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Facial-onset sensory-motor neuronopathy (FOSMN) first manifests with trigeminal sensory loss and pain, then spreads to bulbopontine and spinal motoneurons, sometimes with a fatal outcome.1,2

Painful neuropathy is associated with plasticity changes in the nervous system. Standard repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique used to study changes in cortical excitability and to inhibit pain perception. Deep rTMS is a newer development that allows direct activation of deeper neuronal populations, by a unique coil design termed the H-coil. This study was designed to assess whether deep rTMS applied over the motor cortical lower-limb representation relieves pain in patients with diabetic neuropathy.Patients were randomly assigned to receive daily real or sham H-coil rTMS for 5 consecutive days. After a 5-week washout period, they crossed over to the alternative treatment for additional 5 days (according to a crossover study design). Outcome measures were changes in the visual analogue scale (VAS) for pain and in area and threshold of RIII nociceptive flexion reflex (RIII reflex).Of the 25 patients randomized, 23 completed the study. After real rTMS, the VAS scores decreased significantly (p=0.01), and so did RIII reflex area (p0.01), while no significant effects in these variables were induced by the sham rTMS treatment. The rTMS-induced changes in the outcome measures disappeared about 3 weeks after stimulation. All patients tolerated stimulation well.Deep H-coil rTMS provides pain relief in patients with diabetic neuropathy. This innovative technique can induce a therapeutic effect on brain areas that otherwise remain difficult to target. rTMS may produce its analgesic effects, inducing motor cortex plasticity and activating descending inhibitory pain control systems.

Neuropathic pain (NP) is a major symptom which may be intractable in common neurological disorders such as neuropathy, spinal cord injury, multiple sclerosis and stroke. Pain is a complex sensation strongly modulated by cognitive influences, and understanding the underlying pathophysiological mechanisms in patients remains a challenge for pain specialists. The aim of my Phd-research was to show in according with present evidence-based studies the correlation between clinical manifestations of neuropathic pain and the underlying alteration of the different groups of fibers (Aβ, Aδ or C). In the second chapter I revised the previous guidelines about neuropathic pain assessment. History and clinical examination are a requirement to confirm the presence of a NP, and also an important step in reaching an aetiological diagnosis for NP. History and bedside examination are still fundamental to a correct diagnosis, while screening tools and questionnaires are useful in indicating probable NP. I argued in particular a recent technique, skin biopsy; I approached it at the beginning of my Phd during my stage at the I.R.C.S.S. C. Besta in Milan; then, I imported this procedure in our laboratory (Department of Pathological Anatomy, Sapienza University). We are now able to process skin biopsies and immunoassayed them with polyclonal anti-protein-gene-product 9.5 antibodies (specific for nerve fibers) using immunohistochemistry or immunofluorescence, which allowed demonstrating the extensive innervations of the epidermidis. In the following chapters I approached some common conditions of neuropathic pain. The third chapter is dedicated to the post-herpetic neuralgia, an exceptionally drug-resistant neuropathic pain. To investigate the pathophysiological mechanisms underlying postherpetic neuralgia we clinically investigated sensory disturbances, pains and itching, with an 11-point numerical rating scale in 41 patients with ophthalmic postherpetic neuralgia. In all the patients we recorded the blink reflex, mediated by non-nociceptive myelinated Aβ-fibers, and trigeminal laser evoked potentials (LEPs) related to nociceptive myelinated Aδ- and unmyelinated C-fiber activation. We also sought possible correlations between clinical sensory disturbances and neurophysiological data. Neurophysiological testing yielded significantly abnormal responses on the affected side compared with the normal side. The blink reflex delay correlated with the intensity of paroxysmal pain, whereas the Aδ- and C-LEP amplitude reduction correlated with the intensity of constant pain . Allodynia correlated with none of the neurophysiological data. Our study shows that postherpetic neuralgia impairs all sensory fiber groups. The neurophysiological-clinical correlations suggest that constant pain arises from a marked loss of nociceptive afferents, whereas paroxysmal pain is related to Aβ-fiber demyelination. These findings might be useful for a better understanding of pain mechanisms in postherpetic neuralgia. In the fourth chapter I treated the differential involvement of Aδ and Aβ fibers in neuropathic pain related to carpal tunnel syndrome (CTS). We studied 70 patients with a diagnosis of CTS (117 CTS hands). We used the DN4 questionnaire to select patients with neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to assess the intensity of the various qualities of neuropathic pain. All patients underwent a standard nerve conduction study (NCS) to assess the function of non-nociceptive Aβ-fibres, and the cutaneous silent period (CSP) after stimulation of the IIIrd and Vth digits, to assess the function of nociceptive Aδ-fibres. In 40 patients (75 CTS hands) we also recorded LEPs in response to stimuli delivered to the median nerve territory and mediated by nociceptive Aδ-fibres. We sought possible correlations between neurophysiological data and the various qualities of neuropathic pain as assessed by the NPSI. We found that the median nerve sensory conduction velocity correlated with paroxysmal pain and abnormal sensations, whereas LEP amplitude correlated with spontaneous constant pain. Our findings suggest that whereas paroxysmal pain and abnormal sensations reflect demyelination of non-nociceptive Aβ-fibres, spontaneous constant pain arises from damage to nociceptive Aδ-fibres. In the fifth chapter I treated the mechanisms of pain in multiple sclerosis. In this clinical and neurophysiological study we sought information on the clinical characteristics and underlying mechanisms of neuropathic pain related to the disease. A total of 302 consecutive patients with multiple sclerosis were screened for neuropathic pain by clinical examination and the DN4 tool. In patients selected for having ongoing extremity pain or Lhermitte’s phenomenon, we recorded somatosensory evoked potentials, mediated by Aβ non-nociceptive fibres, and LEP, mediated by Aδ nociceptive fibres. Of the 302 patients, 92 had pain (30%), and 42 (14%) neuropathic pain. Patients with neuropathic pain had more severe multiple sclerosis, as assessed by the expanded disability severity score, than those without pain. Whereas in patients with ongoing neuropathic pain laser evoked potentials were more frequently abnormal than somatosensory evoked potentials we found the opposite in patients with Lhermitte’s phenomenon. Our data underline the clinical importance of pain in multiple sclerosis and indicate that a more severe disease is associated with a higher risk of developing neuropathic pain. The prevalence of pain we found, lower than that reported in previous studies, may reflect the lower disease severity in our patients. Neurophysiological data show that whereas ongoing extremity pain is associated with spinothalamic pathway damage, Lhermitte’s phenomenon is related to damage of non-nociceptive pathways. These findings may be useful in designing a new therapeutic approach to neuropathic pain related to multiple sclerosis. The sixth chapter is dedicated to the mechanisms of pain in distal symmetric neuropathy. I and my colleagues performed a clinical, neurophysiological and histomorphological study on patients with neuropathic pain in distal symmetric neuropathy. In patients with distal symmetric polyneuropathy we assessed non-nociceptive Aβ- and nociceptive Aδ- and C-afferents to investigate their role in the development of neuropathic pain. We screened 2240 consecutive patients with sensory disturbances and collected 269 patients with distal symmetric polyneuropathy (57% with pain and 43% without). All patients underwent the Neuropathic Pain Symptom Inventory to rate ongoing, paroxysmal and provoked pains, a standard NCS to assess Aβ-fibre function, LEPs to assess Aδ-fibre function, and skin biopsy to assess the unmyelinated innervations of the epidermidis. Patients with pain had the same age, but a longer delay since symptom onset than those without . Loss of intraepidermal innervation did not correlate with the presence of neuropathic pain. Whereas the LEP amplitude was significantly lower in patients with pain than in those without , NCS and intraepidermal fibre nerves data did not differ between groups. LEPs were more severely affected in patients with ongoing pain than in those with provoked pain. Our findings indicate that the impairment of Aβ-fibres has no role in the development of ongoing or provoked pain. In patients with ongoing pain the severe LEP suppression and the correlation between pain intensity and LEP attenuation may indicate that this type of pain reflects damage to nociceptive axons. The partially preserved LEPs in patients with provoked pain suggest that thistype of pain is related to the abnormal activity arising from partially spared and sensitised nociceptive terminals. Because clinical and neurophysiological abnormalities followed similar patterns regardless of aetiology, pain should be classified and treated on mechanism-based grounds. In the seventh chapter I treated the mechanisms of allodynia in distal symmetric polyneuropathy allodynia. Patients with painful neuropathy frequently complain of allodynia, i.e. pain in response to a normally non-painful stimulus. Many authors consider allodynia to be generated by sensitization of the second-order nociceptive neurons to Aβ-fibre input (central sensitization). With the hypothesis that patients suffering from this type of pain probably have a relative sparing of Aβ-fibres in comparison with patients with ongoing pain only, we sought aimed at seeking information on mechanisms underlying allodynia. In 200 patients with distal symmetric polyneuropathy (114 with pain, 86 without) we assessed non-nociceptive Aβ- and nociceptive Aδ-afferents to investigate their role in the development of allodynia. After a detailed clinical examination and pain questionnaires patients underwent a standard nerve conduction study (NCS) to assess Aβ-fibre function, and LEPs to assess Aδ-fibre function. Forthy-four out of 114 patients with painful neuropathy suffered from allodynia. While NCS data did not differ between patients with and without allodynia, LEP amplitude was higher in patients with allodynia than in those without. Our data argue against a role of Aβ-fibres and central sensitization as the main mechanism for the development of allodynia in distal symmetric polyneuropathy. The partially preserved LEPs in patients with allodynia suggests that this type of pain might be related to the abnormal reduction of mechanical threshold of nociceptive terminals (peripheral sensitization). In the eighth chapter I treated neuropathic pain in patient with crioglobulinemia. The study aimed at gaining information on peripheral neuropathy and neuropathic pain in patients with cryoglobulinaemia. We collected 48 consecutive patients with cryoglobulinaemia. All patients underwent a standard NCS to assess A-fibre function, LEPs to assess A-fibre function, and skin biopsy to assess C-fibre terminals. We used DN4 questionnaire to diagnose neuropathic pain, and the Neuropathic Pain Symptom Inventory to rate the intensity of the different qualities of neuropathic pain. Thirty patients had a peripheral neuropathy. Twenty-three had neuropathic pain as assessed by the DN4 questionnaire. NPSI questionnaire showed that the most frequent type of pain was the burning pain. Patients with peripheral neuropathy had an older age than those without . The duration of the disease correlated with the density of epidermal innervation as assessed by skin biopsy. The severity of the ongoing burning pain correlated with the amplitude of LEPs, but not with the density of epidermal innervation . Our findings showed that an older age is associated with the development of peripheral neuropathy, and a longer duration of disease with a more severe peripheral nerve damage, as assessed by skin biopsy. The correlation between the intensity of ongoing pain and LEP attenuation indicate that neuropathic pain reflects damage to nociceptive axons. In the ninth chapter I discussed the research on a peptide, the kiss-peptine, whose antagonist could be a new analgesic drug. More studies should be perform in the next future about it . Kisspeptin is a neuropeptide known for its role in the hypothalamic regulation of the reproductive axis. Following the recent description of kisspeptin and its 7-TM receptor, GPR54, in the dorsal root ganglia and dorsal horns of the spinal cord, we examined the role of kisspeptin in the regulation of pain sensitivity in mice. Immunofluorescent staining in the mouse skin showed the presence of GPR54 receptors in PGP9.5-positive sensory fibers. Intraplantar injection of kisspeptin (1 or 3 nmol/5 μl) induced a small nocifensive response in naive mice, and lowered thermal pain threshold in the hot plate test. Both intraplantar and intrathecal (0.5 or 1 nmol/3 μl) injection of kisspeptin caused hyperalgesia in the first and second phases of the formalin test, whereas the GPR54 antagonist, p234 (0.1 or 1 nmol), caused a robust analgesia. Intraplantar injection of kisspeptin combined with formalin enhanced TRPV1 phosphorylation at Ser800 at the injection site, and increased ERK1/2 phosphorylation in the ipsilateral dorsal horn as compared to naive mice and mice treated with formalin alone. These data demonstrate for the first time that kisspeptin regulates pain sensitivity in rodents and suggest that peripheral GPR54 receptors could be targeted by novel drugs in the treatment of inflammatory pain. In the tenth last chapter I gathered all the conclusion of the single studies. Here I tried to associate each quality of pain to an underling pathophysiological alteration, since the aim of y studies was to show the correlation between clinical manifestations of neuropathic pain and the underlying alteration of the different groups of fibers (A-β, A-δ or C).

In this clinical and neurophysiological study, we examined the clinical characteristics and underlying mechanisms of neuropathic pain related to multiple sclerosis. A total of 302 consecutive patients with multiple sclerosis were screened for neuropathic pain by clinical examination and the DN4 tool. In patients selected for having ongoing extremity pain or Lhermitte's phenomenon, we recorded somatosensory evoked potentials, mediated by Aβ non-nociceptive fibres, and laser evoked potentials, mediated by Aδ nociceptive fibres. Of the 302 patients, 92 had pain (30%), and 42 (14%) neuropathic pain. Patients with neuropathic pain had more severe multiple sclerosis, as assessed by the expanded disability severity score, than those without pain. Whereas, in patients with ongoing neuropathic pain, laser evoked potentials were more frequently abnormal than somatosensory evoked potentials, we found the opposite in patients with Lhermitte's phenomenon. Our data underline the clinical importance of pain in multiple sclerosis and indicate that a more severe disease is associated with a higher risk of developing neuropathic pain. The prevalence of pain that we found, which was lower than that reported in previous studies, may reflect the lesser disease severity in our patients. Neurophysiological data show that whereas ongoing extremity pain is associated with spinothalamic pathway damage, Lhermitte's phenomenon is related to damage of non-nociceptive pathways. These findings may be useful in designing a new therapeutic approach to neuropathic pain related to multiple sclerosis.