G Cruccu

Sapienza University of Rome, Roma, Latium, Italy

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Publications (278)937.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Emerging evidence associates fibromyalgia (FM) with pain system dysfunction. In this study, using laser evoked potentials (LEPs) and paired laser stimuli, we tested excitability in the pain matrices and sought possible changes in patients with FM. In 20 patients with FM and 15 healthy subjects, after recording control nociceptive system-mediated Aδ- and C-fibre-related LEPs, we measured excitability in the pain matrices by testing the Aδ-LEP conditioned by a preceding C-LEP. No difference was found in control LEP amplitudes for Aδ- or C-fibres between patients and healthy subjects. Conversely, the Aδ-LEP amplitude, conditioned by a preceding C-LEP, was significantly higher in patients than in healthy subjects (p<0.001). Objective evidence from increased conditioned Aδ-LEP amplitudes reflecting hyperexcitability in the pain matrices in FM, provides diagnostically useful information and might help in developing new therapeutic approaches.
    Clinical and experimental rheumatology 03/2015; 33(1 Suppl 88):68-72. · 2.97 Impact Factor
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    ABSTRACT: We aimed at seeking more precise diagnostic information on the sensory nervous system involvement described in patients with amyotrophic lateral sclerosis (ALS). We investigated large myelinated nerve fibres with nerve conduction study and small-nerve fibres with Quantitative Sensory Testing (QST) (assessing thermal-pain perceptive thresholds) and skin biopsy (assessing intraepidermal nerve fibre density) in 24 consecutive patients with ALS, 11 with bulbar-onset and 13 with spinal-onset. In 23 of the 24 patients, regardless of ALS onset, nerve conduction study invariably showed large myelinated fibre sparing. In patients with bulbar-onset ALS, QST found normal thermal-pain perceptive thresholds and skin biopsy disclosed normal intraepidermal nerve fibre density. Conversely, in patients with spinal-onset, thermal-pain thresholds were abnormal and distal intraepidermal nerve fibre density was reduced. Sensory nervous system involvement in ALS differs according to disease onset. Patients with spinal-onset but not those with bulbar-onset ALS have concomitant distal small-fibre neuropathy. Neurologists should therefore seek this ALS-related non-motor feature to improve its diagnosis and treatment.
    Journal of Neurology 02/2015; DOI:10.1007/s00415-015-7672-0 · 3.84 Impact Factor
  • Neurology 01/2015; DOI:10.1212/WNL.0000000000001216 · 8.30 Impact Factor
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    ABSTRACT: Background Patients presenting with bilateral trigeminal hypoesthesia may go on to have trigeminal isolated sensory neuropathy, a benign, purely trigeminal neuropathy, or facial-onset sensory motor neuronopathy (FOSMN), a malignant life-threatening condition. No diagnostic criteria can yet differentiate the two conditions at their onset. Nor is it clear whether the two diseases are distinct entities or share common pathophysiological mechanisms.Methods Seeking pathophysiological and diagnostic information to distinguish these two conditions at their onset, in this neurophysiological and morphometric study we neurophysiologically assessed function in myelinated and unmyelinated fibres and histologically examined supraorbital nerve biopsy specimens with optic and electron microscopy in 13 consecutive patients with recent onset trigeminal hypoesthesia and pain.ResultsThe disease course distinctly differed in the 13 patients. During a mean 10 year follow-up whereas in eight patients the disease remained relatively stable, in the other five it progressed to possibly life-threatening motor disturbances and extra-trigeminal spread. From two to six years elapsed between the first sensory symptoms and the onset of motor disorders. In patients with trigeminal isolated sensory neuropathy (TISN) and in those with FOSMN neurophysiological and histological examination documented a neuronopathy manifesting with trigeminal nerve damage selectively affecting myelinated fibres, but sparing the Ia-fibre-mediated proprioceptive reflex.Conclusions Although no clinical diagnostic criteria can distinguish the two conditions at onset, neurophysiological and nerve-biopsy findings specify that in both disorders trigeminal nerve damage manifests as a dissociated neuronopathy affecting myelinated and sparing unmyelinated fibres, thus suggesting similar pathophysiological mechanisms.
    BMC Neurology 12/2014; 14(1):248. DOI:10.1186/s12883-014-0248-2 · 2.49 Impact Factor
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    ABSTRACT: Background Fibromyalgia diagnosis is a challenging and long process, especially among primary care physicians (PCPs), because of symptom heterogeneity, co-morbidities and clinical overlap with other disorders. The purpose was to develop and validate a screening tool in French (FR), German (DE) and English (UK) to help primary care physicians (PCPs) identify patients with fibromyalgia.Methods The FibroDetect questionnaire was simultaneously developed in FR, DE and UK based on information obtained from a literature review, focus groups conducted with clinicians, and face-to-face interviews with fibromyalgia patients (FR, DE and UK, n¿=¿23). The resulting tool was comprehension-tested in patients with diagnosed or suspected fibromyalgia (n¿=¿3 and n¿=¿2 in each country, respectively). Acceptability and applicability were assessed and the tool modified accordingly, then assessed in clinical practice. A scoring method was created using an iterative process based on statistical and clinical considerations with American College of Rheumatology¿+¿(ACR+) patients and ACR¿ patients (n¿=¿276), and validated with fibromyalgia and non-fibromyalgia patients (n¿=¿312).ResultsThe FibroDetect included 14 questions assessing patients¿ pain and fatigue, personal history and attitudes, symptoms and impact on lives. Six questions were retained in the final scoring, demonstrating satisfactory discriminative power between ACR¿+¿and ACR- patients with area under the Receiver Operating Characteristic curve of 0.74. The predictive accuracy of the tool increased to 0.86 for fibromyalgia and non-fibromyalgia patient detection, with a sensitivity of 90% and a specificity of 67% for a cut-off of 6 on the score.Conclusions The FibroDetect is a self-administered tool that can be used as a screening classification surrogate to the ACR criteria in primary care settings to help PCPs detect potential fibromyalgia patients among a population complaining of chronic widespread pain.
    Health and Quality of Life Outcomes 10/2014; 12(1):128. DOI:10.1186/s12955-014-0128-x · 2.10 Impact Factor
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    ABSTRACT: Sensory profiles are heterogeneous in neuropathic pain disorders and subgroups of patients respond differently to treatment. To further explore this, patients in the COMBO-DN study were prospectively assessed by the Neuropathic Pain Symptom Inventory (NPSI) at baseline, after initial 8- week therapy with either duloxetine or pregabalin, and after subsequent 8-week combination/highdose therapy. Exploratory post-hoc cluster analyses were performed to identify and characterize potential subgroups through their scores in the NPSI items. In patients not responding to initial 60 mg/day duloxetine, adding 300 mg/day pregabalin for combination treatment was particularly effective regarding the dimensions pressing pain and evoked pain whereas maximizing the duloxetine dose to 120 mg/day appeared more beneficial regarding paresthesia/dysesthesia. In contrast, adding 60 mg/day duloxetine to 300 mg/day pregabalin in case of non-response to initial pregabalin led to numerically higher decreases in all NPSI dimensions/items compared to maximizing the pregabalin dose to 600 mg/day. Cluster analysis revealed 3 patient clusters (defined by baseline scores for the 10 NPSI sensory items) with different pain profiles, not only in terms of overall pain severity, but also across NPSI items. Mean Brief Pain Inventory average pain improved in all clusters during combination/high-dose therapy. However, in patients with severe pain, the treatment effect showed a trend in favor of high-dose monotherapy while combination therapy appeared more beneficial in patients with moderate and mild pain (not significant). These complementary exploratory analyses further endorse the idea that sensory phenotyping might lead to a more stratified treatment and potentially to personalized pain therapy.
    Pain 08/2014; 155(10). DOI:10.1016/j.pain.2014.08.020 · 5.64 Impact Factor
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    ABSTRACT: The guidelines on trigeminal neuralgia management that have been agreed and jointly published by the American Academy of Neurology and the European Federation of Neurological Societies recommend carbamazepine (CBZ) and oxcarbazepine (OXC) as the first-choice medical treatments in patients with trigeminal neuralgia (TN). The aim of this retrospective study was to analyze the natural history of classical trigeminal neuralgia in a large cohort of patients, focusing on drug responsiveness, side effects related to CBZ and OXC, and changes in pain characteristics during the course of disease.
    The Journal of Headache and Pain 06/2014; 15(1):34. DOI:10.1186/1129-2377-15-34 · 3.28 Impact Factor
  • Clinical Neurophysiology 06/2014; 125:S311. DOI:10.1016/S1388-2457(14)51023-1 · 2.98 Impact Factor
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    ABSTRACT: Though classical trigeminal neuralgia (CTN) is frequently caused by neurovascular contact (NVC) at the trigeminal root entry zone (REZ), both anatomical and MRI studies have shown that NVC of the trigeminal nerve frequently occurs in people without CTN. To assess the accuracy of MRI in distinguishing symptomatic from asymptomatic trigeminal NVC, we submitted to high definition MRI the series of CTN patients referred to our outpatient service between June 2011 and January 2013 (n=24), and a similar number of age-matched healthy controls. Two neuroradiologists, blinded to the clinical data, evaluated whether the trigeminal nerve displayed NVC in the REZ or non-REZ, whether it was dislocated by the vessel or displayed atrophy at the contact site, and whether the offending vessel was an artery or a vein. Our data were meta-analyzed with those of all similar studies published from January 1970 to June 2013. In our sample, REZ contact, nerve dislocation and nerve atrophy were independently associated with CTN (p=0.027; p=0.005; p=0.035 respectively). Compared to a rather low sensitivity of each of these items (alone or in combination), their specificity was high. When REZ contact and nerve atrophy coexisted, both specificity and positive predictive value rose to 100%. Meta-analysis showed that REZ NVC was detected in 76% of symptomatic and 17% of asymptomatic nerves (p<0.0001), while anatomical changes were detected in 52% of symptomatic and 9% of asymptomatic nerves (p<0.0001). Trigeminal REZ NVC, as detected by MRI, is highly likely to be symptomatic when it is associated with anatomical nerve changes.
    Pain 04/2014; 155(8). DOI:10.1016/j.pain.2014.04.020 · 5.64 Impact Factor
  • A Truini, A Biasiotta, G Cruccu
    Pain 03/2014; DOI:10.1016/j.pain.2014.03.006 · 5.64 Impact Factor
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    ABSTRACT: Hepatitis C virus (HCV)-related cryoglobulinemia commonly causes disabling complications including peripheral neuropathy and neuropathic pain. In this prospective clinical, neurophysiological, and skin biopsy study we aimed at assessing clinical characteristics and risk factors of peripheral neuropathy and neuropathic pain in patients with HCV-related cryoglobulinemia. We enrolled 69 consecutive patients with HCV-related cryoglobulinemia. We diagnosed neuropathic pain with the DN4 (Neuropathic Pain Diagnostic) questionnaire, and rated the various neuropathic pains with the Neuropathic Pain Symptom Inventory (NPSI). All patients underwent a standard nerve conduction study to assess Aβ-fiber function, laser-evoked potentials to assess Aδ-fiber function, and skin biopsy to assess C-fiber terminals. Of the 69 patients studied, 47 had a peripheral neuropathy, and 29 had neuropathic pain. Patients with peripheral neuropathy were older than those without (P < 0.0001). While peripheral neuropathy was significantly associated with the duration of HCV infection (P < 0.01), it was unrelated to the duration of cryoglobulinemia and cryocrit (P > 0.5). The severity of peripheral neuropathy significantly correlated with the duration of HCV infection (P < 0.05). Laser-evoked potential amplitudes were significantly lower in patients with than in those without neuropathic pain (P < 0.05). Conversely, no difference was found in nerve conduction study and skin biopsy findings (P > 0.05). Our findings show that peripheral neuropathy is related to age and HCV infection, rather than to cryoglobulinemia, and neuropathic pain is associated with damage to nociceptive pathways as assessed with laser-evoked potentials; this might be useful for designing more effective clinical interventions for these common HCV related-cryoglobulinemia complications.
    Journal of Neurology 02/2014; 261(4). DOI:10.1007/s00415-014-7261-7 · 3.84 Impact Factor
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    ABSTRACT: An international panel of pain specialists (anesthesiology, neurology, neurosurgery, and psychology) and research methodologists developed a screening tool to identify patients who may be suitable for spinal cord stimulation (SCS)-the Refractory Chronic Pain Screening Tool (RCPST) prototype. We describe a feasibility study to explore practicality and validity of this prototype. Consecutive outpatients were screened in two centers (United Kingdom and United States). Sixty chronic pain adults without satisfactory pain relief despite treatment were assessed using RCPST (by pain specialist without expertise in neurostimulation) and then evaluated by two pain specialists experienced in SCS implantation and management to determine whether the patient should be referred for SCS. To maintain blinding, the participating physicians did not inform each other or the patient of assessment outcome. Sensitivity and specificity of the RCPST prototype were calculated using implanters' judgment as "gold standard." The average age of patients was 47.7 years; 53% were female. Fifty-seven patients completed the study (one withdrew consent, two lost to follow-up). The pain specialists agreed the prototype was easy to use and took <10 minutes to complete. Implanter agreement was moderate (Kappa: 0.63, 95% confidence interval: 0.35-0.91). The prototype had low sensitivity (40%, 19-61%) and moderate specificity (78%, 65-92%). Using the same questionnaire with a modified decision algorithm, new prototypes were generated with range of high sensitivity (80-100%) and specificity (89-97%) values. The RCPST aims to identify patients that should be referred for consideration for neurostimulation. The final implant decision requires appropriate neurological diagnostic workup, psychological assessment, and trial stimulation. RCPST was considered practical for routine clinical practice and contained appropriate questions. Sensitivity needs to be improved. A future study should select and validate the ideal RCPST prototype.
    Pain Medicine 02/2014; 15(2):281-91. DOI:10.1111/pme.12272 · 2.24 Impact Factor
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    ABSTRACT: The different neuropathic pain types (e.g. ongoing burning pain and allodynia) are frequent and disabling complaints in patients with peripheral neuropathies. Although the reference standard technique for diagnosing painful small fibre neuropathies is nerve fibre density assessment by skin biopsy, the relationship between the epidermal nerve fibre (ENF) density and neuropathic pain is still unclear. In a clinical and skin biopsy study designed to investigate whether changes in ENF density are directly related to pain, we enrolled 139 consecutive patients with distal symmetric peripheral neuropathy. All patients underwent clinical examination. The Neuropathic Pain Symptom Inventory was used to distinguish the different neuropathic pain types. A skin biopsy was conducted and ENFs were immunostained with the antiprotein gene product 9.5 and their linear density was quantified with bright-field microscopy. No difference was found in ENF density between patients with and without neuropathic pain, nor between patients with and without ongoing burning pain. Conversely, ENF density was higher in patients with provoked pains (including mechanical dynamic allodynia) than in those without. The variable association between ENF density and symptoms of neuropathic pain supports the idea that neuropathic pain symptoms arise through distinct underlying mechanisms. The lack of relationship between ongoing burning pain and ENF density suggests that this type of pain reflects factors other than loss of nociceptive afferents. The association between ENF density and provoked pain (including mechanical dynamic allodynia) suggests that this type of pain might be mediated by spared and sensitised nociceptive afferents.
    Pain 01/2014; 155(4). DOI:10.1016/j.pain.2014.01.022 · 5.64 Impact Factor
  • Clinical Neurophysiology 11/2013; 124(11):e197. DOI:10.1016/j.clinph.2013.06.064 · 2.98 Impact Factor
  • Clinical Neurophysiology 11/2013; 124(11):e192-e193. DOI:10.1016/j.clinph.2013.06.043 · 2.98 Impact Factor
  • Clinical Neurophysiology 11/2013; 124(11):e198. DOI:10.1016/j.clinph.2013.06.067 · 2.98 Impact Factor
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    ABSTRACT: Neuropathic pain-that is, pain arising directly from a lesion or disease that affects the somatosensory system-is a common clinical problem, and typically causes patients intense distress. Patients with neuropathic pain have sensory abnormalities on clinical examination and experience pain of diverse types, some spontaneous and others provoked. Spontaneous pain typically manifests as ongoing burning pain or paroxysmal electric shock-like sensations. Provoked pain includes pain induced by various stimuli or even gentle brushing (dynamic mechanical allodynia). Recent clinical and neurophysiological studies suggest that the various pain types arise through distinct pathophysiological mechanisms. Ongoing burning pain primarily reflects spontaneous hyperactivity in nociceptive-fibre pathways, originating from 'irritable' nociceptors, regenerating nerve sprouts or denervated central neurons. Paroxysmal sensations can be caused by several mechanisms; for example, electric shock-like sensations probably arise from high-frequency bursts generated in demyelinated non-nociceptive Aβ fibres. Most human and animal findings suggest that brush-evoked allodynia originates from Aβ fibres projecting onto previously sensitized nociceptive neurons in the dorsal horn, with additional contributions from plastic changes in the brainstem and thalamus. Here, we propose that the emerging mechanism-based approach to the study of neuropathic pain might aid the tailoring of therapy to the individual patient, and could be useful for drug development.
    Nature Reviews Neurology 09/2013; DOI:10.1038/nrneurol.2013.180 · 15.52 Impact Factor
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    ABSTRACT: This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) were given. Thereafter, in the 8-week combination/high-dose therapy period, only non-responders received 120mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary endpoints included response rates, BPI-MSF-severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. 804 patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; p=0.370) and most secondary endpoints, which, however, consistently favored combination therapy. 50%-response rates were 52.1% for combination and 39.3% for high-dose monotherapy (p=0.068). In exploratory analyses of the As initial 8-week therapy uncorrected for multiple comparisons, 60mg/day duloxetine was found superior to 300mg/day pregabalin (p<0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe and well tolerated. For initial 8-week treatment at half their maximum doses, duloxetine provided better analgesia.
    Pain 05/2013; 154(12). DOI:10.1016/j.pain.2013.05.043 · 5.64 Impact Factor
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    ABSTRACT: Lack of habituation during repetitive stimulation is the most consistent interictal abnormality of cortical information processing observed in migraine. Preventive migraine treatments might act by stabilizing cortical excitability level and thus the habituation to external stimuli. We examined the effects of preventive treatment with topiramate on migraineur's habituation to nociceptive stimulation. Scalp potentials were evoked by Nd-YAP Laser stimulation of the hand dorsum and supraorbital region in 13 patients with migraine without aura (MO) and 15 healthy volunteers (HV). The exam was repeated in MO before and after treatment. We observed a lack of habituation and lower initial amplitudes in MO compared to HV. These abnormalities reached statistical significance for N1 LEPs component, generated in the secondary somatosensory cortex (SII), but not for N2/P2 complex, generated in the insula and anterior cingulated cortex (ACC). Topiramate normalized the N1 habituation pattern in MO, with a significant correlation between clinical effects and normalization of neurophysiological responses. Our results indicate a modulating action of topiramate on cortical processing of sensorial stimuli, mainly regarding the sensory-discriminative component of pain, elaborated by SII, without a significant effect on the affective dimension of pain, in which the ACC has an important role.
    The Journal of Headache and Pain 03/2013; 14(1):25. DOI:10.1186/1129-2377-14-25 · 3.28 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: The periaqueductal gray (PAG), a brain area belonging to the descending pain modulatory system, plays a crucial role in pain perception. Little information is available on the relationship between PAG activation and perceived pain intensity. In this study, we acquired functional magnetic resonance imaging (fMRI) scans from the PAG during the cold pressor test, a model for tonic pain, in 12 healthy volunteers. fMRI data were acquired with a 12-channel head-coil and a 3-Tesla scanner and analyzed with Statistical Parametric Mapping (SPM8) software. During the cold pressor test, fMRI showed significant activation clusters in pain-related brain areas: bilateral middle and superior frontal gyrus, anterior cingulate cortex, and thalamus, left insula, right inferior frontal gyrus, left inferior temporal gyrus and in the bilateral PAG (cluster level corrected threshold p < 0.05). PAG activation correlated directly with the pain threshold and inversely with the participant’s perceived pain intensity (cluster level corrected threshold (p < 0.05). The cold pressor test consistently activated the PAG as well as other pain-related areas in the brain. Our study, showing that the greater the PAG activation the higher the pain threshold and the weaker the pain intensity perceived, highlights the key role of the PAG in inhibiting the pain afferent pathway function. Our findings might be useful for neuroimaging studies investigating PAG activation in patients with chronic idiopathic pain conditions possibly related to dysfunction in the descending pain modulatory system.
    Magnetic Resonance Imaging 01/2013; DOI:10.1016/j.mri.2013.12.003 · 2.02 Impact Factor

Publication Stats

8k Citations
937.91 Total Impact Points


  • 1984–2015
    • Sapienza University of Rome
      • • Department of Neurology and Psychiatry
      • • Department of Anatomical, Histological, Forensic Medicine and Orthopedic Science
      Roma, Latium, Italy
  • 2011
    • ORTON Foundation, Helsinki, Finland
      Helsinki, Uusimaa, Finland
  • 2007
    • The University of Edinburgh
      Edinburgh, Scotland, United Kingdom
  • 1987–2007
    • The American University of Rome
      Roma, Latium, Italy
  • 2004–2005
    • Johannes Gutenberg-Universität Mainz
      • Neurobiology
      Mainz, Rhineland-Palatinate, Germany
  • 2000–2002
    • IRCCS Istituto Neurologico Mediterraneo Neuromed
      Poczilli, Molise, Italy
  • 2001
    • Università degli Studi di Genova
      • Centro interuniversitario per la neurofisiologia del dolore
      Genova, Liguria, Italy
  • 1983–2001
    • University of Rome Tor Vergata
      • Dipartimento di Scienze e Tecnologie Chimiche
      Roma, Latium, Italy