Giulia Di Stefano

Mechanisms of pain in multiple sclerosis: a combined clinical and neurophysiological study.

Summary In patients with multiple sclerosis, ongoing extremity pain is associated with damage to the spinothalamic pathway, whereas Lhermitte’s phenomenon is related to damage of non‐nociceptive pathways. ABSTRACT 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.

Trigeminal neuralgia - Diagnosis and treatment

Introduction Trigeminal neuralgia (TN) is characterized by touch-evoked unilateral brief shock-like paroxysmal pain in one or more divisions of the trigeminal nerve. In addition to the paroxysmal pain, some patients also have continuous pain. TN is divided into classical TN (CTN) and secondary TN (STN). Etiology and pathophysiology Demyelination of primary sensory trigeminal afferents in the root entry zone is the predominant pathophysiological mechanism. Most likely, demyelination paves the way for generation of ectopic impulses and ephaptic crosstalk. In a significant proportion of the patients, the demyelination is caused by a neurovascular conflict with morphological changes such as compression of the trigeminal root. However, there are also other unknown etiological factors, as only half of the CTN patients have morphological changes. STN is caused by multiple sclerosis or a space-occupying lesion affecting the trigeminal nerve. Differential diagnosis and treatment Important differential diagnoses include trigeminal autonomic cephalalgias, posttraumatic or postherpetic pain and other facial pains. First line treatment is prophylactic medication with sodium channel blockers, and second line treatment is neurosurgical intervention. Future perspectives Future studies should focus on genetics, unexplored etiological factors, sensory function, the neurosurgical outcome and complications, combination and neuromodulation treatment as well as development of new drugs with better tolerability.

Triggering trigeminal neuralgia

Introduction Although it is widely accepted that facial pain paroxysms triggered by innocuous stimuli constitute a hallmark sign of trigeminal neuralgia, very few studies to date have systematically investigated the role of the triggers involved. In the recently published diagnostic classification, triggered pain is an essential criterion for the diagnosis of trigeminal neuralgia but no study to date has been designed to address this issue directly. In this study, we set out to determine, in patients with trigeminal neuralgia, how frequently triggers are present, which manoeuvres activate them and where cutaneous and mucosal trigger zones are located. Methods Clinical characteristics focusing on trigger factors were collected from 140 patients with trigeminal neuralgia, in a cross-sectional study design. Results Provocation of paroxysmal pain by various trigger manoeuvres was reported by 136 of the 140 patients. The most frequent manoeuvres were gentle touching of the face (79%) and talking (54%). Trigger zones were predominantly reported in the perioral and nasal region. Conclusion This study confirms that in trigeminal neuralgia, paroxysmal pain is associated with triggers in virtually all patients and supports the use of triggers as an essential diagnostic feature of trigeminal neuralgia.

Pharmacological treatment of trigeminal neuralgia

ABSTRACT Introduction: Unique among the different neuropathic pain conditions, trigeminal neuralgia frequently has an excellent response to some selected drugs, which, on the other hand, often entail disabling side effects. Physicians should be therefore acquainted with the management of these drugs and the few alternative options. Areas covered: This article, based on a systematic literature review, describes the pharmacological options, and indicates the future perspectives for treating trigeminal neuralgia. The article therefore provides current, evidence-based knowledge about the pharmacological treatment of trigeminal neuralgia, and suggests a practical approach to the various drugs, including starting dose, titration and side effects. Expert commentary: Carbamazepine and oxcarbazepine are the reference standard drugs for treating patients with trigeminal neuralgia. They are effective in most patients. The undesired effects however cause withdrawal from treatment or a dosage reduction to an insufficient level in many patients. Sodium channel blockers selective for the sodium channel 1.7 (Nav1.7) receptor, currently under development, might be an alternative, better-tolerated pharmacological option in the next future.

Trigeminal isolated sensory neuropathy (TISN) and FOSMN syndrome: despite a dissimilar disease course do they share common pathophysiological mechanisms?

BackgroundPatients 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.MethodsSeeking 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.ConclusionsAlthough 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.

Diagnostic accuracy of laser-evoked potentials in diabetic neuropathy

Abstract Although the most widely agreed neurophysiological tool for investigating small fiber damage is laser-evoked potential (LEP) recording, no study has documented its diagnostic accuracy. In this clinical, neurophysiological, and skin biopsy study, we collected age-corrected LEP normative ranges, verified the association of LEPs with pinprick sensory disturbances in the typical diabetic mixed fiber polyneuropathy, and assessed the sensitivity and specificity of LEPs in diabetic small fiber neuropathy. From 288 LEP recordings from the face, hand, and foot in 73 healthy subjects, we collected age-corrected normative ranges for LEPs. We then selected 100 patients with mixed-fiber diabetic neuropathy and 25 patients with possible small-fiber diabetic neuropathy. In the 100 patients with mixed fiber neuropathy, we verified how LEP abnormalities were associated with clinically evident pinprick sensory disturbances. In the 25 patients with possible pure small fiber neuropathy, using the skin biopsy for assessing the intraepidermal nerve fiber density as a reference standard, we calculated LEP sensitivity and specificity. In healthy participants, age strongly influenced normative ranges for all LEP variables. By applying age-corrected normative ranges for LEPs, we found that LEPs were strongly associated with pinprick sensory disturbances. In relation to the skin biopsy findings, LEPs yielded 78% sensitivity and 81% specificity in the diagnosis of diabetic small fiber neuropathy. Our study, providing age-corrected normative ranges for the main LEP data and their diagnostic accuracy, helps to make LEPs more reliable as a clinical diagnostic tool, and proposes this technique as a less invasive alternative to skin biopsy for diagnosing diabetic small fiber neuropathy.

Pain‐processing abnormalities in bipolar I disorder, bipolar II disorder, and schizophrenia: A novel trait marker for psychosis proneness and functional outcome?

Overlapping neural system dysfunctions, mainly involving the secondary somatosensory cortex (S2), the anterior cingulate cortex (ACC) and the anterior insular cortex (AIC), seem to be related to both pain‐perception abnormalities and psychotic symptoms in schizophrenia (SCZ) and bipolar disorder (BD). Laser‐evoked potentials (LEPs) were used to investigate pain‐perception and central pain‐processing abnormalities in SCZ, bipolar I disorder (BD‐I), and bipolar II disorder (BD‐II), and to evaluate their relationship with history of psychosis, and social‐cognitive and functional impairments.

Cutaneous silent period recordings in demyelinating and axonal polyneuropathies

OBJECTIVE To investigate the cutaneous silent period (CSP), a spinal inhibitory reflex mainly mediated by A-delta fibres, in demyelinating and axonal polyneuropathy (PNP) and evaluate whether CSP parameters differ between patients with and without neuropathic pain. METHODS Eighty-four patients with demyelinating PNP, 178 patients with axonal PNP and 265 controls underwent clinical examination, DN4 questionnaire, standard nerve conduction study, motor-root stimulation and CSP recordings from abductor digiti minimi. We calculated the afferent conduction time of CSP (a-CSP time) with the formula: CSP latency-root motor evoked potential latency. RESULTS In the demyelinating PNP group the a-CSP time was significantly longer; in the axonal PNP group, CSP duration was shorter than the demyelinating group (p=0.010) and controls (p=0.001). CSP parameters were not different between patients with and without neuropathic pain. CONCLUSIONS The abnormality of a-CSP time in the demyelinating PNP group suggests the crucial role of A-delta fibres in the mechanism of CSP; the shorter CSP duration in the axonal PNP group supports the strong influence of the number of axons on this parameter. Our study suggests that neuropathic pain could be related to pathophysiological mechanisms differing from mere A-delta fibre loss. SIGNIFICANCE CSP evaluation is effective in detecting A-delta fibre dysfunction in axonal as well as demyelinating PNP.

Trigeminal Neuralgia Completely Relieved After Stent-Assisted Coiling of a Superior Cerebellar Artery Aneurysm

BACKGROUND Although secondary trigeminal neuralgia is usually due to tumors or multiple sclerosis, other major neurologic diseases, such as aneurysms, should be taken into account when the history or the symptoms suggest a secondary origin. CASE DESCRIPTION A 67-year-old lady presented with a 6-month history of trigeminal neuralgia involving exclusively the right ophthalmic division. A dedicated 3-dimensional-magnetic resonance imaging-magnetic resonance angiography study documented rare contact with a wide-necked aneurysm of the superior cerebellar artery, which distorted the trigeminal root. The patient underwent an endovascular treatment by stent-assisted coiling with the complete disappearance of neuralgic pain attacks within 24 hours. CONCLUSION The complete relief from the neuralgic paroxysms immediately after endovascular stent-assisted occlusion of a superior cerebellar artery aneurysm demonstrates the crucial role of a pulsating stimulus on the demyelinated nerve fibers in evoking the ectopically generated discharges.

An Unusual Case of Simultaneous Bilateral Trigeminal Neuralgia Due to Multiple Sclerosis

Although several reports have indicated that trigeminal neuralgia related to multiple sclerosis may occur bilaterally in the orofacial region, trigeminal neuralgia pain usually involves the two sides in different time lapses, and the simultaneous involvement of trigeminal territories on both sides is commonly considered incompatible with its diagnosis. This case report describes a patient with bilateral trigeminal neuralgia related to multiple sclerosis that started simultaneously on both sides of the orofacial region. A 55-year-old man presented with a 16-year history of relapsing/remitting multiple sclerosis. For 1 year, the patient had been complaining of electric shock-like, paroxysmal pain of severe intensity that lasted from a fraction of a second to a few minutes and involved the first and second trigeminal divisions of both sides simultaneously. The neurophysiologic testing of trigeminal reflexes showed bilateral delayed latencies of reflex responses compatible with a trigeminal afferent pathway impairment related to multiple sclerosis. A dedicated 3T magnetic resonance imaging scan revealed pontine demyelinating plaque and a bilateral neurovascular conflict at the trigeminal root entry zone. The finding of an unusual case of simultaneous bilateral trigeminal neuralgia due to multiple sclerosis should prompt neurologists to consider a diagnosis of trigeminal neuralgia in patients with multiple sclerosis in cases of simultaneous involvement of trigeminal territories on both sides.