Recommendations for terminology and the identification of neuropathic pain in people with spine-related leg pain. Outcomes from the NeuPSIG working group.

ABSTRACT: Pain radiating from the spine into the leg is commonly referred to as "sciatica," "Sciatica" may include various conditions such as radicular pain or painful radiculopathy. It may be associated with significant consequences for the person living with the condition, imposing a reduced quality of life and substantial direct and indirect costs. The main challenges associated with a diagnosis of "sciatica" include those related to the inconsistent use of terminology for the diagnostic labels and the identification of neuropathic pain. These challenges hinder collective clinical and scientific understanding regarding these conditions. In this position paper, we describe the outcome of a working group commissioned by the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) which was tasked with the following objectives: (1) to revise the use of terminology for classifying spine-related leg pain and (2) to propose a way forward on the identification of neuropathic pain in the context of spine-related leg pain. The panel recommended discouraging the term "sciatica" for use in clinical practice and research without further specification of what it entails. The term "spine-related leg pain" is proposed as an umbrella term to include the case definitions of somatic referred pain and radicular pain with and without radiculopathy. The panel proposed an adaptation of the neuropathic pain grading system in the context of spine-related leg pain to facilitate the identification of neuropathic pain and initiation of specific management in this patient population.

SEZ6L2 Antibody-Associated Cerebellar Ataxia Responsive to Sequential Immunotherapy.

OBJECTIVES: Seizure-related 6 homolog like 2 (SEZ6L2) antibody-associated ataxia is an extremely rare disease. Six patients have been reported and none of them improved significantly with immunotherapy. Herein, we present the case of a patient with cerebellar ataxia and SEZ6L2 antibodies who benefited from immunotherapy, which dramatically altered the course of her disease. METHODS: We present a case report of a 73-year-old woman with progressive balance problems. Her condition had rapidly deteriorated in the 2 weeks before the admission to our hospital leading to repeated falls and eventually left her bed-ridden. RESULTS: She presented with severe trunk ataxia, bidirectional nystagmus, dysarthric speech, and persistent nausea. With the exception of cerebellar atrophy, extensive imaging studies revealed no pathology. SEZ6L2 antibodies were found in both CSF and serum. Over a period of 9 months, our patient received immunotherapy consisting of steroid pulse therapy, IV immunoglobulin infusions, rituximab, and cyclophosphamide. Consequently, her condition improved markedly, and she was discharged home from the neurologic rehabilitation unit. DISCUSSION: Our case report shows that intense sequential immunotherapy may considerably improve level of functioning in some patients with SEZ6L2 antibody-associated cerebellar ataxia. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.

Is the Preoperative Use of Antidepressants and Benzodiazepines Associated with Opioid and Other Analgesic Use After Hip and Knee Arthroplasty?

BACKGROUND: Mental health disorders can occur in patients with pain conditions, and there have been reports of an increased risk of persistent pain after THA and TKA among patients who have psychological distress. Persistent pain may result in the prolonged consumption of opioids and other analgesics, which may expose patients to adverse drug events and narcotic habituation or addiction. However, the degree to which preoperative use of antidepressants or benzodiazepines is associated with prolonged analgesic use after surgery is not well quantified. QUESTION/PURPOSES: (1) Is the preoperative use of antidepressants or benzodiazepine medications associated with a greater postoperative use of opioids, NSAIDs, or acetaminophen? (2) Is the proportion of patients still using opioid analgesics 1 year after arthroplasty higher among patients who were taking antidepressants or benzodiazepine medications before surgery, after controlling for relevant confounding variables? (3) Does analgesic drug use decrease after surgery in patients with a history of antidepressant or benzodiazepine use? (4) Does the proportion of patients using antidepressants or benzodiazepines change after joint arthroplasty compared with before? METHODS: Of the 10,138 patients who underwent hip arthroplasty and the 9930 patients who underwent knee arthroplasty at Coxa Hospital for Joint Replacement, Tampere, Finland, between 2002 and 2013, those who had primary joint arthroplasty for primary osteoarthritis (64% [6502 of 10,138] of patients with hip surgery and 82% [8099 of 9930] who had knee surgery) were considered potentially eligible. After exclusion of another 8% (845 of 10,138) and 13% (1308 of 9930) of patients because they had revision or another joint arthroplasty within 2 years of the index surgery, 56% (5657 of 10,138) of patients with hip arthroplasty and 68% (6791 of 9930) of patients with knee arthroplasty were included in this retrospective registry study. Patients who filled prescriptions for antidepressants or benzodiazepines were identified from a nationwide drug prescription register, and information on the filled prescriptions for opioids (mild and strong), NSAIDs, and acetaminophen were extracted from the same database. For the analyses, subgroups were created according to the status of benzodiazepine and antidepressant use during the 6 months before surgery. First, the proportions of patients who used opioids and any analgesics (that is, opioids, NSAIDs, or acetaminophen) were calculated. Then, multivariable logistic regression adjusted with age, gender, joint, Charlson Comorbidity Index, BMI, laterality (unilateral/same-day bilateral), and preoperative analgesic use was performed to calculate odds ratios for any analgesic use and opioid use 1 year postoperatively. Additionally, the proportion of patients who used antidepressants and benzodiazepines was calculated for 2 years before and 2 years after surgery. RESULTS: At 1 year postoperatively, patients with a history of antidepressant or benzodiazepine use were more likely to fill prescriptions for any analgesics than were patients without a history of antidepressant or benzodiazepine use (adjusted odds ratios 1.9 [95% confidence interval 1.6 to 2.2]; p < 0.001 and 1.8 [95% CI 1.6 to 2.0]; p < 0.001, respectively). Similarly, patients with a history of antidepressant or benzodiazepine use were more likely to fill prescriptions for opioids than patients without a history of antidepressant or benzodiazepine use (adjusted ORs 2.1 [95% CI 1.7 to 2.7]; p < 0.001 and 2.0 [95% CI 1.6 to 2.4]; p < 0.001, respectively). Nevertheless, the proportion of patients who filled any analgesic prescription was smaller 1 year after surgery than preoperatively in patients with a history of antidepressant (42% [439 of 1038] versus 55% [568 of 1038]; p < 0.001) and/or benzodiazepine use (40% [801 of 2008] versus 55% [1098 of 2008]; p < 0.001). The proportion of patients who used antidepressants and/or benzodiazepines was essentially stable during the observation period. CONCLUSION: Surgeons should be aware of the increased risk of prolonged opioid and other analgesic use after surgery among patients who were on preoperative antidepressant and/or benzodiazepine therapy, and they should have candid discussions with patients referred for elective joint arthroplasty about this possibility. Further studies are needed to identify the most effective methods to reduce prolonged postoperative opioid use among these patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

Predictors of the use of analgesic drugs 1 year after joint replacement: a single-center analysis of 13,000 hip and knee replacements.

BACKGROUND: Pain persists in a moderate number of patients following hip or knee replacement surgery. Persistent pain may subsequently lead to the prolonged consumption of analgesics after surgery and expose patients to the adverse drug events of opioids and NSAIDs, especially in older patients and patients with comorbidities. This study aimed to identify risk factors for the increased use of opioids and other analgesics 1 year after surgery and focused on comorbidities and surgery-related factors. METHODS: All patients who underwent a primary hip or knee replacement for osteoarthritis from 2002 to 2013 were identified. Redeemed prescriptions for acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opioids (mild and strong) were collected from a nationwide Drug Prescription Register. The user rates of analgesics and the adjusted risks ratios for analgesic use 1 year after joint replacement were calculated. RESULTS: Of the 6238 hip replacement and 7501 knee replacement recipients, 3591 (26.1%) were still using analgesics 1 year after surgery. Significant predictors of overall analgesic use (acetaminophen, NSAID, or opioid) were (risk ratio (95% CI)) age 65-74.9 years (reference < 65), 1.1 (1.03-1.2); age > 75 years, 1.2 (1.1-1.3); female gender, 1.2 (1.1-1.3); BMI 30-34.9 kg/m2 (reference < 25 kg/m2), 1.1 (1.04-1.2); BMI > 35 kg/m2, 1.4 (1.3-1.6); and a higher number of comorbidities (according to the modified Charlson Comorbidity Index score), 1.2 (1.1-1.4). Diabetes and other comorbidities were not significant independent predictors. Of the other clinical factors, the preoperative use of analgesics, 2.6 (2.5-2.8), and knee surgery, 1.2 (1.1-1.3), predicted the use of analgesics, whereas simultaneous bilateral knee replacement (compared to unilateral procedure) was a protective factor, 0.86 (0.77-0.96). Opioid use was associated with obesity, higher CCI score, epilepsy, knee vs hip surgery, unilateral vs bilateral knee operation, total vs unicompartmental knee replacement, and the preoperative use of analgesics/opioids. CONCLUSIONS: Obesity (especially BMI > 35 kg/m2) and the preoperative use of analgesics were the strongest predictors of an increased postoperative use of analgesics. It is remarkable that also older age and higher number of comorbidities predicted analgesic use despite these patients being the most vulnerable to adverse drug events.

Use of prescription analgesic drugs before and after hip or knee replacement in patients with osteoarthritis.

BACKGROUND: Analgesic drugs are recommended to treat pain caused by osteoarthritis, and joint replacement should decrease the need for them. We aimed to determine the user rates of analgesic drugs before and after joint replacement. METHODS: All patients who underwent a primary hip or knee replacement for osteoarthritis from 2002 to 2013 in a region of 0.5 million people were identified. Patients with revision or other joint replacements during the study period (operation date +/- two years) were excluded, leaving 6238 hip replacements (5657 patients) and 7501 knee replacements (6791 patients) for analyses. Medication data were collected from a nationwide Drug Prescription Register and the prevalence (with its 95% confidence intervals) of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), mild opioids, strong opioids, and medications used for neuropathic pain was calculated in three-month periods two years before and after surgery. RESULTS: Between two years and three months preoperatively, the proportion of patients who redeemed at least one type of analgesic drug increased from 28% (95% CI, 27-30%) to 48% (47-50%) on hip replacement patients and from 33% (32-34%) to 41% (40-42%) on knee replacement patients. Postoperatively, the proportions decreased to 23% (22-24%) on hip and to 30% (29-31%) on knee patients. Hip replacement patients used more NSAIDs (34% (32-35%) hip vs 26% (25-27%) knee, p < 0.001), acetaminophen (14% (13-15%) vs 12% (11-13%), p < 0.001), and mild opioids (14% (13-15%) vs 9% (8-9%), p < 0.001) than knee patients preoperatively, but postoperatively hip patients used less NSAIDs (12% (11-13%) vs 16% (15-16%), p < 0.001), acetaminophen (9% (8-10%) vs 11% (11-12%), p < 0.001), and mild opioids (5% (5-6%) vs 8% (7-8%), p < 0.001). CONCLUSION: Use of analgesic drugs increases prior to joint replacement, and is reduced following surgery. However, a considerable proportion of patients continue to use analgesics in two-year follow-up.

Screening for Fabry disease and Hereditary ATTR amyloidosis in idiopathic small-fiber and mixed neuropathy.

INTRODUCTION: In this study we assessed the value of genetic screening for Fabry disease (FD) and hereditary ATTR amyloidosis in patients with idiopathic small-fiber neuropathy (SFN) or mixed neuropathy in a clinical setting. METHODS: This was a Nordic multicenter study with 9 participating centers. Patients with idiopathic SFN or mixed neuropathy were included. Genetic sequencing of the TTR and GLA genes was performed. RESULTS: There were 172 patients enrolled in the study. Genetic screening was performed in 155 patients. No pathogenic mutations in the TTR gene were found. A single patient had a possible pathogenic variant, R118C, in the GLA gene, but clinical investigation showed no firm signs of FD. DISCUSSION: Screening for hereditary ATTR amyloidosis and FD in patients with idiopathic SFN or mixed neuropathy without any additional disease-specific symptoms or clinical characteristics in a Nordic population appears to be of little value in a clinical setting. Muscle Nerve 59:354-357, 2019.

Clinical Management of Epilepsy With Glutamic Acid Decarboxylase Antibody Positivity: The Interplay Between Immunotherapy and Anti-epileptic Drugs.

Background: There is scanty guidance in the literature on the management of patients with glutamic acid decarboxylase (GAD65) antibody associated autoimmune epilepsy (GAD-epilepsy). GAD-epilepsy is a rare distinct neurological syndrome with a wide clinical spectrum. We describe six GAD-epilepsy patients with special emphasis on the treatment timing and the relationship between immunologic and anti-epileptic therapy. Methods: Six patients diagnosed with GAD-epilepsy in Tampere University Hospital who had received immunotherapy from 2013 to 2017 were retrospectively analyzed from patient records. Data about symptom onset, including antibody levels, magnetic resonance imaging (MRI), electroencephalograms, immunotherapy and anti-epileptic treatment timing and treatment responses were collected and analyzed. Kruskall-Wallis test was used in the statistical evaluation. Results: All patients were female aged 9-54 at symptom onset. Three had hypothyroidism, none had diabetes, two had migraine. Five patients had very high (>2,000 IU/ml) and one had high (52-251 IU/ml) GAD65 antibody titers. All patients presented with seizure disorders. Patients who received early initiation of immunotherapy (3-10 months) responded well to treatment; patients in whom the immunotherapy was started later (15-87 months) did not respond (p = 0.0495). The first patient was seizure-free after 1 year of regular intravenous immunoglobulin and one antiepileptic drug (AED). The second patient developed unilateral temporal lobe T2 signal changes in MRI; she responded well to immunotherapy, experiencing a significant reduction in seizure frequency and resolution of MRI abnormalities. However, seizures continued despite trials with several AEDs. The third patient responded well to immunoadsorption and rituximab with one AED, with lowering of GAD65 titers (from >2,000 to 300). There was a long delay in the diagnosis of GAD-epilepsy in the three patients who had developed refractory epilepsy, one with hippocampal sclerosis. They all received immunotherapy but none responded. However, AED modification or vagus nerve stimulation reduced the seizure frequency in two patients. Epilepsy surgery was ineffective. Conclusions: These results highlight the importance of early detection of GAD65 antibodies in refractory epilepsy as immunotherapy can be effective if administered in the early stages of the disease when it can prevent permanent brain tissue damage.

Pain in SCN4A Mutated P.A1156T muscle sodium channelopathy-a postal survey.

INTRODUCTION: The p.A1156T mutation alters the function of the voltage-gated sodium channel Nav1.4 on the muscle sarcolemma, causing a channelopathy without overt myotonia or periodic paralysis but with myalgic pain. METHODS: A postal survey was conducted to assess the prevalence and characteristics of pain and related symptoms in individuals with the p.A1156T mutation. A specific questionnaire, intensity and interference subscales of the Brief Pain Inventory, pain drawing, Widespread Pain Index, quality of life (RAND-36), and the Beck Depression Inventory were completed. RESULTS: Twenty of 24 patients replied. Current pain was reported by 16 respondents; the other 4 had experienced pain previously. Most commonly, pain was widespread and exercise-induced. The severity and the impact of pain on daily life were considerable, although varied. DISCUSSION: This sodium channelopathy is another entity in the growing number of diseases causing widespread myalgic pain that resembles the pain seen in fibromyalgia syndrome. Muscle Nerve 57: 1014-1017, 2018.

Hirayama disease.

Hirayama is a form of cervical myelopathy affecting mainly young men. The cardinal features include progressive, either symmetrical or asymmetrical muscular weakness and atrophy of muscles innervated by C7-Th1 motoneurons. The application of soft daytime collar during the early stage of illness can halt the progression of illness.

Lack of antibodies to NMDAR or VGKC-complex in GAD and cardiolipin antibody-positive refractory epilepsy.

BACKGROUND: Over the last few years autoantibodies against neuronal proteins have been identified in several forms of autoimmune encephalitis and epilepsy. NMDA receptor (NMDAR) and voltage gated potassium channel (VGKC) complex antibodies are mainly associated with limbic encephalitis (LE) whereas glutamic acid decarboxylase antibodies (GADA) and anticardiolipin (ACL) antibodies are more commonly detected in patients with chronic epilepsy. Clinical features vary between these antibodies suggesting the specificity of different neuronal antibodies in seizures. METHODS: Serum samples of 14 GADA positive and 24 ACL positive patients with refractory epilepsy were analyzed for the presence of VGKC or NMDAR antibodies. RESULTS: No positive VGKC or NMDAR antibodies were found in these patients. CONCLUSIONS: The results confirm the different significance of these neuronal antibodies in seizure disorders. Different autoantibodies have different significance in seizures and probably have different pathophysiological mechanisms of actions.

Investigation of neuropathic pain in treated leprosy patients in Ethiopia: a cross-sectional study.

Pain can be a significant problem for treated leprosy patients. It can be nociceptive due to tissue inflammation occurring during episodes of immune mediated reactions, or neuropathic due to leprosy affecting the somatosensory system. There are sparse epidemiological data on the prevalence and impact of neuropathic pain in treated leprosy patients. Tools for assessing neuropathic pain have not been validated in leprosy. We have examined nature of pain in a cross-sectional study to determine the prevalence of neuropathic pain (NP) in 80 recently treated leprosy patients in Ethiopia. Pain and depression were evaluated using the General Health Questionnaire (GHQ-12) and the Brief Pain Inventory (BPI) questionnaire. The Douleur Neuropathique en 4 Questions (DN4) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) were used as screening tools for NP. Pain of any type was experienced by 60% of the patients. Pure nociceptive pain was experienced by 43%, pure NP by 11%, and mixed pain by 6%. Of the 14 patients who had NP either alone or in combination with nociceptive pain, 12 had high GHQ-12 scores, indicating possible depression. The DN4 had sensitivity and specificity of 100% and 45%, whereas the LANSS had 85% and 42%, respectively. This is the first study to differentiate nociceptive from NP in leprosy patients. The prevalence of NP is high in recently treated Ethiopian leprosy patients. We have validated the use of DN4 in leprosy and it is easier to use than LANSS. Depression is a common co-morbidity in patients with NP. The high prevalence and morbidity of NP in treated leprosy patients warrant clinical trials to assess the efficacy of pain therapies for leprosy-associated NP.

Pain in patients with myotonic dystrophy type 2: a postal survey in Finland.

INTRODUCTION: Widespread musculoskeletal pain is a well-known symptom of myotonic dystrophy type 2 (DM2), but so far it has been addressed in only a few studies. METHODS: A postal survey for all traceable DM2 patients (n = 132) was conducted. A specific questionnaire, and severity and interference subscales of the Brief Pain Inventory, quality of life (RAND-36), and modified Beck Depression Inventory were completed. RESULTS: The response rate was 70%. The mean age of respondents was 53 years, 59% of whom were women. Current pain was reported by 54%. Lifetime prevalence of pain was 76%. The mean intensity of pain at its highest in the last week was 5.9, and 2.3 at its lowest (on a numerical rating scale of 0-10). Quality of life was lower in DM2 patients who reported pain. In 18%, the depression score was noticeably different. CONCLUSIONS: Pain of moderate severity and unpleasant muscular symptoms are common in DM2. DM2 should be taken into consideration in the differential diagnosis of musculoskeletal pain.

Intraepidermal nerve fibre density in cancer patients receiving adjuvant chemotherapy.

BACKGROUND: Chemotherapy-induced neuropathy is a common adverse event in patients receiving vinca alcaloids, platinum derivatives and taxanes. However, the underlying pathogenetic mechanisms have not been completely elucidated. We set up a prospective pilot study on skin biopsies in newly diagnosed cancer patients receiving neurotoxic chemotherapeutic agents as adjuvant treatment in order to study the occurrence of small-fibre pathology and its relationship to clinical symptoms. PATIENTS AND METHODS: Skin biopsies from distal leg were performed in 12 patients before, during and after chemotherapy. Using light microscopy, the intraepidermal nerve fibre (IENF) density was determined from the skin biopsies by counting morphometrically the immunopositive nerves per epidermal area. RESULTS: Reduced IENF density was observed in eight patients at baseline. During the follow-up, the IENF density increased significantly in six patients and remained unchanged in two. In four patients, the IENF density was normal both at baseline and at the end of the follow-up period. Neuropathic symptoms were manifested in nine patients, but no association with the IENF count was found. CONCLUSION: During chemotherapy, results from patients revealed different evolutionary patterns of IENF density, but symptoms and IENF density were not related.

Neuropathic pain and psychological morbidity in patients with treated leprosy: a cross-sectional prevalence study in Mumbai.

BACKGROUND: Neuropathic pain has been little studied in leprosy. We assessed the prevalence and clinical characteristics of neuropathic pain and the validity of the Douleur Neuropathique 4 questionnaire as a screening tool for neuropathic pain in patients with treated leprosy. The association of neuropathic pain with psychological morbidity was also evaluated. METHODOLOGY/PRINCIPAL FINDINGS: Adult patients who had completed multi-drug therapy for leprosy were recruited from several Bombay Leprosy Project clinics. Clinical neurological examination, assessment of leprosy affected skin and nerves and pain evaluation were performed for all patients. Patients completed the Douleur Neuropathique 4 and the 12-item General Health Questionnaire to identify neuropathic pain and psychological morbidity. CONCLUSIONS/SIGNIFICANCE: One hundred and one patients were recruited, and 22 (21.8%) had neuropathic pain. The main sensory symptoms were numbness (86.4%), tingling (68.2%), hypoesthesia to touch (81.2%) and pinprick (72.7%). Neuropathic pain was associated with nerve enlargement and tenderness, painful skin lesions and with psychological morbidity. The Douleur Neuropathique 4 had a sensitivity of 100% and specificity of 92% in diagnosing neuropathic pain. The Douleur Neuropathique 4 is a simple tool for the screening of neuropathic pain in leprosy patients. Psychological morbidity was detected in 15% of the patients and 41% of the patients with neuropathic pain had psychological morbidity.

[Central nervous system vasculitis]. / Keskushermostovaskuliitit.

Central nervous system vasculitides are rare and life-threatening diseases with challenging diagnostics. Their neurological symptom spectrum is multifaceted: the patient may have intense headache, confusion, decreased cognitive function, changes in consciousness, epileptic attacks and symptoms resembling multiple sclerosis. Angiographic investigations, magnetic resonance imaging of the brain and examination of cerebrospinal fluid will clarify the diagnosis, but brain biopsy may be required to confirm the diagnosis. In differential diagnostics, special attention should be paid to cerebrovascular vasoconstriction syndromes. Standard therapy of cerebral vasculitis includes corticosteroids often combined with immunosuppressants.

Histopathological and clinical findings in leprosy patients with chronic neuropathic pain: a study from Hyderabad, India.

BACKGROUND: Chronic neuropathic pain in leprosy patients after completion of multi-drug therapy (MDT) is an under-researched problem. The reason why some leprosy patients develop it is unknown. In this study we evaluated the role of ongoing inflammation and small-fibre neuropathy as possible contributing factors for neuropathic pain. METHODS: We assessed chronic neuropathic pain in 17 leprosy patients who had completed MDT and were attending a referral clinic in Hyderabad, India. All patients had a clinical assessment, intraepidermal nerve (IENF) assessment and quantitative sensory testing (QST), which included the testing of tactile and pinprick sensations using Semmes-Weinstein monofilaments and weighted needles method. Nine patients had a sural nerve biopsy (SNB). RESULTS: Thirteen patients had a glove and stocking pattern of neuropathy. All nerve biopsies showed inflammation with intraneural inflammation and perineural thickening, and intraneural acid fast bacilli were observed in five biopsies. IENF analysis of the skin biopsy specimens in 16/17 patients showed a statistically significant reduction in IENF density (P < 0.001, Mann Whitney test) compared to control skin biopsies. Complete depletion of intraepidermal nerves was observed in six patients. QST also showed marked abnormalities. In 11 patients total sensory loss for all modalities was found, and in the other six patients the sensory function was seriously impaired. DISCUSSION: There is evidence of ongoing intraneural inflammation in leprosy patients who have completed MDT. This may explain the occurrence of chronic neuropathic pain. Using IENF density measurement we have found significant small-fibre neuropathy in leprosy patients and the use of this tool could be expanded.