Massimo Granata

Posterior reversible encephalopathy syndrome--Insight into pathogenesis, clinical variants and treatment approaches.

Posterior reversible encephalopathy syndrome is a rare clinicoradiological entity characterized by typical MRI findings located in the occipital and parietal lobes, caused by subcortical vasogenic edema. It was first described as a distinctive syndrome by Hinchey in 1996. Etiopathogenesis is not clear, although it is known that it is an endotheliopathy of the posterior cerebral vasculature leading to failed cerebral autoregulation, posterior edema and encephalopathy. A possible pathological activation of the immune system has been recently hypothesized in its pathogenesis. At clinical onset, the most common manifestations are seizures, headache and visual changes. Besides, tinnitus and acute vertigo have been frequently reported. Symptoms can be reversible but cerebral hemorrhage or ischemia may occur. Diagnosis is based on magnetic resonance imaging, in the presence of acute development of clinical neurologic symptoms and signs and arterial hypertension and/or toxic associated conditions with possible endotheliotoxic effects. Mainstay on the treatment is removal of the underlying cause. Further investigation and developments in endothelial cell function and in neuroimaging of cerebral blood flow are needed and will help to increase our understanding of pathophysiology, possibly suggesting novel therapies.

Serum interleukin-1 beta is increased in cluster headache

We measured serum interleukin-I beta (IL-1 beta) in 24 episodic cluster headache (CH) patients and 45 normal controls using a specific ELISA method. There was an increase in IL-1 beta in all CH patients compared to controls. IL-1 beta was further increased during the ictal phase of CH compared to patients between attacks and normal individuals. Between attacks, IL-1 beta was also significantly increased compared to controls. We suggest that these results represent an activation of the immune system in CH.

Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: Phase II clinical trial and systematic review

OBJECTIVE To evaluate whether rituximab at a low dose of 250 mg/m(2) × 2 may be as effective as at higher dosages, most commonly 375 mg/m(2)×4, used in previous studies on the treatment of patients with refractory mixed cryoglobulinemia (MC) vasculitis associated with hepatitis C virus (HCV) infection. METHODS We conducted a phase 2, single-arm two-stage trial (EUDRACT n. 2008-000086-38) of low-dose rituximab in 52 patients with HCV-associated MC who were ineligible/intolerant or non-responder to antiviral therapy. The primary outcomes were response of vasculitis evaluated by the Birmingham Vasculitis Activity Score (BVAS) at months 3, 6 and 12, rate of relapses and time to relapse, and rate of adverse events. Our data were compared with those reported in 19 published studies selected among 291 reviewed in a literature search. RESULTS The cumulative response rate (complete and partial) at month 3 was 81% in our patients, and 86% in 208 patients from studies using high-dose rituximab. The relapse rate and median time to relapse were, respectively, 41% and 6 months in our study, and 32% and 7 months in high-dose studies. Treatment-related adverse events were 11.5% in our study and 19.9% in high-dose studies. None of these differences was statistically significant. CONCLUSION Rituximab at a low dosage of 250 mg/m(2) × 2 is as effective as at higher dosages for treating MC vasculitis. This low-dose regimen may improve the cost/benefit profile of rituximab therapy for MC.

Macrophage Activation Syndrome as Onset of Systemic Lupus Erythematosus: A Case Report and a Review of the Literature.

Macrophage activation syndrome (MAS) is a potentially fatal condition. It belongs to the hemophagocytic lymphohistiocytosis group of diseases. In adults, MAS is rarely associated with systemic lupus erythematosus, but it also arises as complication of several systemic autoimmune disorders, like ankylosing spondylitis, rheumatoid arthritis, and adult-onset Stills disease. Several treatment options for MAS have been reported in the literature, including a therapeutic regimen of etoposide, dexamethasone, and cyclosporine. Here we report a case of 42-year-old woman in whom MAS occurred as onset of systemic lupus erythematosus.

A case of tension-type headache in fibromyalgia.

Sir,A 57-year-old-woman was admitted to our ward for a dailytension-type headache, it was not responding to usualpharmacological treatment. Before 5 years, she had hys-terectomy and after 10 days, she had a domestic accidentreporting an injury of the pelvis and the spine. Since then,she begun to suffer of muscular rigor of the neck and theshoulder girdle, daily, intense and constrictive pain local-ized in the occipital spine, not associated with vomiting,ocular symptoms, not worsened by exercise. The diagnosisof daily tension-type headache met the IHCD-II criteria.She also reported weakness of the upper and lower limbs,tingling, tremors and difficulties in walking and climbing.The patient’s medical history reported: Raynaud phenom-enon, chronic gastritis and dysphagia, hepatitis C virusinfection, hyperhomocystenemia, homozygosis for MTHFR677C factor. She also was a heavy smoker. She referredwidespread pain, unusually severe above all joints andmuscular pain, without any sign of inflammation at clinicalexamination. The patient underwent a brain and neck CT, abrain angio-MRI, a color-Doppler examination of the epi-aortic and transcranial vessels and blood tests that resultednegative. Ultrasonography of soft tissues showed fibrosis ofthe shoulder muscles with involvement of the dermis andhypodermis. Since then, the headache could be a symptomof a systemic autoimmune disease, we decided to performseveral immunological tests that showed positive result forANA and negative to ENA, anti-ds DNA, AMA, ASMA,APCA, ANCA. We also performed an electromyographyand a muscle and skin biopsy of the deltoid muscle whichresulted negative. In addition, the patient was examined bya neurologist and a psychiatrist and she underwent a per-sonality test, which emphasized a state of mild depression.The differential diagnosis excluded systemic diseases ofconnective tissue (systemic sclerosis, mixed connectivity,polymyositis and systemic lupus erythematosus), therefore,the most probable diagnosis is tension-type headache inHCV-related fibromyalgia [1–4] (Fig. 1). The diagnosis offibromyalgia was made according to the ACR criteria andcalculating widespread pain index and symptom severity(SS) scale of by Wolfe et al. [7]. The patient had pain causedby digital palpation of the neck, shoulder, chest, hip, kneeand elbow regions. The patient has been treated with anti-depressants, anxiolytics and antiepileptic GABAergic drugswith an improvement of the symptoms.Fibromyalgia is a multifactorial disease of unknownetiology. At the moment, it is considered as a neurosensi-tive disorder characterized by abnormal processing of painby the SNC. In our case, the daily tension-type headachecertainly was a symptom of fibromyalgic syndrome. Thereare many common features between the two pathologies:the symptomatology often overlaps and the origin of pain isregarded as ‘‘central’’; indeed, the same neurotransmitters(serotonin, glutamate, P substance, CGRP) and receptorsare involved [5, 6]. If the pathogenetic hypothesis is thesame, also the pharmacological treatment is common.Antidepressants (SSRI), antiepileptics and anxiolytics areused in both cases, and likewise are useful muscle relax-ation techniques. In our opinion, fibromyalgia should bealways considered, especially in women between 20 and40 years, in differential diagnosis of headache. In our case,

Sterile abscesses complicating monoclonal gammopathy of undetermined significance

A 47-year-old man presented with cough, fever and chest pain. A chest CT scan showed multiple nodules with air cavities in some, and IgGj monoclonal gammopathy of undetermined significance (MGUS) was detected. Blood, sputum and bronchoalveolar lavage cultures were negative for common and acid-fast bacteria or fungi. Antineutrophil cytoplasmic antibodies were negative. Empirical broad-spectrum antibiotic therapy was unsuccessful, while steroid therapy (prednisone 50 mg ⁄d) was followed by rapid clinical and radiological improvement. After steroid withdrawal fever recurred and novel pulmonary nodules developed. An open lung biopsy revealed abscesses with acute and chronic inflammatory areas containing neutrophlis and eosinophils, surrounded by giant epitheloid cells and interstitial fibrosis (Fig. 1A). As steroid therapy was resumed, fever disappeared and nodules regressed. The patient remained well on maintenance steroid therapy for 6 months, but shortly after treatment withdrawal fever relapsed and multiple lung, mesenteric, hepatic and splenic abscesses developed (Fig. 1B). As a predominantly eosinophilic abscess was revealed by liver biopsy, visceral larva migrans was suspected and albendazole was given without success. Based on the absence of microorganisms in the lesions, the failure of antimicrobial therapy, and the efficacy of steroid therapy we diagnosed an ‘aseptic abscesses syndrome,’ a rare condition commonly associated with chronic inflammatory bowel disease or MGUS (1).

Temporary pacemaker in refractory cluster headache treated with verapamil

Sir,We present a 35-year-old malepatient with 10 years’ history ofepisodic cluster headache (3–4attacks per day, previously treatedwith methysergide, lithium and oxy-gen without significant benefit).Therapy with verapamil 240 mg/dayreduced the frequency of attacks (2–3per day). After increasing the dose ofverapamil to 360 mg/day the patientpresented hypotension (75/40 mmHg)and serious bradycardia (HR 32/min),which required the implant of a tem-porary ventricular non-sequentialpacemaker. Once the critical periodhad passed, the blood pressure nor-malised; after the electrophysiologystudy found normal results, it waspossible to remove the pacemaker.Before starting verapamil therapy,cardiac examination and 24-h ECGrecording were normal.In the last 7 years, we have beenobserving four patients treated withverapamil for episodic clusterheadache that have referred hypoten-sion and serious bradycardia. Thepatients have not presented any con-traindication to prophylactic therapywith verapamil. Verapamil is a calci-um channel blocker and its commonadverse effects include constipation,dizziness, nausea, bradycardia andhypotension. It is widely used as afirst-line prophylactic drug for clusterheadache at doses starting at 360 mg[1, 2]. Patients with cluster headachepresent an increase in sympathetictone before the attack of a headache.This “sympathetic storm” could causeshort but hazardous periods ofarrhythmia [3]. On the contrary, aparasympathetic overactivity withconsequent bradycardia is presentduring the attack [4, 5]. Verapamiltherapy prevents episodic clusterheadache but it requires a strict con-trol of blood pressure and heart rate,because an overlap between theeffects of verapamil and the effects ofthe parasympathetic overactivitycharacterising the attack of clusterheadache that could cause serioushypotension and bradycardia can beverified [6].

Altered Circadian Rhythmicity for Angiotensin Converting Enzyme Activity in Migraine

Abstract:This investigation is devoted to the exploration of the 24 h patterns of the serum angiotensin converting enzyme (ACE) activity in clinically healthy subjects and normotensive migraine patients. A comparison was made with cortisol circadian rhythmicity. Time data series were analyzed by means of chronobiology procedures. The biostatistical approach has documented that the enzymatic activity of serum ACE changes with a circadian periodicity in clinically healthy subjects. The crest of this fluctuation is temporally located in the afternoon and shows an approximately 12 h delay when compared with cortisol circadian rhythm. Furthermore, the chronobiologic approach revealed that the enzymatic activity of serum ACE lacks a circadian biorthythmicity in migraine. By contrast, the morning crest of the circadian rhythmicity of cortisol cycle is preserved. The biochemical implication of this phenomenon in migraine patients is not readily evident. There may possibly be a relatively increased catabolism of enkephalins, which in its turn may contribute to the dysnociception of migraine. The altered time structure for the serum ACE circadian activity is, however, a biochemical aspect characterizing migraine syndrome.