Panagiotis Zis

Pharmacological Treatment of Neuropathic Cancer Pain: A Comprehensive Review of the Current Literature

Abstract:  Neuropathic cancer pain (NCP), commonly encountered in clinical practice, may be cancer‐related, namely resulting from nervous system tumor invasion, surgical nerve damage during tumor removal, radiation‐induced nerve damage and chemotherapy‐related neuropathy, or may be of benign origin, unrelated to cancer. A neuropathic component is evident in about 1/3 of cancer pain cases. Although from a pathophysiological perspective NCP may differ from chronic neuropathic pain (NP), such as noncancer‐related pain, clinical practice, and limited publications have shown that these two pain entities may share some treatment modalities. For example, co‐analgesics have been well integrated into cancer pain‐management strategies and are often used as First‐Line options for the treatment of NCP. These drugs, including antidepressants and anticonvulsants, are recommended by evidence‐based guidelines, whereas, others such as lidocaine patch 5%, are supported by randomized, controlled, clinical data and are included in guidelines for restricted conditions treatment. The vast majority of these drugs have already been proven useful in the management of benign NP syndromes. Treatment decisions for patients with NP can be difficult. The intrinsic difficulties in performing randomized controlled trials in cancer pain have traditionally justified the acceptance of drugs already known to be effective in benign NP for the management of malignant NP, despite the lack of relevant high quality data. Interest in NCP mechanisms and pharmacotherapy has increased, resulting in significant mechanism‐based treatment advances for the future. In this comprehensive review, we present the latest knowledge regarding NCP pharmacological management.

Validation of the Dutch Version of the DN4 Diagnostic Questionnaire for Neuropathic Pain

The Douleur Neuropathique 4 questionnaire (DN4) was developed by the French Neuropathic Pain Group and is a simple and objective tool, primarily designed to screen for neuropathic pain. The aim of our study is to validate the DN4 in the Greek language.

Transglutaminase 6 antibodies in gluten neuropathy

BACKGROUND TG6 antibodies have been shown to be a marker of gluten ataxia but their presence in the context of other neurological manifestations of gluten sensitivity has not been explored. We investigated the presence of TG6 antibodies in gluten neuropathy (GN), defined as as an otherwise idiopathic peripheral neuropathy associated with serological markers of gluten sensitivity (one or more of antigliadin IgG and/or IgA, endomysial and transglutaminase-2 antibodies). METHODS This was a cross-sectional study conducted at the Sheffield Institute of Gluten Related Diseases, Royal Hallamshire Hospital, Sheffield, UK. Blood samples were collected whilst the patients were on a gluten containing diet. Duodenal biopsies were performed to establish the presence of enteropathy. RESULTS Twenty-eight patients were recruited (mean age 62.5±13.7 years). Fifteen (53.6%) had sensory ganglionopathy, 12 (42.9%) had symmetrical axonal neuropathy and 1 had mononeuritis multiplex. The prevalence of TG6 antibodies was 14 of 28 (50%) compared to 4% in the healthy population. TG6 antibodies were found in 5/15 (33.3%) patients with sensory ganglionopathy and in 8/12 (66.7%) with symmetrical axonal neuropathy. Twenty-four patients underwent duodenal biopsy 11 (45.8%) of which had enteropathy. The prevalence of TG6 was not significantly different when comparing those with or without enteropathy. CONCLUSIONS We found a high prevalence of antibodies against TG6 in patients with GN. This suggests that TG6 involvement is not confined to the central nervous system. The role of transglutaminase 6 in peripheral nerve function remains to be determined but TG6 antibodies may be helpful in the diagnosis of GN.

Depression and chronic pain in the elderly: links and management challenges

Aging is an inevitable process and represents the accumulation of bodily alterations over time. Depression and chronic pain are highly prevalent in elderly populations. It is estimated that 13% of the elderly population will suffer simultaneously from the two conditions. Accumulating evidence suggests than neuroinflammation plays a critical role in the pathogenesis of both depression and chronic pain. Apart from the common pathophysiological mechanisms, however, the two entities have several clinical links. Their management is challenging for the pain physician; however, both pharmacologic and nonpharmacologic approaches are available and can be used when the two conditions are comorbid in the elderly patients.

Peripheral neuropathy in idiopathic Parkinson's disease: A systematic review

BACKGROUND Parkinsons disease (PD) has been associated with peripheral neuropathy (PN). PN has been demonstrated in some rare genetic forms of PD (e.g. PARK2 mutations) but has also been linked to levodopa exposure. OBJECTIVE The aim of this systematic review is to clarify any evidence of peripheral nervous system involvement in idiopathic PD. METHODS A systematic computer-based literature search was conducted on PubMed database. FINDINGS The pooled estimate of the prevalence of large fiber PN in PD was 16.3% (based on 1376 patients). The pooled estimate of the prevalence of biopsy-proven small fiber neuropathy was 56.9% (based on 72 patients). Large fiber PN in PD is in the majority of cases distal, symmetrical, axonal and predominantly sensory. There are, however, few reports of chronic idiopathic demyelinating polyneuropathy and very occasional cases of acute neuropathies. Although nerve conduction studies have been performed in the majority of the studies, they included only a limited number of nerves, mainly in the lower limbs. There is little evidence to support a direct link between levodopa treatment and the development of PN in idiopathic PD. In the majority of the cases PN has been linked to abnormalities in vitamin B12, methylmalonic acid or fasting homocysteine levels. Additional aetiological risk factors for PN may be responsible for any apparent link between PD and PN. CONCLUSIONS Large-scale prospective studies with long-term follow-up with detailed baseline assessments are needed in order to understand the natural history of PN in PD, both on clinical and neurophysiological parameters.

The Effect of Intravenous Lidocaine on Trigeminal Neuralgia: A Randomized Double Blind Placebo Controlled Trial

Trigeminal neuralgia is the most common neuralgia. Its therapeutic approach is challenging as the first line treatment often does not help, or even causes intolerable side effects. The aim of our randomized double blind, placebo controlled, crossover study was to investigate in a prospective way the effect of lidocaine in patients with trigeminal neuralgia. Twenty patients met our inclusion criteria and completed the study. Each patient underwent four weekly sessions, two of which were with lidocaine (5 mgs/kg) and two with placebo infusions administered over 60 minutes. Intravenous lidocaine was superior regarding the reduction of the intensity of pain, the allodynia, and the hyperalgesia compared to placebo. Moreover, contrary to placebo, lidocaine managed to maintain its therapeutic results for the first 24 hours after intravenous infusion. Although, intravenous lidocaine is not a first line treatment, when first line medications fail to help, pain specialists may try it as an add-on treatment. This trial is registered with NCT01955967.

Cerebellar ataxia and sensory ganglionopathy associated with light-chain myeloma.

BackgroundCerebellar ataxia with sensory ganglionopathy is a rare neurological combination that can occur in some hereditary ataxias including mitochondrial diseases and in gluten sensitivity. Individually each condition can be a classic paraneoplastic neurological syndrome. We report a patient with this combination who was diagnosed with light-chain myeloma ten years after initial presentation.Case presentationA 65-year-old Caucasian lady was referred to our Ataxia Clinic because of a 6-year history of progressive unsteadiness and a 2-year history of slurred speech. Past medical history included arterial hypertension. The patient was a non-smoker was not consuming alcohol excessively. There was no family history of ataxia.Neurological examination revealed prominent gaze-evoked nystagmus, heel to shin ataxia, gait ataxia, reduced reflexes and loss of vibration sensation in the legs.Cerebellar ataxia was confirmed using magnetic resonance spectroscopy of the cerebellum and sensory ganglionopathy using neurophysiological assessments including blink reflex study. A muscle biopsy that was arranged to explore the possibility of mitochondrial disease revealed amyloidosis. Urinalysis confirmed the presence of light chains. A bone marrow biopsy confirmed the diagnosis of light chain multiple myeloma.ConclusionsWhilst it could be argued that this could simply be a coincidence, the rarity of these conditions and the absence of an alternative aetiology for the neurological dysfunction argue in favour of a paraneoplastic phenomenon.

Nocebo in Alzheimer's disease; meta-analysis of placebo-controlled clinical trials

BACKGROUND AND PURPOSE Nocebo is very prevalent among neurological diseases resulting in low adherence and treatment outcome. We sought to examine the AEs following placebo administration in Randomized Controlled Studies (RCTs) for Alzheimers Disease (AD). METHODS After a systematic Medline search for RCTs for AD pharmacological treatments, we assessed the number of placebo-treated patients reporting at least one AE and the number of discontinuations because of placebo intolerance and searched for factors correlating to nocebos extent. RESULTS Data were extracted from 20 RCTs fulfilling our search criteria. Of 3049 placebo-treated patients, 57.8% (95% CI: 50.1%-66.7%) reported at least one AE and 6.6% (95% CI: 5.3%-8.4%) discontinued placebo treatment because of AEs. All patients participating in these RCTs reported similar AEs independently of the study arm they belonged. Nocebo AE rate and dropout rate were positively related to study population size. The rates of AEs and dropouts because of AEs were parallel between placebo and active arms of RCTs (r=0.812, p<0.001 and r=0.787, p<0.001, respectively). Effectiveness rates correlated significantly to ΑΕs rate and dropout rate because of AEs in placebo treated patients (r=0.787, p<0.001 and r=0.812, p<0.001, respectively). CONCLUSION In RCTs for AD one out of fifteen patients treated with placebo dropped out because of AEs and three out of five experienced AEs indicating that adherence and effectiveness may be adversely affected with additional implications for clinical practice. The principal implications of this paper are that nocebo deserves much.

Rapid neurophysiological screening for sensory ganglionopathy: A novel approach

Pure sensory neuropathies involving the dorsal root ganglia are commonly referred to as sensory ganglionopathies (SG). Causes of SG can be inherited (as seen in Friedreichs ataxia) or acquired (e.g. immune‐mediated or paraneoplastic). Diagnostic criteria for confirming SG have been published and consist of a combination of clinical and neurophysiological parameters. The aim of our study was to develop a neurophysiological method for rapid screening for diagnosis of SG.

Polymorphisms in prothrombotic genes in young stroke patients in Greece: a case-controlled study.

Mechanisms of ischemic stroke in young adults are poorly understood. The aim of the study was to investigate and compare the frequency of common variations in prothrombotic genes between young patients with ischemic stroke and controls. Fifty-one cases of first-ever ischemic stroke and 70 community-based controls aged below 50 years were studied. In both groups, the insertion/deletion 4G/5G variation (−675 4G/5G PAI-1) as well as the single-nucleotide polymorphism-844 G/A of the PAI-1 (−844 G/A PAI-1) gene promoter, factor V Leiden (FVL) G1691&Agr;, the prothrombin variant (allele 20210A, FIIG20210A), factor XIII-A Val34Leu polymorphism (FXIII-AVal34Leu) and C677T methylenotetrahydrofolate reductase (C677T MTHFR) polymorphism have been assessed. The −675 4G/5G PAI-1 allele distribution differed significantly between patients and controls (P = 0.020), but no difference was found regarding the distribution of −844 G/A PAI-1 (P = 0.493), FVL (P = 0.199), FIIG20210A (P = 0.410), FXIII-AVal34leu (P = 0.160) and C677T MTHFR (P = 0.788). A lower frequency of 5G/5G genotype and a higher frequency of the 4G/5G genotype of the PAI −675 4G/5G polymorphism was found in young ischemic stroke patients compared to healthy controls. Further epidemiological studies are needed to investigate the differences between different geographic areas, and prospective cohort studies are needed to investigate the possible protective role of 5G/5G polymorphism.