Francesca Magrinelli

Neuropathic pain: diagnosis and treatment

Neuropathic pain (NP) develops as a consequence of a lesion or disease affecting the somatosensory pathways in the peripheral or central nervous system, and occurs in many neurological diseases (eg, peripheral neuropathy, radiculopathy, spinal cord injury, stroke and multiple sclerosis). It affects 6%–8% of the general population and its impact on quality of life, mood and sleep exceeds the burden of its causative pathology. A peculiar feature of NP is the coexistence of negative and positive symptoms and signs, reflecting loss-of-function and gain-of-function of the somatosensory system, respectively. NP has long been considered a difficult clinical issue because of the lack of a diagnostic gold standard and the unsatisfactory response to treatment. In recent years, a redefinition, diagnostic algorithm, and some guidelines on diagnosis and treatment of NP have been published. This review offers an updated overview on the definition, pathophysiology, clinical evaluation, diagnosis and treatment of NP and focuses on some of the most frequent NP conditions. We intend to help overcome uncertainties on NP and bridge the gap between evidence based medicine and the real clinical world.

Pathophysiology of Motor Dysfunction in Parkinson’s Disease as the Rationale for Drug Treatment and Rehabilitation

Cardinal motor features of Parkinsons disease (PD) include bradykinesia, rest tremor, and rigidity, which appear in the early stages of the disease and largely depend on dopaminergic nigrostriatal denervation. Intermediate and advanced PD stages are characterized by motor fluctuations and dyskinesia, which depend on complex mechanisms secondary to severe nigrostriatal loss and to the problems related to oral levodopa absorption, and motor and nonmotor symptoms and signs that are secondary to marked dopaminergic loss and multisystem neurodegeneration with damage to nondopaminergic pathways. Nondopaminergic dysfunction results in motor problems, including posture, balance and gait disturbances, and fatigue, and nonmotor problems, encompassing depression, apathy, cognitive impairment, sleep disturbances, pain, and autonomic dysfunction. There are a number of symptomatic drugs for PD motor signs, but the pharmacological resources for nonmotor signs and symptoms are limited, and rehabilitation may contribute to their treatment. The present review will focus on classical notions and recent insights into the neuropathology, neuropharmacology, and neurophysiology of motor dysfunction of PD. These pieces of information represent the basis for the pharmacological, neurosurgical, and rehabilitative approaches to PD.

The Association between Serum Cytokines and Damage to Large and Small Nerve Fibers in Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN) is a frequent complication of type 2 diabetes mellitus (DM) and may involve small and large peripheral nerve fibers. Recent evidence suggests a role of cytokines in DPN. The paper is aimed at exploring whether the serum concentration of cytokines is associated with small and large nerve fiber function and with neuropathic pain (NP). We recruited a group of 32 type 2 DM patients who underwent serum cytokines (TNF-α, IL-2, IL-4, IL-6, and IL-10) dosage as well as electrodiagnostic and quantitative sensory testing (QST) assessment to explore damage to large and small nerve fibers. Raised serum levels of IL-6 and IL-10 correlated with markers of large nerve fiber sensory and motor axonal damage. Raised IL-10 serum level was associated with signs of motor nerve demyelination. No differences were found in pain characteristics and electrodiagnostic and QST markers of small nerve fiber function in relation to cytokines serum levels. IL-6 and IL-10 serum levels were associated with large nerve fiber damage but not to small fibers function or NP. IL-6 and IL-10 cytokines might play a role in the pathogenesis of nerve fiber damage or represent a compensatory or neuroprotective mechanism.

The Italian Consensus Conference on Pain in Neurorehabilitation: rationale and methodology

Pain is very common in the neurorehabilitation setting, where it may not only represent a target for treatment but can also negatively influence rehabilitation procedures directly or through the side effects of painkillers. To date, there are neither guidelines nor consensus on how to assess and treat pain in neurorehabilitation. Because of the very scanty pieces of evidence on this topic, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCPN) was promoted under the auspices of different scientific societies. This article illustrates the rationale, methodology, and topics of the ICCPN. The recommendations of the ICCPN will offer some information on how to deal with pain in neurorehabilitation and may represent the starting point for further studies.

Long-term response of neuropathic pain to intravenous immunoglobulin in relapsing diabetic lumbosacral radiculoplexus neuropathy. A case report.

Diabetic lumbosacral radiculoplexus neuropathy (DLRPN) is a rare painful peripheral neuropathic complication of diabetes mellitus. The clinical features of DLRPN include severe neuropathic pain, weakness, atrophy, and sensory loss in the lower limbs with asymmetrical distribution. Nerve ischemia due to inflammation and microvasculitis has been suggested as the pathophysiological mechanism for DLRPN. Analgesics and drugs for neuropathic pain often cannot achieve adequate pain control in DLRPN. Some reports suggest that intravenous immunoglobulin (IVIg) may reduce pain in DLRPN, but the mechanisms of this effect are unclear.

Effect of 5% Lidocaine Medicated Plaster on Pain Intensity and Paroxysms in Classical Trigeminal Neuralgia

Objective: Trigeminal neuralgia (TN) is a neuropathic pain condition affecting one or more branches of the trigeminal nerve. It is characterized by unilateral, sudden, shock-like, and brief painful attacks, which follow the distribution of trigeminal nerve branches, and with no other accompanying sensorimotor or autonomic signs and symptoms. Current guidelines stipulate which therapies represent first-, second-, and third-line treatments for TN, but there is a consistent mismatch between the therapeutic guidelines and the patient’s preferences and expectations. Case Summary: We report on 2 patients with classical TN in whom conventional drugs for TN were not tolerated. In these patients, treatment with 5% lidocaine medicated plaster (LMP) resulted in reduction of pain intensity and the number of pain paroxysms. Discussion: LMP is known to block the sodium channels on peripheral nerves and may cause a selective and partial block of Aδ and C fibers. According to the TN ignition hypothesis, blockage of peripheral afferents by LMP may reduce pain paroxysms. The effect of LMP may outlast the pharmacokinetics of the drug by reducing pain amplification mechanisms in the central nervous system. LMP has limited or no systemic side effects. Conclusions: LMP may be an effective and well-tolerated treatment option for TN in those patients who do not tolerate or who refuse other therapies. Future randomized controlled studies should better address this issue.

Diagnostic methods and emerging treatments for adult neuronal ceroid lipofuscinoses (Kufs disease)

ABSTRACT Introduction: Adult-onset neuronal ceroid lipofuscinoses (ANCL) are a group of rare inherited neurodegenerative diseases of early adulthood, named after the presence of intralysosomal autofluorescent lipopigment with characteristic ultrastructural features in neurons and other cell types. Over the last decade, six ANCL genes have been identified, three of them being related to exclusively adult-onset phenotypes, the remaining three shared with childhood-onset NCL (CNCL). Areas covered: Even in the molecular era, the contribution of neuropathological assessment is essential since genetic heterogeneity foresees new genes to be detected and validated. No disease-modifying therapy (DMT) is available for neuronal ceroid lipofuscinoses (NCL), but patients may benefit from improved symptomatic and supportive treatments, and recent advances in cellular and molecular biology (utilizing both cellular and animal models of the disease) have provided important contributions to the knowledge of NCL pathophysiology. DMT strategies aim to prevent storage formation and/or deplete accumulated substrate; few of them have already been translated into clinical practice in CNCL only. Expert opinion: The complexity of pathophysiological mechanisms underlying NCL, such as neuronal excitotoxicity, unfavourable condition of the neuropil and enhanced vulnerability of the affected cells, requires the identification of multiple targets suitable for treatments to prevent neuronal progressive dysfunction and death.

Diagnostic and Therapeutic Pitfalls in Considering Chronic Pain as a Disease

Dear Editor, We read with great interest the article by Cohen and coworkers [1], who critically discussed the view that chronic pain may be considered as a disease on its own because the pathophysiological grounds of chronic pain conditions are still uncertain and there are big difficulties in separating eudynia (good pain) from maldynia (bad pain) [2]. In addition to the pathogenic and taxonomic issues [1], the concept of chronic pain as a disease may carry the risk of a delay in the diagnosis of the pathology underlying pain and inappropriate treatment, as demonstrated by the following cases. ### Case 1 A 15-year-old boy reported a 2-year history of severe low back pain (LBP) with a numeric rating scale (NRS) of 8–9/10, right lower-limb irradiation, and that worsened during walking. Four months after the onset of LBP, he underwent a lumbar magnetic resonance imaging (MRI; Figure ⇓A), which was performed without gadolinium (Gd), and was reported as unremarkable. Different treatments, including nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, gabapentin, and physical therapies were only slightly effective on LBP (NRS reduced to 6–7/10). Chronic LBP with reactive depression and psychogenic LBP were suspected in two different pain centers, and psychotherapy was started with no consistent change in …

No evidence of a neuropathic origin in hemiplegic shoulder pain

To the Editor, Hemiplegic shoulder pain (HSP) is the most common pain condition after stroke (30% to 40%), with a heavy burden and a challenging treatment [4]. We read with great interest the recent article by Zeilig et al., who explored the pathophysiology of HSP [8]. They compared HSP patients, poststroke patients without HSP (NHSP), and normal control subjects, and on quantitative sensory testing (QST) data, they concluded that HSP has a neuropathic component [8]. Unfortunately, their conclusion is biased by some methodological issues and overstatement of the results. The patient groups were small and differed for some baseline conditions, including time after stroke (HSP 12.1 ± 3.9, NHSP 19.4 ± 10.2, t test: P = .01) and severity of motor impairment (HSP 50% plegia, NHSP 28.5%). Patients with neglect (HSP 12.5%, NHSP 14.3%) were included, but their QST data were not reliable because of the diminished body awareness [2]. Given the large number of right hemisphere lesions (HSP 68.8%, NHSP 71.4%) and of parietal strokes in the HSP group (43.8%), extinction and subclinical neglect should have been explored with a battery of paper-and-pencil tests [1]. Finally, university and hospital workers were the control group, but they were not matched for conditions (eg, obesity, diabetes mellitus), which may influence pain perception and are common in stroke patients. Only the first 2 of 4 mandatory criteria for central poststroke pain (CPSP) [4] were met in the HSP population but were not specific to the HSP group (Table 1). Stroke location was apparently outside the somatosensory system in 6 of 16 patients (basal ganglia 4, external capsula 1, occipital lobe 1) and undetermined in 2 (brainstem 1, periventricular 1). Analysis of brain computed tomography and magnetic resonance imaging scans with a software like MRIcron [6] would have helped to better define whether

Teaching Video NeuroImages: Bent spine syndrome as an early presentation of late-onset Pompe disease

Bent spine syndrome (BSS), an abnormal trunk anteroflexion of at least 45° that increases during walking and abates in supine position, is described in parkinsonism and myopathies.1 We report a 56-year-old man with genetically proven late-onset Pompe disease (LOPD) showing BSS (figure 1 and video at Neurology.org). He complained of axial weakness that progressively forced him to walk stretching his arms backward since his 20s. Whole-body muscle MRI revealed severe fatty replacement of lumbar paraspinal (figure 2) and iliopsoas muscles, and spirometry showed restrictive ventilatory defect. Periodic acid-Schiff–positive vacuoles and reduced acid α-glucosidase activity were demonstrated in muscle biopsy. While lumbar hyperlordosis is a typical feature of LOPD, other trunk abnormalities may appear early in the disease. LOPD must be included in the differential diagnosis of BSS.2