severity of an ischemic brain lesion. Tissue-type plasminogen activator (tPA) enhances such effects. This study aimed to expand clinical evidence in this connection. Methods— We measured MMPs 1, 2, 3, 7, 8, 9, and tissue inhibitors of metalloproteinases 1, 2, 4 circulating level in blood taken before and 24 hours after tPA from 327 patients (mean age, 68.9±12.1 years; median National Institutes of Health Stroke Scale, 11) with acute ischemic stroke. Delta median values ([24 hours post tPA–pre tPA]/pre tPA) of each MMP or tissue inhibitors of metalloproteinase were analyzed across subgroups of patients undergoing symptomatic intracerebral hemorrhage, 3-month death, or 3-month modified Rankin Scale score 3 to 6. Results— Adjusting for major clinical determinants, only matrix metalloproteinase-9 variation proved independently associated with death (odds ratio [95% confidence interval], 1.58 [1.11–2.26]; P=0.045) or symptomatic intracerebral hemorrhage (odds ratio [95% confidence interval], 1.40 [1.02–1.92]; P=0.049). Both matrix metalloproteinase-9 and tissue inhibitors of metalloproteinase-4 changes were correlated with baseline, 24 hours, and 7 days National Institutes of Health Stroke Scale (Spearman P from <0.001 to 0.040). Conclusions— Our clinical evidence corroborates the detrimental role of matrix metalloproteinase-9 during ischemic stroke treated with thrombolysis, and prompts clinical trials testing agents antagonizing its effects.

Long-term intrathecal Baclofen infusion in supraspinal spasticity of adulthood.

Objectives– To evaluate long‐term results of chronic intrathecal Baclofen infusion on the spasticity, on the spasms and to evaluate the side‐effects of the intrathecal Baclofen in patients with supraspinal spasticity. Clinical materials and methods– Fourteen patients with severe progressive refractory to medical therapy spasticity were evaluated after chronic intrathecal Baclofen infusion performed by implantation of subcutaneous pump. The patients had suffered traumatic or anoxic acquired brain injuries. The clinical evaluation was made using Ashworth Scale (AS) and the Spasm Frequency Scale (SFS). Results– The intrathecal therapy showed a statistically significant improvement of the tone and of the spasms. Conclusions– The intrathecal infusion of Baclofen seems to be an effective treatment in patients with supraspinal spasticity.