A Descriptive Review of Medication-Overuse Headache: From Pathophysiology to the Comorbidities.

PURPOSE OF REVIEW: Medication-overuse headache (MOH) is an important problem worldwide, with different areas of controversy regarding its entity. This article reviews the risk factors, comorbidities, pathophysiology, clinical presentation, effective management, and prognosis of MOH by summarizing and integrating the results and findings from previously performed more than 15,000 studies (from 2010 to 2023) available from the scientific database of the University Medical Library in the University Clinical Center of Nis, which aimed to investigate and define the complexity of this type of headache. RECENT FINDING: It has been proposed that all acute migraine medications can lead to MOH, with differences in the propensity of different agents to cause the problem. Early data suggests that triptans and other painkillers used for the acute treatment of migraine may be an exception. Recent studies show that practitioners and the general public are still largely unaware of the problem of medication overuse and its damaging effects. SUMMARY: Although it is likely that MOH does occur, restricting the number of acute medications is necessary to prevent it. It is also possible that increasing amounts of acute medications are simply a reflection of poorly controlled headaches rather than a cause. Further research needs to be developed to identify more precise mechanisms for effective MOH management and its evolution.

Values of Nitric Oxide and Superoxide Dismutase in Cerebrospinal Fluid of Patients with Sporadic Amyotrophic Lateral Sclerosis.

Introduction: Neurons are highly energy-dependent and highly specialized cells, showing great sensitivity to oxidative stress (OS). Nitric oxide (NO) and its oxidation products play a central role in neurodegeneration. This study aimed to contribute to the further elucidation of the role of OS in the pathogenesis of amyotrophic lateral sclerosis (ALS). Methods: We assessed NO and superoxide dismutase (SOD) levels in cerebrospinal fluid (CSF) of 24 sporadic ALS (sALS) patients (13 of them presented with spinal form while 11 patients had bulbar form) and 20 controls (CG). Results: The obtained SOD levels in sALS patients were lower than those in CG (p < 0.001), while NO showed higher levels compared to CG (p < 0.001). Observed separately, there were no significant differences in the levels of NO and SOD in CSF between patients about their clinical presentations (p > 0.05). There were significant negative correlations between SOD and NO levels in all sALS patients (r = 0.31, P = 0.025). Significant correlation between SOD and functional rating scale as well as disease progression index was recorded in patients with sALS (r = 0.618. r = 0.425, P < 0.01), while NO levels were significantly associated with disease progression only (r = 0.348, P < 0.01). Conclusion: The data presented clearly support the role of impaired oxidant/antioxidant balance in the pathogenesis of ALS, where NO overproduction and decreased SOD defense activity seem to be particularly involved. The CSF SOD and NO level might serve as useful biomarkers for functional disorder and progression of the disease.

Headache secondary to nontraumatic brain hemorrhage: a single-center, retrospective clinical study.

Introduction: The predictive accuracy of clinical and paraclinical findings for headache occurrence in patients having nontraumatic intracerebral hemorrhage (ICH) was tested. Material and methods: The medical records of 341 consecutive nontraumatic ICH patients (106 females and 235 males), average age 56.2 ±7.7 years, presenting with headache (25.5%) and without a headache (74.5%), over a period of 5 years, were retrospectively analyzed. Results: The presence of focal neurological symptoms (OR = 0.129, 95% CI: 0.044-0.372, p = 0.000), loss of consciousness (OR = 0.174, 95% CI: 0.060-0.504, p = 0.001), body temperature (OR = 0.586, 95% CI: 0.389-0.882, p = 0.010), and the values of C-reactive protein (OR = 0.989, 95% CI: 0.978-0.999, p = 0.048) at admission, as well as the presence of hematoma in the basal ganglia (OR = 0.308, 95% CI: 0.159-0.596, p = 0.000) and the presence of arterial hypertension in the medical history (OR = 0.478, 95% CI: 0.230-0.991, p = 0.047), are recognized as negative predictors for headache occurrence in ICH. The regular use of antihypertensive therapy is a prominent positive predictor for headache occurrence in ICH (OR = 1.906, 95% CI: 1.075-3.381, p = 0.027). Patients presenting with headache had a favorable clinical outcome compared to those without headache in ICH presentation (p < 0.001). Conclusions: The present results might be clinically useful for considering further diagnostic and therapeutic procedures as early as possible in patients with symptoms clinically suggestive of ICH, with and without headache in ICH clinical presentation. These data require confirmation in a prospective large-scale study.

The Ruminative Thought Style with Associated Anxiety Influences the Occurrence of Medication-Overuse Headache.

BACKGROUND AND PURPOSE: To determine the relationships between the ruminative thought style, parameters of psychological distress, and the occurrence of medication-overuse headache (MOH). METHODS: The study included 164 subjects: 83 patients (11 males and 72 females) who were first diagnosed as MOH, and 81 healthy subjects (22 males and 59 females) as a control group (CG). The study participants were aged 40.2±11.9 years (mean±standard deviation), and they were assessed using the Ruminative Thought Style Questionnaire and Depression Anxiety Stress Scales. RESULTS: The degree of rumination was higher in patients with MOH than in the CG (p<0.001). Among patients with MOH, females, patients with comorbidities, and those who overuse combined analgesic therapy had a higher degree of rumination (p=0.038, p=0.008, and p=0.015, respectively). In both the MOH patients and CG, the degree of rumination was directly correlated with depression, anxiety, and stress (r=0.473-0.557, p<0.001, for MOH; r=0.303-0.322, p<0.005, for CG). Rumination and anxiety were associated with MOH [odds ratio (OR)=1.123, 95% confidence interval (CI)=1.071-1.178, p<0.001; OR=1.091, 95% CI=1.005-1.185, p=0.039; respectively]. The analysis of the mediation model showed that the link between rumination and MOH is largely direct (86%), and to a lesser extent is additionally influenced by anxiety as a mediator (14%). CONCLUSIONS: A ruminative thought style is associated with MOH both directly and via anxiety. Psychological strategies aimed at decreasing ruminative responses and anxiety could be useful in the prevention of MOH in selected patients.

Depression, Anxiety, Stress, and Health-Related Quality of Life Among Patients With Medication Overuse Headache in a Tertiary Headache Center: A Cross-Sectional Study.

OBJECTIVE: The investigators examined the association of patient-related and headache-related parameters and the effect of medication overuse headache (MOH); the occurrence of depression, anxiety, and stress; and the importance of different domains of health-related quality of life in these associations. METHODS: Eighty-three patients (women, N=72, men, N=11; mean age, 40.54 years, SD=11.58), who were first diagnosed with MOH during the study period were included in the analyses. The Headache Impact Test-6 (HIT-6), the 36-item Short-Form Survey (SF-36) Questionnaire for quality of life, and the Depression Anxiety Stress Scales were used. RESULTS: The findings revealed mild depression, moderate anxiety, and stress, as well as changes in all examined health domains, in the study patients (p<0.05). Risk factors were identified for higher HIT-6 scores (role functioning/physical functioning [odds ratio=0.977, p=0.024] and social functioning [odds ratio=0.963, p=0.032]); for depression (emotional well-being [odds ratio=0.928, p=0.007], social functioning [odds ratio=0.950, p=0.009], and the presence of comorbidity [odds ratio=5.417, p=0.013]); for anxiety (age [odds ratio=1.091, p=0.007], MOH duration [odds ratio=1.422, p=0.047], emotional well-being [odds ratio=0.933, p=0.012], and social functioning [odds ratio=0.943, p=0.001]); and for stress (emotional well-being [odds ratio=0.902, p<0.001]). CONCLUSIONS: MOH has a significant negative impact on the personal, family, and social life of patients and is associated with depression, anxiety, and stress. Patients' age, duration of MOH, presence of comorbidities, and adverse effects of physical, emotional, and social dysfunction are particularly important contributors to the negative effects of MOH.

Recurrent Painful Ophthalmoplegic Neuropathy: Migraine, Neuralgia, or Something Else?

Recurrent painful ophthalmoplegic neuropathy (RPON) is a very rare disease characterized by recurrent attacks (at least two) of unilateral headache associated with ipsilateral ophthalmoplegia due to paresis of one or more cranial motor nerves, not due to any orbital, parasellar, or posterior fossa lesions. The differential diagnoses for this condition are broad. In addition to disability during an acute attack, this disease could also cause a permanent neurologic deficit. The understanding of RPON pathogenesis has changed over time, leading to a change in the classification of this disorder between editions of the International Classification of Headache Disorders, in which the condition was moved from the chapter on migraine to the chapter on cranial neuralgias and central causes of facial pain. There is no consensus on the pathogenesis of RPON. It is possible that multiple pathogenic mechanisms underlie various clinical forms of the disease. A depiction of pathologic analyses of patients with radiologically confirmed changes in the affected nerves during and outside of attacks would significantly contribute to knowledge of its pathogenesis. Brain imaging should be performed in each patient during an acute RPON attack and at a regular schedule between attacks. Further case reports and case series are required before further conclusions can be made regarding RPON pathogenesis and proposals for treatment options.

Postdural puncture headache as a complication of lumbar puncture: clinical manifestations, pathophysiology, and treatment.

OBJECTIVE: This manuscript is a narrative review of peer-reviewed studies of postdural puncture headache (PDPH) as the most common complication of a diagnostic and therapeutic lumbar puncture (LP) and LP due to the damage of the dura mater in epidural anesthesia. METHODS: Author searched articles related to the PDPH and its risk factors, pathophysiology diagnosis, differential diagnosis, and therapy. All studies according to the analyzed parameters and their relevance to the clinical practice, as well as quality of the study methods, were selected for further analysis. RESULTS: The review presents the clinical and paraclinical prediction criteria for the onset, clinical features, course, and efficiency of specific therapeutic interventions which are of a particular clinical benefit for the prevention, pathogenetic treatment, and differential diagnosis of PDPH. The analysis of prediction parameters for the onset, clinical course, and associated symptoms and signs of PDPH is a contribution to the understanding of pathophysiology of intracranial hypotension, since PDPH can be considered a clinical model of intracranial hypotension. CONCLUSIONS: Given that LP is a common procedure in clinical practice, it is necessary to have a comprehensive knowledge of the risk factors, pathophysiological, diagnostic, differentially diagnostic, and therapeutic aspects of PDPH.

Postdural puncture headache leads to clinical worsening of pre-existing chronic headache.

The incidence of postdural puncture headache (PDPH) in relation to pre-existing chronic headache (CH) was assessed, as was the clinical course of CH, at one, three, and six months after PDPH. The study was conducted as a single center cohort prospective study that included 252 patients (105 men and 147 women), average age of 47.3 ± 15.0 years, on whom lumbar puncture (LP) was performed. PDPH was reported in 133 (52.8%) patients; CH was reported in 82 (32.5%) patients. Patients with CH were more likely to have PDPH (p = 0.003). The individual clinical type of CH did not have an effect on the incidence of PDPH (p = 0.128). Patients with PDPH had a clinical deterioration of CH three and six months after LP (p = 0.047, p = 0.027, respectively) in terms of increased headache days per month and/or incomplete efficacy of performed therapy in relation to baseline values. Six months after LP, the worsening of CH was more common in women with PDPH (OR 5,687 [95% CI: 1526-21,200], p = 0.010) and patients with a longer history of CH (OR 1064 [95% CI: 1007-1124], p = 0.027). Multivariate analysis confirmed the direct association of female sex and duration of CH and its worsening six months after PDPH (OR 4478 [95% CI: 1149-17,452], p = 0.031; OR 1448 [95% CI: 1292-1808], p = 0.022). The presented results could be significant for the prediction/differential diagnosis of PDPH in patients with CH and for the prediction/prevention of CH clinical worsening after PDPH.

Parameters Related to Lumbar Puncture Do not Affect Occurrence of Postdural Puncture Headache but Might Influence Its Clinical Phenotype.

BACKGROUND: Post-dural puncture headache (PDPH) has been the most common complication of diagnostic and therapeutic lumbar puncture (LP). The occurrence and clinical features of PDPH in relationship to different demographic, clinical, and paraclinical parameters and parameters related to LP were assessed. METHODS: We conducted a cohort, prospective, single-center study of 252 consecutive patients (105 men and 147 women; average age, 47.3 ± 15.0 years), who had undergone LP for different medical reasons from February 2018 to June 2018 at the Clinic for Neurology Clinical Center of Serbia (Belgrade, Serbia). RESULTS: Of the 252 patients, PDPH was reported in 133 (52.8%). The incidence of PDPH was more frequent in women (64.7%; P = 0.043). Univariate analyses identified the following significant risk factors for PDPH: female gender (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.05-2.89), age (OR, 0.95; 95% CI, 0.94-0.97), smoking duration (OR, 0.91; 95% CI, 0.88-0.95), preexisting headaches (OR, 2.40; 95% CI, 1.39-4.17), circulatory system disease (OR, 0.52; 95% CI, 0.29-0.92), and musculoskeletal system and connective tissue disease (OR, 0.31; 95% CI, 0.12-0.81). In the multivariable model, duration of smoking and preexisting headaches remained independent risk factors for PDPH (OR, 0.93; 95% CI, 0.88-0.97; P = 0.002; and OR, 4.23; 95% CI, 1.27-14.08; P = 0.019, respectively). For various PDPH characteristics, significant risk factors were identified, including age, female gender, body mass index, circular or endocrine system diseases, and the use of caffeinated drinks before LP. In addition, the caliber of the traumatic needle, direction and number of needle stitches during LP, occurrence, intensity, and radiation of pain during LP, volume of sampled cerebrospinal fluid, rest and hydration after LP, preexisting headache, and earlier PDPH were significant. All these models were well-calibrated (Hosmer-Lemeshow test, P > 0.05). CONCLUSION: The results of the present study are important for the prediction of the occurrence of PDPH and the differential diagnosis of headaches after LP.

Cluster headache: pathophysiology, diagnosis and treatment.

Cluster headache (CH) is characterized by attacks of severe, strictly unilateral pain that is orbital, supraorbital, temporal, or any combination of these, lasts 15-180 min, and occurs from once every other day to eight times a day. The pain is associated with ipsilateral conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial sweating, miosis, ptosis and/or eyelid edema, and/or with restlessness or agitation. The understanding of the pathophysiological mechanisms behind CH is far from complete, but CH is considered to be a neurovascular and chronobiologic headache disorder, with a pivotal role played by the central brain mechanisms. The diagnosis of CH is based on a careful history that elicits the clinical features of attacks, ipsilateral autonomic phenomena, and the cyclical nature of the bouts in which the attacks occur. Additional diagnostic interventions are needed to rule out secondary causes of CH. The main focus of therapy is to abort attacks once they have begun and to prevent future attacks. Alternative interventions in patients with CH who have not experienced any meaningful benefit from preventive drugs are well defined. Although there have been advances in the diagnosis and therapy of CH, a significant number of CH patients experience misdiagnoses and diagnostic delay, which stalls the possibility of the timely application of adequate abortive and preventive therapy.

The cerebrospinal fluid values of advanced oxidation protein products and total thiol content in patients with amyotrophic lateral sclerosis.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is recognized as a progressive neurodegenerative disorder of unknown origin. Oxidative stress (OS) is considered as one of the most challenging hypothesis in the disease pathogenesis. The aim of this study was to contribute to the understanding of what extent there is involvement of OS in ALS. PATIENTS AND METHODS: We assessed Advanced Oxidation Protein Products (AOPP) and total thiol (-SH) groups in cerebrospinal fluid (CSF) of 24 ALS patients (13 of them presented with spinal form while 11 patients had bulbar form) and 20 controls (CG). RESULTS: The obtained AOPP levels in ALS patients were higher than those in CG (p <0.001), while -SH groups showed lower values compared to CG (p<0.001). The AOPP values were higher in ALS patients with bulbar compared with ALS patients with common spinal manifestation (p<0.001). There were no differences in -SH group's levels among these different clinical forms (p>0.05). The negative correlation between AOPP and the levels of -SH groups was confirmed (p <0.01). Significant mild correlations between tested parameters and functional rating scale as well as disease progression index were recorded for both of tested parameters in spinal form of ALS (p<0.01). CONCLUSION: The data presented here clearly support the fact that OS is involved in patophysiology of ALS, where oxidation of -SH groups represents an important aspect of protein oxidation. The CSF AOPP level and -SH groups may serve as potential useful biomarker for functional disorder and progression of the disease in the spinal form of ALS.

Retinal ganglion cell/inner plexiform layer thickness in patients with Parkinson's disease.

Introduction: The aim of the paper was to analyze the changes in the macular ganglion cell layer and inner plexiform layer (GCL-IPL) thickness in patients with Parkinson's disease. Material and methods: The study enrolled 46 patients with established diagnosis of Parkinson's disease and 46 healthy subjects. Both groups were age- and gender-matched. An OCT protocol, namely standardized Ganglion Cell Analysis algorithm was used to measure the thickness of the macular GCL-IPL layer. The average, minimum, and six sectoral (superotemporal, superior, superonasal, inferonasal, inferior, inferotemporal) GCL-IPL thicknesses were measured from the elliptical annulus centered on the fovea. Results: The mean value of the clinical severity of Parkinson's disease was between 2 and 3, according to the Hoehn and Yahr scale. Statistically significant thinning of the GCL-IPL layer was registered in average and minimum GCL-IPL thickness, as well as in the sectoral layer thicknesses in patients with Parkinson's disease in comparison to the controls. There was no correlation between structural changes in the retina and disease duration or severity. A statistically significant difference in thickness between the different stages of the disease was registered only in the inferior sector. Conclusions: Parkinson's disease is accompanied by thinning of the GCL-IPL complex of macula even in the earliest stages. This may indicate a possible retinal dopaminergic neurodegeneration. There is no correlation between duration or severity of Parkinson's disease with thinning of the GCL-IPL complex. .

Identification of clinical and paraclinical findings predictive for headache occurrence during spontaneous subarachnoid hemorrhage.

OBJECTIVES: Headache is recognized as the main but unwarranted symptom of subarachnoid hemorrhage (SAH). There are no enough findings identified as predictive for headache occurrence in SAH. We evaluated the clinical and paraclinical factors predictive for headache occurrence in SAH. PATIENTS AND METHODS: We retrospectively analyzed medical records of 431 consecutive non traumatic SAH patients (264 females and 167 males), ages from 19 to 91 years, presenting with headache (70.3%) and without headache (29.7%) during period of 11years. RESULTS: Among all tested parameters, as negative predictors for headache occurrence were recognized: patients' ages (OR 0.97 [95%CI: 0.96-0.99], p=0.025), persistence of coagulation abnormality (OR 0.23 [95%CI: 0.08-0.67], p=0.006), atrial fibrilation (OR 0.23 [95%CI: 0.09-0.59], p=0.002), chronic renal failure (OR 0.26 [95%CI: 0.09-0.76], p=0.014) and more diseases (OR 0.11 [95%CI: 0.04-0.32], p<0.0001), as higher clinical score (OR 0.94 [95%CI: 0.90-0.99], p=0.018) including positive neurological findings (OR 0.34 [95%CI: 0.21-0.55], p<0.001) and loss of consciousness (OR 0.22 [95%CI: 0.12-0.39], p<0.001) at the SAH onset, while the complaint of neck stiffness was identified as its positive predictor (OR 1.93 [95%CI: 1.19-3.10], p=0.007). CONCLUSIONS: Although diagnosis based solely on clinical presentation is not reliable and speculative, our findings could provide physicians with evidence to consider SAH not only in conditions of its headache occurrence but also in those with headache absence.

Refractory burning mouth syndrome: clinical and paraclinical evaluation, comorbiities, treatment and outcome.

BACKGROUND: Burning Mouth Syndrome (BMS) is a chronic pain condition characterized by persistent intraoral burning without related objective findings and unknown etiology that affects elderly females mostly. There is no satisfactory treatment for BMS. We aimed to observe the long-term efficacy of high velanfaxine doses combined with systemic and topical administered clonazepam in a particular subgroup of BMS patients who do not respond to current clinical management. RESULTS: Eight (66.1 ± 6.2 years old females) out of 14 BMS patients fulfilled the inclusion criteria and were treated with venlafaxine (300 mg/d) and clonazepam (5 mg/d) for 35.4 ± 12.1 (mean ± SD) months. The average duration of the symptoms at baseline was 4.3 ± 1.4 years and the overall mean daily pain intensity score was 8.6 ± 1.3 (VAS); pain was in tongue and within the oral mucosa, accompanying by oral and facial dysesthesia. In five patients tasting was abnormal. All patients had positive history of concomitant primary headache. The average score of Hamilton Rating scale for Anxiety and Depression was 21 ± 4.2, and 26.1 ± 2.9, respectively. Previous ineffective treatments include anticonvulsants and anti-depressants. All patients responded (more than 50% decrease in VAS) after three months treatment (mean VAS 3.2 ± 2.2) with no remarkable adverse events. CONCLUSION: BMS deserves bottomless psychiatric evaluation and management when current available treatments fail. Treatment with venlafaxine combined with topical and systemic clonazepam may be effective in refractory BMS cases but further investigation in a large-scale controlled study is needed to confirm these results.

The Rare Painful Phenomena - Chronic Paroxysmal Hemicrania-tic Syndrome as a Clinically Isolated Syndrome of the Central Nervous System.

The association of paroxysmal hemicrania with trigeminal neuralgia (TN) has been described and called paroxysmal hemicrania-tic syndrome (PH-tic). We report the case of a patient diagnosed as having chronic PH-tic (CPH-tic) syndrome as a clinically isolated syndrome of the central nervous system (CNS) (CIS).A forty year old woman was admitted to our hospital suffering from right facial pain for the last 2 years. The attacks were paroxysmal, neuralgiform, consisting of throb-like sensations, which developed spontaneously or were triggered by different stimuli in right facial (maxilar and mandibular) areas. Parallel with those, she felt a throbbing orbital and frontal pain with homolateral autonomic symptoms such as conjunctival injection, lacrimation, and the feeling that the ear on the same side was full. This pain lasted most often between 15 and 20 minutes. Beyond hemifacial hypoesthesia in the region of right maxilar and mandibular nerve, the other neurological finding was normal. Magnetic resonance imaging (MRI) study showed a T2-weighted multiple hyperintense paraventricular lesion and hyperintense lesion in the right trigeminal main sensory nucleus and root inlet, all of them being hypointense on T1-weighted image. All of these lesions were hypointense in gadolinium-enhanced T1-weighted images. Neurophysiological studies of trigeminal nerve (somatosensory evoked potentials and blink reflex) correlated with MRI described lesions. The patient's pain bouts were improved immediately after treatment with indomethacin, and were completely relieved with lamotrigine for a longer period. According to the actual McDonald's criteria, clinical state was defined as CIS which was clinically presented by CPH-tic syndrome.Even though it is a clinical rarity and its etiology is usually idiopathic, CPH-tic syndrome can also be symptomatic. When dealing with symptomatic cases, like the one described here, when causal therapy is not possible due to the nature of the primary pathological process, a therapeutic approach, although symptomatic, can be fully effective in controlling this painful syndrome. The case report could be a contribution to the pathophysiological and clinical understanding of the association of CPH and TN.Key words: Paroxysmal hemicrania, trigeminal neuralgia, clinically isolated syndrome.

The Differences in the Cellular and Plasma Antioxidative Capacity Between Transient and Defined Focal Brain Ischemia: Does it Suggest Supporting Time-Dependent Neuroprotection Therapy?

There are many opened questions about the precocious role of oxidative stress in the physiopathology of the early stage of transitory ischemic attack (TIA) and defined focal brain ischemia, as well as about its correlation with clinical severity, short-lasting and clinical outcome prediction in these conditions. The study evaluates the values of glutathione (GSH), glutathione peroxidase, and superoxide dismutase (SOD) in hemolysates and total thiol content (-SH), advanced oxidation protein products (AOPP), SOD, and malondialdehyde (MDA) in plasma, in TIA and stroke patients in the early stage of their neurological onset. The results are interpreted in view of the potential relationship between tested parameters and clinical severity and clinical outcome prediction. Better hemolysates' and total antioxidant profile with higher values of AOPP were observed in TIA compared to stroke patients (p < 0.05). The stroke patients with initially better clinical presentation showed better antioxidant profile with lower values of AOPP (p < 0.05). In TIA patients, this was observed for GSH, -SH content, and AOPP (p < 0.05), which correlated with a short risk for stroke occurrence in this group (p < 0.01). Beyond MDA values, all tested parameters showed correlation with clinical outcome in stroke patients (p < 0.05). The measurement of oxidative stress in TIA and stroke patients would be important for identifying patients' subgroups which might receive supporting therapy providing better neurological recovery and clinical outcome. That approach might give us an additional view of a short-lasting risk of stroke occurrence after TIA, and its clinical outcome and prognosis.

Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol.

OBJECTIVE: To evaluate correlation between cumulative dose of gadobutrol and signal intensity (SI) within dentate nucleus and globus pallidus on unenhanced T1-weighted images in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios, and renal and liver functions, were evaluated after multiple intravenous administrations of 0.1 mmol/kg gadobutrol at 27, 96-98, and 168 weeks. We compared SI ratios based on the number of administrations, total amount of gadobutrol administered, and time between injections. RESULTS: Globus pallidus-to-thalamus (p = 0.025) and dentate nucleus-to-pons (p < 0.001) SI ratios increased after multiple gadobutrol administrations, correlated with the number of administrations (ρ = 0.263, p = 0.046, respectively) and depended on the length of administration (p = 0.017, p = 0.037, respectively). Patients receiving gadobutrol at 27 weeks showed the greatest increase in both SI ratios (p = 0.006; p = 0.014, respectively, versus 96-98 weeks). GGT increased at the end of the study (p = 0.004). CONCLUSION: In patients with RRMS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images after multiple gadobutrol injections. Administration of the same total amount of gadobutrol over a shorter period caused greater SI increase. KEY POINTS: Gadolinium deposition may occur within the human brain after multiple gadolinium contrast administrations. Increasing T1W signal intensity occurs within the dentate nucleus and globus pallidus. Increasing signal intensity may be a consequence of multiple administrations of gadobutrol. Administration of gadobutrol over a shorter period causes greater signal intensity increase.

Oxidative Stress and Neurobiology of Demyelination.

Despite a large amount of research which aims at defining the pathophysiology of human demyelination (i.e., multiple sclerosis), etiological bases of disease have been unknown so far. The point of intersection of all assumed etiological factors, which are mainly based upon immunological cascades, is neuroinflammation. The precise definition of the place and role of all pathogenetic factors in the occurrence and development of the disease is of crucial importance for understanding the clinical nature and for finding more effective therapeutic options. There are few studies whose results give more precise data about the role and the importance of other factors in neuroinflammation, besides immunological ones, with regard to clinical and paraclinical correlates of the disease. The review integrates results found in previously performed studies which have evaluated oxidative stress participation in early and late neuroinflammation. The largest number of studies indicates that the use of antioxidants affects the change of neuroinflammation course under experimental conditions, which is reflected in the reduction of the severity and the total reversibility in clinical presentation of the disease, the faster achieving of remission, and the delayed and slow course of neuroinflammation. Therapies based on the knowledge of redox biology targeting free radical generation hold great promise in modulation of the neuroinflammation and its clinical presentations.

Apparent diffusion coefficient in the evaluation of cerebral gliomas malignancy.

BACKGROUND/AIM: Magnetic resonance imaging (MRI) is a key modality not only for lesion diagnosis, but also to evaluate the extension, type and grade of the tumor. Advanced MRI techniques provide physiologic information that complements the anatomic information available from conventional MRI. The aim of this study was to determine whether there is a correlation between apparent diffusion coefficient (ADC) maps of intracranial glial tumors and histopathologic findings and whether ADCs can reliably distinguish low-grade from high-grade gliomas. METHODS: This retrospective study included 25 patients with MRI examination up to seven days before surgery, according to the standard protocol with the following sequences: T1WI, T2WI, FLAIR, DWI and post contrast T1WI. Data obtained from DW MRI were presented by measuring the value of ADC. The ADC map was determined by utilizing Diffusion-Perfusion (DP) Tools software. All the patients underwent surgical resection of the tumor. Histological diagnosis of tumors was determined according to the World Health Organization (WHO) classification. The ADC values were compared with the histopathologic findings according to the WHO criteria. RESULTS: The ADC values of astrocytomas grades I (0.000614 +/- 0.000032 mm2/s) were significantly higher (< 0.001) than the ADC values of anaplastic astrocytomas (0.000436 +/- 0.000016 mm2/s) and the ADC values of glioblastomas multiforme (0.000070 +/- 0.000008 mm2/s). The ADC values of astrocytomas grades II (0.000530 +/- 0.000114 mm2/s) were significantly higher (< 0.001) than the ADC values of anaplastic astrocytomas (0.000436 +/- 0.000016 mm2/s) and glioblastomas multiforme (0.000070 +/- 0.000008 mm2/s). The ADC values of anaplastic astrocy-omas (0.000436 +/- 0.000016 mm2/s) were significantly higher (< 0.001) than the ADC values of glioblastomas multiforme (0.000070 +/- 0.000008 mm2/s). The ADC values in the cystic part of the tumor for astrocytomas grades I (0.000775 +/- 0.000023 mm2/s) were significantly higher (< 0.001) than the ADC values of anaplastic astrocytomas (0.000119 +/- 0.000246 mm2/s) and glioblastomas multiforme (0.000076 +/- 0.000004 mm2/s). The ADC values astrocytomas grades II (0.000511 +/- 0.000421 mm2/s) were significantly higher (< 0.001) than the ADC values of glioblastomas multiforme (0.000076 +/- 0.000004 mm2/s). CONCLUSION: DWI with calculation of ADC maps can be regarded as a reliable useful diagnostic tool, which indirectly reflects the proliferation and malignancy of gliomas. The ADCs maps can both predict the results of histopathological tumor and distinguish between low- and high-grade gliomas, and provide significant information for presurgical planning, treatment and prognosis for patients with high-grade astrocytomas.

The Use of Agmatine Provides the New Insight in an Experimental Model of Multiple Sclerosis.

The aim of the study is to investigate the hypothesis that agmatine (AGM) enhances blood brain barrier (BBB) compounds properties in experimental autoimmune encephalomyelitis (EAE), which is an established animal model for studying multiple sclerosis (MS). Wild-type (WT) and knockout (KO) CBA/H iNOS-/- mice, 3 months old (15 ± 5 g) were used for EAE induction by myelin basic protein (MBP) dissolved in complete Freund's adjuvant (CFA). The animals were divided into control, CFA, EAE, EAE + AGM and AGM groups. After the development of full clinical remission, the animals were sacrificed and the immunohistochemical and biochemical examinations were performed in brain homogenates. We had noticed the increased expressions of occludin in WT and KO mice with EAE + AGM, compared to EAE groups in which these expressions were significantly decreased compared to the controls. The significant elevations of matrix metalloproteinases (MMPs)-MMP-3 and MMP-9 in WT and KO EAE animals were decreased during AGM treatment in both groups. AGM application post EAE in WT and KO mice caused decreased level of Iba-1 stain, compared to EAE groups. The obtained results suggest beneficial AGM effects in EAE on BBB components, which might be useful for novel therapeutic strategies in MS.