Unmet needs and gaps in the identification of secondary progression in multiple sclerosis: a Southern Italy healthcare professionals' perspective.

OBJECTIVE: Multiple sclerosis (MS) is a chronic disease with different clinical courses and a tendency to worsening. The relapsing-remitting MS presents acute onset and relapses of neurological symptoms, followed by their remission. This form can convert to secondary progressive MS (SPMS) with irreversible neurological worsening and disability. The identification of signs, symptoms, markers of progression, and strategies to manage MS patients is mandatory to allow early identification of those at higher risk of conversion to SPMS, for prompt intervention to cope with the progression of the disease. METHODS: A panel of Italian experts from Southern Italy have reviewed the current knowledge on MS and its management and identified the crucial tools for SPMS recognition. RESULTS: More effective communication between patients and clinicians should be established, with the support of digital tools. Moreover, the improvement in the clinical use of biomarkers for progression (cellular structures and tissue organization, such as neurofilaments and chitinase 3-like 1, axonal and neurons density) and of instrumental analyses for recognition of whole-brain atrophy, chronic active lesions, spinal cord lesions and atrophy, and the improvement the combination of the Expanded Disability Status Scale and the evaluation of cognitive dysfunction are discussed. CONCLUSION: Given the availability of a pharmacological option, adequate education both for patients, regarding the evolution of the disease and the specific treatment, and for professionals, to allow more effective and sensitive communication and the best use of diagnostic and management tools, could represent a strategy to improve patient management and their quality of life.

Hypnotherapy as a Nonpharmacological Treatment for the Psychological Symptoms of Multiple Sclerosis.

Context: Stress and chronic pain are the factors that most influence the quality of life and well-being of people with MS, and 90% of adults with MS suffer from persistent fatigue. These symptoms can be associated with other disorders such as depression, and drug treatments provide inadequate comfort for most people with them. Objective: The study intended to examine the impact of hypnosis and hypnotherapy in the management of symptoms of people with multiple sclerosis (MS), such as stress, chronic pain, an inferior quality of life, and a lack of psychological well-being. Design: The research team performed a systematic narrative review by searching the PubMed and Web of Science databases, including review articles and other studies for additional citations. Setting: The study was conducted at our Scientific Institute for Research (IRCCS) in Messina. Results: Only 14 of 121 publications met the inclusion criteria and were selected. Hypnotic treatment is an effective therapy that has beneficial impacts on the intensity of perceived pain, psychological well-being, mood disorders, and fatigue, and in addition, it significantly improves physical functioning in MS patients. The same effects haven't been obtained with other nonpharmacological techniques. Conclusion: Hypnosis is an appropriate psychological therapy for the management of MS patients' symptoms.

Psychological well-being in people with multiple sclerosis: a descriptive review of the effects obtained with mindfulness interventions.

Multiple sclerosis is a neuroinflammatory and neurodegenerative disease causing several psychosocial problems that significantly impairs quality of life. The most common physical and mental symptoms are anxiety, depression, stress, fatigue, and pain. Several studies investigated the effectiveness of non-pharmacological approaches in improving psychological well-being. This review focused on the impact of mindfulness interventions in patients with multiple sclerosis to reduce psychopathological symptoms and improve well-being. We searched on PubMed database and screening references of included studies and review articles for additional citations. From initial 107 studies, only 8 met search criteria. Our studies showed the efficacy of mindfulness treatment with a reduction in depressive symptoms, a better quality of life (both mental and physical), and a decreased level of fatigue. Findings demonstrated that mindfulness is useful for the improvement of psychological symptoms and pain management and this improvement has also been shown to have a positive impact on the quality of life and coping and adaptation strategies. However, according to the poor available clinics evidence, on cannot conclude that mindfulness interventions are superior to other active interventions in the treatment of psychological symptoms of SM.

Is there a correlation between dyslipidemia and cognitive impairment in patients with multiple sclerosis?

Background. Multiple sclerosis (MS) is an autoimmune and demyelination disease of the central nervous system that causes progressive accumulation of disability over time. Recent studies have highlighted the correlation between metabolic disorders and cognitive dysfunctions. The present study aims to evaluate the correlation between components of the lipid profile and cognitive dysfunctions in patients affected by MS.Methods. 90 MS inpatients were included in this study. We divided the sample into three subgroups to evaluate the influence of the presence of dyslipidemia: G1 (patients with dyslipidemia), G2 (patients without dyslipidemia), G3 (patients with a higher than normal lipid value). Patients underwent rehabilitation treatment which included conventional physiotherapy, speech therapy, psychological support, cognitive rehabilitation, nutritional therapy, robotic rehabilitation, cognitive rehabilitation, and virtual reality.Results. The results showed that the three subgroups had a significant improvement in global cognitive functioning (MOCA p < 0.00), working memory (BRB-NV SRT-LTS p < 0.00) and in attention process (BRB-NV SDMT p < 0.00). Only in the G2, we observed a significant improvement in visuospatial abilities (RAO SPART p < 0.00). Moreover, we found that the cholesterol was negatively correlated with the cognitive functioning score of the patients after rehabilitation and the EDSS score. While the triglyceride scores were negatively correlated with the working memory score before and after rehabilitation. BMI scores were negatively correlated with the visuospatial ability score.Conclusion. Investigating these aspects could help in managing patients, preventing alterations that compromise the patient's quality of life.

The role of teriflunomide in Multiple Sclerosis patient: an observational study.

Teriflunomide is a drug with immunosuppressive and selective immunomodulatory action, characterized by anti-inflammatory and antiproliferative properties. Several clinical studies have demonstrated the efficacy and safety of this drug in Multiple Sclerosis, estimating a significant improvement in cognitive performance.The aim of our study is to evaluate the effects of teriflunomide by analysing the correlation between brain atrophy and the general cognitive profile and evaluating long-term changes. The effect of teriflunomide was studied in 30 patients with multiple sclerosis and 30 control subjects. Patients underwent a full cognitive profile assessment using the Brief Repeatable Battery of Neuropsychological Tests and a neuroimaging examination with a 3.0 T working scanner.Our results suggested that treatment with teriflunomide could potentially not only slow down the accumulation of microstructural tissue damage in Grey Matter and With Matter, but also better preserve the cognitive profile, particularly by highlighting the benefits in the memory domain. Thanks to drug therapy, brain volume in our patients has remained constant, leading to improvements in memory, indicating teriflunomide as a neuroprotective potential and further strengthening the evidence of a link between loss of brain volume and cognitive impairment.

Neuropsychological Disability in the Case of Natalizumab-Related Progressive Multifocal Leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a viral disease characterized by progressive damage or inflammation of the cerebral white matter that can be encountered in patients with multiple sclerosis (MS). There are cases of PML caused by pharmacological agents including natalizumab. Therefore, in patients treated with this drug, early identification of PML allows changes in the treatment plan, reducing the risks of morbidity and mortality. CASE PRESENTATION: We reported the case of a 57-year-old female diagnosed with relapsing-remitting MS, who presented with PML related to natalizumab. The patient presented with change in behavioral, radiological abnormalities in the left parieto-temporal lobes. We described the longitudinal course of PML, from the diagnosis until the patient's death, documenting the progressive deterioration of her cognitive functioning, supported by changes on sequential brain scans and neurophysiological data. CONCLUSION: The neuropsychological impairment documented in this case study expands the range of treatment-related complications associated with natalizumab, and provides evidence that occurrence of "atypical" cognitive deficits in MS may support the early diagnosis of PML.

Nabiximols discontinuation rate in a large population of patients with multiple sclerosis: a 18-month multicentre study.

INTRODUCTION: Delta-δ-tetrahydrocannabinol and cannabidiol (THC:CBD) oromucosal spray is used as an add-on therapy option for moderate to severe multiple sclerosis (MS) spasticity resistant to other medications. Aims of this study were to provide real-life data on long-term clinical outcomes in a large population of Italian patients treated with THC:CBD and to evaluate predictors of THC:CBD therapy continuation. MATERIALS AND METHODS: This prospective observational multicentre Italian study screened all patients with MS consecutively included in the Agenzia Italiana del Farmaco e-registry at the start of THC:CBD treatment (baseline), after 4 weeks (T1), 12±3 weeks (T2), 24±3 weeks (T3), 48±3 weeks (T4) and 72±3 weeks (T5) from baseline. RESULTS: A total of 1845 patients were recruited from 32 MS Italian centres. At T1, 1502 (81.4%) of patients reached a Numerical Rating Scale (NRS) improvement of ≥20%, with an NRS reduction of 26.9% at T1 and of 34.4% at T5. At T5, 725 patients (48.3% of 1502) discontinued treatment with highest discontinuation rate at T2 and T3. Daily number of puffs was generally stable through the observation period. The multivariate analysis showed that higher NRS scores at baseline (OR 2.28, 95% CI 1.15 to 6.36, p<0.01) and higher differences of NRS between T0 and T1 (OR 2.11, 95% CI 1.08 to 8.26, p<0.05) were associated with an increased probability to continue therapy after 18 months. DISCUSSION: THC:CBD effects were sustained for 18 months with a relatively stable number of puffs per day. About 50% of patients abandoned THC:CBD therapy for loss of efficacy or adverse events.

Thought disorder in atypical schizophrenia-like psychosis after stroke: analysis of clinical cases.

Formal thought disorder refers to disorganized thinking and it represents a hallmark of schizophrenia and psychosis. Psychosis is a rare complication after stroke. We described two cases of female patients, who developed an atypical schizophrenia-like psychosis post-stroke, characterized by formal thought disorder, hallucinations, and delusion. Cerebrovascular disease affected the right temporal lobe, areas devoted to modulation of higher order cognitive processes. To date, the relation between stroke and psychosis remain unclear, maybe due to the involvement of a complex brain networks. However, the high impact of this disorder on physical, psychological and social wellbeing suggests the importance of improving specific treatments.

Body image in multiple sclerosis patients: a descriptive review.

OBJECTIVE: Multiple sclerosis is a neurological disorder-may in some patients have impact on body image; this could contribute to neurological disability, psychological distress, and can reduce quality of life. This review has been conducted on studies investigating the representation of body image. METHOD: We have researched PubMed and Web of Science databases and included screening references for studies and review articles about this topic. From the initial 316 publications, we included only 9 studies that met the search criteria. RESULT AND CONCLUSION: The results showed that this construct has been little emphasized over time and has a significant impact on the patient.

A complex relation between depression and multiple sclerosis: a descriptive review.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating neurodegenerative disease that affects central nervous system (CNS). MS patients are more likely to develop depressive symptoms than patients with other chronic diseases. OBJECTIVE: In this review, we have analysed if there is a correlation between brain lesions (BL), structural damage (SD) and depressive symptoms (DS). METHODS: We Searched on PubMed and Web of Science databases and screening references of included studied and some review article for additional citations. From initial 745 studies, only 9 met the inclusion criteria. All studies conducted research on 389 patients with MS associated with DS and 120 HC (healthy controls). RESULTS: The selected researches highlighted the involvement of limbic system, the role of hippocampus and the impact of brain lesions on the emotional status of MS patients. DISCUSSION: In the genesis of depression are implicated many mechanisms including genetic, biochemical, immunological and psychosocial factors, even if a prominent role in the onset of DS seem to be associated with structural and functional brain alterations.

Relation among Psychopathological Symptoms, Neuropsychological Domains, and Functional Disability in Subacute Poststroke Rehabilitation.

BACKGROUND: Neuropsychiatric disorders are commonly observed in patients following a stroke. Among 30%-60% of poststroke patients suffer from depression and anxiety (18%-25%). Some authors suggest an association between psychological symptoms and lesions in specific brain areas. In particular, lesions in left frontal cortex and left basal ganglia are frequently associated with poststroke depression and with comorbidity of anxiety and depression, whereas isolated anxiety symptoms are frequently observed after right hemispheric lesions. METHODS: We investigated the relationship between depressive symptoms and anxiety in patients with subacute stroke and lesion side, motor disability, and cognitive impairment. We enrolled 100 patients undergoing a rehabilitative program within 1-3 months after a first-onset stroke. RESULTS: Our patients presented mild to moderate depressive and anxious symptoms after stroke. In the comparison between patients with right and left lesions, during subacute poststroke phase, we did not find a specific link between existence of psychiatric symptoms and lesion side. However, in left lesion, depression correlated with age and alteration in delayed memory and attention, whereas memory deficit influenced anxiety symptoms. On the contrary, in right lesion, depressive symptoms were associated with attention ability, whereas anxiety was related to memory and attention. Depression and anxiety were not related to degree of neurological and functional deficits. CONCLUSIONS: The comorbidity between stroke and psychopathological disorders has been recognized as syndrome and should be diagnosed early and treated in order to improve the quality of life of patients and caregivers, and to improve rehabilitative process.

Evaluating Sativex® in Neuropathic Pain Management: A Clinical and Neurophysiological Assessment in Multiple Sclerosis.

OBJECTIVE: The aim of our study was to better investigate the role of Sativex(®) in improving pain in multiple sclerosis (MS) patients by means of either clinical or neurophysiological assessment. SETTING: Pain is a common symptom of MS, affecting up to 70% of patients. Pain treatment is often unsatisfactory, although emerging drugs (including cannabinoids) are giving encouraging results. Clinical pain assessment in MS is very difficult, and more objective tools are necessary to better quantify this symptom and its potential response to the treatments. SUBJECTS AND METHODS: We enrolled 20 MS patients (10 with and 10 without neuropathic pain), who underwent a specific clinical (such as visual analog scale) and neurophysiological assessment (by means of laser-evoked potentials and transcranial magnetic stimulation), before and after 4 weeks of Sativex administration. RESULTS: One month of drug administration in MS patients with neuropathic pain successfully reduced pain rating and improved quality of life. Interestingly, such effects were paralleled by an increase of fronto-central γ-band oscillation and of pain-motor integration strength. CONCLUSIONS: Our data suggest that Sativex may be effective in improving MS-related neuropathic pain, maybe through its action on specific cortical pathways.

Sativex in the management of multiple sclerosis-related spasticity: role of the corticospinal modulation.

Sativex is an emergent treatment option for spasticity in patients affected by multiple sclerosis (MS). This oromucosal spray, acting as a partial agonist at cannabinoid receptors, may modulate the balance between excitatory and inhibitory neurotransmitters, leading to muscle relaxation that is in turn responsible for spasticity improvement. Nevertheless, since the clinical assessment may not be sensitive enough to detect spasticity changes, other more objective tools should be tested to better define the real drug effect. The aim of our study was to investigate the role of Sativex in improving spasticity and related symptomatology in MS patients by means of an extensive neurophysiological assessment of sensory-motor circuits. To this end, 30 MS patients underwent a complete clinical and neurophysiological examination, including the following electrophysiological parameters: motor threshold, motor evoked potentials amplitude, intracortical excitability, sensory-motor integration, and Hmax/Mmax ratio. The same assessment was applied before and after one month of continuous treatment. Our data showed an increase of intracortical inhibition, a significant reduction of spinal excitability, and an improvement in spasticity and associated symptoms. Thus, we can speculate that Sativex could be effective in reducing spasticity by means of a double effect on intracortical and spinal excitability.

Sexual dysfunction induced by intrathecal baclofen administration: is this the price to pay for severe spasticity management?

INTRODUCTION: Intrathecal administration of baclofen (ITB) is widely recognized as an effective treatment for severe spasticity of both spinal and supraspinal origin with fewer side effects. The lower drug dosages used for spinal intrathecal administration, acting directly on the receptor sites, result in greater therapeutic efficacy with less systemic toxicity than with oral preparations. AIM: This study aims to prospectively evaluate the effects of ITB on erectile function in male patients affected by severe spasticity. METHODS: Twenty adult male patients, with a 34.85 ± 10.27 mean age, affected by severe spasticity mainly due to spinal cord lesions (10 traumatic, three vascular, six degenerative, and one congenital in origin) and treated with ITB, were enrolled in the study. All participants underwent specific clinical scales to evaluate force, muscle tone, cognition and mood, and specific sexual questionnaires, including an accurate semi-structured interview. MAIN OUTCOME MEASURE: The International Index of Erectile Function (IIEF) was used to evaluate sexual function before and after pump implantation. RESULTS: A comparative analysis of the neurological scales and psychometric scores at T1 (baseline) and T2 (follow-up) showed statistically significant differences before and after pump implantation. In particular, we noted a significant decrease in the IIEF median scores (from 0.42 ± 0.07 to 0.14 ± 0.02, P value < 0.0001) and a correlation between ITB dosage and IIEF scores (ρ = -0.60; P < 0.05). CONCLUSIONS: This study supports previous findings on a possible negative effect of ITB on sexual function, with regard to erection. Patients who are considering ITB for treatment of severe spasticity should be informed about possible but reversible sexual side effects, especially at higher dosage. Future studies with larger samples should be fostered to confirm these findings for a better management of these, often young, patients.

The Relationship between Body Image, Disability and Mental Health in Patients with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis is a progressive degenerative disorder that frequently involves the development of physical and emotional changes, including loss of limb function or sensitivity, sexual dysfunction, and cognitive and mood alterations. It is likely that these alterations lead to changes in body aspects. However, knowledge about body image perception in multiple sclerosis is lacking. PURPOSE: The present study investigated the relationship between body image perception and its correlation with a disability, neuropsychiatric symptoms, and self-esteem. METHODS: A total of 100 outpatients with relapsing-remitting multiple sclerosis underwent neurological assessment using the Expanded Disability Status Scale. Participants also completed the Body Image Scale (BIS), Rosenberg Self-Esteem Scale (RSES), and Symptom Checklist-90-Revised (SCL-90-R). RESULTS: We found a significant positive correlation between body image and disability (r = 0.21; p = 0.03), body image and self-esteem (r = -0.52; p < 0.001), body image and somatization (r = 0.44; p < 0.001), body image and depression (r = 0.57; p < 0.001), and body image and anxiety (r = 0.5; p < 0.001). CONCLUSIONS: The body is considered one of the main parts of a person's identity. Dissatisfaction with one's own body changes the general evaluation of the "self". The body image construct has important health outcomes and should be studied more in patients with multiple sclerosis.

Psychological symptoms in Multiple Sclerosis and the role of marital status: results from a retrospective single-center study.

BACKGROUND: Married people have, on average, better mental health than no married people. Psychological symptoms as anxiety and depression occur frequently in patients with multiple sclerosis (MS), increasing the severity of neurologic disability. The aim of this retrospective study was to investigate the relationship between functional disability and psychological symptoms differentiating by marital status. METHODS: In this study 150 MS outpatients without a history of psychological disorders were selected from the hospital database. The outpatient procedure for all patients includes the administration of the Expanded Disability Status Scale and the questionnaire Symptoms Checklist-90-Revised (SCL-90-R) a multidimensional self-report inventory, consisting of 90 items covering nine clinical dimensions: somatization (SOM), obsessive-compulsive (OC), interpersonal sensitivity (IS), depression (DEP), anxiety (ANX), hostility (HOS), phobic anxiety (PHOB), paranoid ideation (PAR), psychoticism (PSY), and three global indices of distress: global severity index (GSI), positive symptoms total (PST) and positive symptom distress index (PSDI). According to marital status, subjects were subdivided in single, married (including cohabitants), and divorced (including separated). A nonparametric group comparisons analysis was performed, as well as multivariate analysis which included generalized linear regression models. RESULTS: Regression results showed that functional disability was a significant predictor for all SCL- 90-R subscales. Moreover, it would seem that the single condition might be a protective factor for the development of psychological symptoms in SM patients. Notably, findings showed that younger subjects were predominantly single and had less psychological symptoms, whereas patients with greater psychological alterations were older in a stable affective couple relationship, presenting an elevation in depression, anxiety, somatization and compulsive, and obsessive scales. CONCLUSION: Numerous factors contribute to the onset of psychological disorders in multiple sclerosis. Marriage does not represent a protective factor for the development of psychological symptoms in SM patients. Future investigation is needed to ascertain the prevalence and underlying causes of psychological symptoms.

Anxiety and Perception of Disease Control in Multiple Sclerosis Subjects Treated with Natalizumab.

Multiple sclerosis subjects treated with natalizumab face anxiety about developing progressive multifocal leukoencephalopathy (PML), besides the psychological distress caused by the disease. The aim of this study is to investigate whether increasing the frequency of neurological and nuclear magnetic resonance screening may affect anxiety and the perception of disease control in patients treated with natalizumab. A total of 62 relapsing-remitting multiple sclerosis patients were recruited from 2019 to 2020. All patients received conventional infusion treatments with natalizumab, along with a screening protocol for PML. Three clinical assessments were considered: at the beginning of the study (T0), after 3 months (T1) and after 6 months (T2). Patients were classified into three levels of risk, where level 1 represented a low risk of PML and level 3 a high risk. This classification determined treatment and screening protocol, i.e., the frequency of performing the Stratify test and the brain 3T NMR exam, as well as the frequency of infusion treatments. Anxiety and perception of disease control were assessed at T0, T1, and T2 by a skilled psychologist. The Friedman test and the Wilcoxon signed-rank test were used to compare outcomes at baseline with the two follow-ups. Statistical test results showed that the risk of PML (per 1000 patients) was significantly lower in women than in men (W = 198.5; p = 0.01). Moreover, significant differences between baseline and the two follow-ups were found, both for anxiety (F(2) = 122.6, p < 0.001) and for perception of disease control (F(2) = 123.5, p < 0.001). In both cases, there was significant improvement between baseline (T0) and the end of the study (T2) in any risk level (p < 0.001). An increase in the number of follow-ups, as well as an increase in instrumental investigations, might have a positive effect on both anxiety and the perception of disease control. However, there are many variables involved in the disease process that have an impact on patients' psychological well-being. Therefore, further and more extensive studies are necessary to evaluate how, and how much, each variable impacts the disease course.

Low molecular weight heparin administration in cancer patients with hypercoagulability-related complications and carrying brain metastases: a case series study.

BACKGROUND: Venous thromboembolism (VTE) and brain metastases (MTS) are significant clinical problems in the cancer patient population. Brain MTS and deep vein thrombosis are life-threatening conditions because of the risk of fatal endocranic hypertension and pulmonary embolism. Low molecular weight heparin (LMWH) is a major treatment for cancer patients suffering from VTE with regard to the management of the acute phase and subsequent secondary prophylaxis. Treatment with anticoagulants is feared because of the risk of triggering a massive intracranial hemorrhage. METHODS: The medical records of patients with hypercoagulability-related complications and carrying brain MTS treated with LMWH, in a 10-year period, were scrutinized. The authors aimed to focus on the occurrence of intracranial hemorrhage in anticoagulated patients; furthermore, data were collected with regard to the characteristics of the administered LMWHs along with the duration and dosing of the anticoagulative treatment. RESULTS: A total of 38 patients (pts) carrying an intracranial metastatic tumor were administered LMWHs: calcium nadroparin (32 pts); enoxaparin (2 pts); reviparin (2 pts); parnaparin (2 pts). Reason for LMWH therapy: deep vein thrombosis and/or pulmonary embolism (15 pts); superficial thrombophlebitis (15 pts); intracardiac thrombus (1 pt); mild DIC (5 pts); acute DIC (1 pt); Raynaud phenomenon (1 pt); atrial fibrillation (1 pt). Median duration of LMWH therapy: 13 weeks (range 1-52). None of the patients developed clinical and/or radiographic findings imputable to intracranial hemorrhage. CONCLUSION: There is no standard medical approach for the management of patients who require anticoagulant treatment and are suffering from brain MTS. These patients as necessary, might be anticoagulated with LMWH and its dose reduction is to be considered.

Neuropsychological implication in possible antibody-negative limbic encephalitis: a clinical case report.

Autoimmune limbic encephalitis is an antibody-mediated brain inflammatory process, which typically involves the medial temporal lobe. Diagnosis requires the presence of antineuronal antibodies, but sometimes patients present clinical features of limbic encephalitis despite negative serology. Thus, the diagnosis of antibody-negative limbic encephalitis is difficult to make, and it must often rely largely on exclusion of other causes. This current case report describes a 28-year-old male that presented 2 months after the acute event with radiological changes typical of limbic encephalitis, but with no identifiable antibody and neuropsychological impairment. Antibody responses to neurotropic viruses and antibody-mediated encephalitis were negative in serum and cerebrospinal fluid. Magnetic resonance imaging showed signs of hyperintensity in the hippocampus bilaterally, amygdala and left pulvinar. The neuropsychological evaluation showed a deficit in emotional face recognition and severe autobiographical amnesia. Bilateral damage to the medial temporal lobe and hippocampus, including the amygdala, is associated with alterations in autobiographical memories. The neuropsychological impairment documented in this current case expands the range of clinical features of antibody-negative encephalitis and provides evidence that the memory deficit in this disorder is more extensive than was previously recognized.