Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results.

The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). TBI, CY and antithymocyte globulin were followed by transplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; four of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.

Prevalence of sleep problems in individuals with multiple sclerosis.

BACKGROUND: Sleep disturbance in multiple sclerosis has received little research attention despite the potential influence it may have on disease impact. OBJECTIVE: To estimate the prevalence of sleep disorders in a large community sample of individuals with multiple sclerosis. METHODS: A cross-sectional self-report survey of 1063 persons with multiple sclerosis. Sleep was assessed using the Women's Health Initiative Insomnia Rating Scale and Medical Outcomes Study Sleep measure. RESULTS: The prevalence of sleep problems in multiple sclerosis is significantly higher than in the general population or other chronic diseases and may affect women with multiple sclerosis more than men. CONCLUSION: Sleep disturbance should routinely be evaluated in patients with multiple sclerosis and new interventions developed.

Setting the agenda for multiple sclerosis rehabilitation research.

BACKGROUND: Recognizing the need for more evidence-based multiple sclerosis (MS) rehabilitation, in the mid-2000s several initiatives were undertaken to explore why there had been a paucity of such research and to determine strategies to reverse this pattern. EXPERT-OPINION-PAPER: In 2004 the National Multiple Sclerosis Society (NMSS) convened an expert opinion panel, reviewed evidence-based MS rehabilitation research, and published the paper on the web. It was concluded that much of the MS rehabilitation carried out was based on experience, with little research backing it up. INCREASING THE QUALITY AND QUANTITY OF MS REHABILITATION RESEARCH: Largely as a result of the conclusions of the Expert-Opinion-Paper, the NMSS convened a conference of a large number of MS and rehabilitation experts in New York in May, 2005. This conference made many recommendations of ways to increase the quantity and quality of MS research. STATE OF THE SCIENCE CONFERENCE: In September, 2006, a follow-up conference was held in Washington, D.C... This conference, primarily sponsored by the University of Washington Multiple Sclerosis Rehabilitation Research and Training Center (MS RRTC), focused on some of the under-studied "hidden" disabilities present in persons with MS. This paper discusses the details and recommendations of these latter two conferences.

Antidepressant use in multiple sclerosis: epidemiologic study of a large community sample.

Depressive symptoms and disorders among individuals with multiple sclerosis (MS) are more common when compared to other chronic illnesses and the general population, but relatively little is known about the use of antidepressant medication in this population. In this cross-sectional study of 542 community-dwelling adults with MS, we examined the prevalence of antidepressant use and employed multivariate logistic regression modeling to identify factors significantly associated with antidepressant use. Thirty-five percent of the sample reported currently using at least one antidepressant medication. Gender, marital status, insurance status, fatigue, and use of disease modifying therapies were all significantly associated with antidepressant use. Just over half of the sample endorsed a clinically significant level of depressive symptoms, and the majority of this group was not currently taking an antidepressant. Conversely, 41% of those with depressive symptoms reported taking at least one antidepressant medication. More research is needed to better understand why people with MS and depressive symptoms use or do not use antidepressant medications and to further explore the possibility of an under-treatment of depressive disorder in this population. Rigorous studies testing the feasibility, acceptability, and efficacy of currently available therapies for depression in the MS population should also be conducted.

The scope and nature of pain in persons with multiple sclerosis.

Much remains unknown about the scope, nature, and impact of pain on the lives of persons with multiple sclerosis (MS). In the present study, 180 community dwelling adults with MS completed a postal survey that included demographic measures, MS disease measures, and several standardized measures of pain, including pain intensity, variability, location, and pain-related interference. Some 66% of the sample reported pain, 25% of whom reported severe pain. Persons with pain reported an average of 6.6 distinct pain sites. Using the Brief Pain Inventory Interference Scale, the average level of overall pain interference was 3.33 (0-10 scale) in the group reporting pain. The highest levels of pain interference were reported for sleep, recreational activities, and work in and outside the home. Persons with pain were more likely to report greater MS disease severity, poorer psychological functioning, and poorer health than persons with MS but not pain. Persons with pain were also less likely to be employed. These findings are consistent with previous research that shows that pain is common in MS, that it is severe in a substantial subset of these individuals and has the potential to negatively impact physical and psychosocial functioning over and above the effects of MS itself.

Alcohol and drug abuse among persons with multiple sclerosis.

OBJECTIVE: To examine the one-month prevalence and impact of substance abuse in a large community sample of persons with multiple sclerosis (MS). METHOD: Members of the Multiple Sclerosis Society of King County were surveyed by mail. This multifaceted health survey included questions pertaining to substance abuse. Seven hundred and thirty-nine out of 1374 potential participants (54%) returned the survey, while 708 reported a medically confirmed diagnosis of MS and provided sufficient data. RESULTS: Fourteen per cent of the sample screened positive for possible alcohol abuse or dependence, and 7.4% reported misusing illicit drugs or prescription medications within the previous month. Possible alcohol abuse and drug misuse were associated with younger age, less severe MS related disability and being employed, as well as greater self-reported depressive symptomatology. Most persons with alcohol problems indicated interest in learning more about ways to stop or cut down. CONCLUSIONS: Substance abuse may be present in up to 19% of this sample and contribute to high rates of depression. There may be greater risk of harm due to substance abuse in people with MS because of the potential magnification of motor and cognitive impairments. Comprehensive MS care should include substance abuse screening and advice to cut down or abstain.

Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes.

Charcot-Marie-Tooth Hereditary Neuropathy is a heterogeneous syndrome associated with mutations in several different genes including peripheral myelin protein 22, myelin P0, connexin 32, and early growth response 2. There is considerable variability in the phenotypic expression of this syndrome and the relationship of this variability to mutation genotypes requires extensive analysis. Here we describe the phenotypes and genotypes of four new mutations underlying the Charcot-Marie-Tooth syndrome and document segregation with disease. Four families with Charcot-Marie-Tooth were ascertained, examined, and evaluated electrophysiologically. Each family had peripheral blood DNA screened for mutations in myelin protein 22, myelin P0, and connexin 32. Two families were found with new mutations in the myelin P0 gene: S140T in the extracellular domain and K236del in the cytoplasmic domain. All families showed segregation of the mutations with the Charcot-Marie-Tooth phenotype as did a new family with the rare G163R mutation in the membrane domain. A 49-year-old man with the S140T mutation demonstrated conduction block on electrophysiological testing. A family with a novel S49P mutation in the connexin 32 gene had a neuropathy with very slow nerve conduction. These new mutations in the myelin P0 and connexin 32 genes help to clarify the pathophysiology of the clinical Charcot-Marie-Tooth syndrome. The S140T mutation in myelin P0 can be associated with conduction block and Charcot-Marie-Tooth should be part of the differential diagnosis of that phenomenon. Mutations in the cytoplasmic domain of myelin P0 can cause clinical neuropathy. The S49P mutation in the connexin 32 gene can produce aspects of a demyelinating type of X-linked hereditary neuropathy.

Physiologic studies of male sexual dysfunction in multiple sclerosis.

OBJECTIVE: We conducted this investigation to better define the neural disruptions that result in sexual dysfunction in men with multiple sclerosis (MS), using genital electrodiagnostic testing and nocturnal penile tumescence and rigidity monitoring. METHODS: Thirteen men with MS and sexual dysfunction were recruited for the study. Twelve healthy, sexually potent men were enrolled as controls. All underwent pudendal somatosensory evoked potential (SEP) testing using standard methods, and a new modification to isolate the right and left dorsal nerves of the penis. RigiScan testing was performed on the MS subjects to assess nocturnal erectile function. RESULTS: Unilateral and bilateral DNP SEPs were able to be performed on the control subjects. In all but one MS subjects, DNP SEP abnormalities were found. Three men had normal latency bilateral DNP SEP latencies, but on unilateral DNP testing, abnormalities were identified. Seven men, including those with abnormal or absent SEP latencies, had normal nocturnal erectile activity. There was no correlation between overall functional status, presence of abnormal or absent SEP, and quality of nocturnal erectile activity. CONCLUSIONS: Genital SEP abnormalties are common in men with MS and sexual dysfunction. Unilateral DNP SEP testing was more sensitive in identifying abnormalities than the standard method of pudendal SEP testing. One of the causes of sexual dysfunction in men with MS may be due to genital somatosensory pathway disruption, with sparing of the efferent tracts in some men.

Self-administered Expanded Disability Status Scale with functional system scores correlates well with a physician-administered test.

BACKGROUND: Patient-administered measures are needed to assess disability cost-effectively in large epidemiological studies. SETTING: An outpatient clinic in a large multiple sclerosis center. METHODS: A self-administered EDSS questionnaire was developed (EDSS-S). Consecutive patients with clinically definite multiple sclerosis completed the EDSS-S (n=95). During the same visit, a physician completed an EDSS (EDSS-P). Scores below 4.0 were determined using functional system (FS) scores. Scores above 4.0 were calculated by two methods, using gait alone and using gait and functional system scores combined. RESULTS: EDSS-P scores ranged from 0-9.5 (mean 5.1, median 5.0, 78% female, age 17-78, mean age 45). Mean EDSS-P, EDSS-S and intraclass correlation coefficients of agreement were: EDSS using ambulation alone (4.6, 5.1, 0.89), EDSS using ambulation and FS scores (4.6, 5.3, 0.87), bowel/bladder FS scores (1.6, 1.7, 0.79), pyramidal FS scores (2.1, 2.4, 0.67), sensory FS scores (1.6, 2.1, 0.60), cerebellar FS scores (1.1, 1.6, 0.55), brainstem FS scores (0.5, 1.2, 0.45), vision FS scores (1.9, 1.3, 0.38), cerebral FS scores (0.6, 2.3, 0.27). CONCLUSIONS: Very good correlation was seen between patient and physician scores for EDSS and the bowel/bladder FS score. Four other FS scores correlated moderately. In general, patients scored themselves more disabled than physicians.

Idiopathic shoulder girdle neuropathy.

Idiopathic shoulder girdle neuropathy is the syndrome of acute upper extremity pain located primarily in the shoulder, which is subsequently replaced by painless neurologic weakness and sensation loss. The disease is self-limited and generally carries with it a favorable prognosis. The clinical presentation, electrodiagnostic picture and natural history are discussed.

Cortical evoked potentials of the dorsal nerve of the clitoris and female sexual dysfunction in multiple sclerosis.

PURPOSE: We evaluated whether disrupting genital central nervous system pathways is associated with subjective reports of sexual dysfunction in women with multiple sclerosis. MATERIALS AND METHODS: We performed pudendal somatosensory evoked potential testing in and had sexual questionnaires completed by 14 women with a mean age of 47 years who had multiple sclerosis. RESULTS: The mean expanded disability status score was 5. All but 1 woman reported the desire for sexual intercourse. There was a high rate of dissatisfaction with their sex life and all study participants had concomitant bladder and bowel function problems. The most common sexual complaint was difficult or no orgasm, which was statistically associated with abnormalities or absence of 1 or both pudendal cortical evoked potentials. Fatigue and arousal disorders were also common. CONCLUSIONS: Women with multiple sclerosis have a high self-reported rate of sexual dysfunction, which decreases quality of life. Electrodiagnostic data imply that pudendal somatosensory innervation is necessary for normal female orgasmic function. More study is needed to confirm these findings.

Electrodiagnostic evaluation of traumatic nerve injuries.

This article reviews the techniques of motor and sensory nerve conduction studies and needle electromyography methods, which are particularly useful for localizing nerve injuries in upper extremity and hand trauma. Included are details of methods for detecting and quantifying the degree of axon loss and for using this information to make treatment decisions and predict outcomes. The epidemiology and classification of traumatic peripheral nerve injuries, the effects of these injuries on nerve and muscle, and the means by which electrodiagnosis is used to help classify the injury are described. An overview of recovery mechanisms also is presented.

Neurological worsening due to infection from renal stones in a multiple sclerosis patient.

Symptomatic bladder dysfunction occurs in the majority of patients with multiple sclerosis (MS). Although guidelines have been established for diagnosis and management of bladder dysfunction in these patients, they are sometimes overlooked in the primary care setting, leading to severe, life threatening complications. A 64-year-old male with a 31-year history of spastic quadriparetic MS and neurogenic bladder dysfunction managed with an indwelling catheter, presented to the hospital with worsening neurological function. He had developed increased weakness and cognitive impairment several weeks after being treated for a urinary tract infection (UTI). He had become unable to perform any activities of daily living or drive his power wheelchair. After an extensive work-up, he was found to have a large (14 x 18 x 30 cm) retroperitoneal abscess and multiple renal stones, including a large obstructing calculus in the collecting system near the ureteropelvic junction, and he underwent nephrectomy and abscess drainage. Of note, he had been found to have multiple renal stones and hydronephrosis on renal ultrasound 3 years earlier, but he had received no treatment. Following drainage of the abscess, his upper extremity neurological function returned to baseline, his cognitive status improved, and he regained the ability to perform activities of daily living. Patients with paralysis from MS, much like those with traumatic spinal cord injuries, are at grave risk of mortality and morbidity from undiagnosed and under-treated urinary complications. This case demonstrates that evaluation and appropriate treatment for complications of neurogenic bladder should be part of routine care for patients with MS. Current recommendations for evaluation and management of bladder dysfunction in patients with MS will be reviewed.

The role of spouse responses to disability and family environment in multiple sclerosis.

Research in the area of family issues and multiple sclerosis has mainly focused on the impact of multiple sclerosis on the spouse. The aim of the current study was to examine the relationship between patients' ratings of their spouses' responses to multiple sclerosis patient disability behaviors and the impact on patient psychological and physical functioning. Multiple sclerosis patients were interviewed over the telephone using standardized questionnaires to assess patient physical and psychological functioning, spouse responses to patient disability and well behaviors (i.e., how does the spouse respond when you're having difficulties related to multiple sclerosis?), and family environment factors. The study was set in a large university-based Multiple Sclerosis Clinical Center. Forty-four of 64 patients approached with definite multiple sclerosis participated in the study. Physical functioning was assessed by the Kurtzke-EDSS, SIP, SF-36, and psychological functioning was assessed by the CES-D and SF-36. Scores on the SF-36 were generally lower compared with a normative sample of individuals with major medical problems; however, mean Kurtzke scores of 5.60 reflected moderate to severe impairment. Exploring spouse responses to disability, correlation analyses revealed that solicitous spouse responses to patient disability behaviors were significantly associated with greater multiple sclerosis-related physical disability. This relationship was stronger for patients who were more depressed. Spouse negative responses to patient disability behaviors were associated with poorer mental health, whereas spouses' encouragement of patient well behaviors was associated with lower emotional distress. Poorer psychological functioning was found in patients with families who were reported to have higher conflict and/or who were more controlling. Higher levels of independence in families were associated with better psychological and physical functioning in the patients. These preliminary findings suggest that patients' perceptions of their families' responses to disability and family environment factors may be important areas for further research. The findings may also provide potential targets for clinical intervention in the future.

Neuropathic pain in Charcot-Marie-Tooth disease.

OBJECTIVES: To determine the frequency and extent to which subjects with Charcot-Marie-Tooth (CMT) disease report pain and to compare qualities of pain in CMT to other painful neuropathic conditions. STUDY DESIGN: Descriptive, nonexperimental survey, using a previously validated measurement tool, the Neuropathic Pain Scale (NPS). PARTICIPANTS: Participants were recruited from the membership roster of a worldwide CMT support organization. MAIN OUTCOME MEASURES: NPS pain descriptors reported in CMT were compared with those reported by subjects with postherpetic neuralgia (PHN), complex regional pain syndrome, type 1 (CRPS-1), also known as reflex sympathetic dystrophy, diabetic neuropathy (DN), and peripheral nerve injury (PNI). RESULTS: Of 617 CMT subjects (40% response rate), 440 (71%) reported pain. with the most severe pain sites noted as low back (70%), knees (53%), ankles (50%), toes (46%), and feet (44%). Of this group, 171 (39%) reported interruption of activities of daily living by pain; 168 (38%) used non-narcotic pain medication and 113 (23%) used narcotics and/or benzodiazepines for pain. The use of pain description was similar for CMT, PHN, CRPS-1, DN, and PNI in terms of intensity and the descriptors hot, dull, and deep. CONCLUSIONS: Neuropathic pain is a significant problem for many people with CMT. The frequency and intensity of pain reported in CMT is comparable in many ways to PHN, CRPS-1, DN. and PNI. Further studies are needed to examine possible pain generators and pharmacologic and rehabilitative modalities to treat pain in CMT.

Rehabilitation principles for patients with multiple sclerosis.

The purpose of this review was to discuss some newer rehabilitation techniques and their applications in MS. There are a number of other rehabilitation problems--bladder dysfunction, cognitive impairment, and pain, to name a few--that are important to address in the rehabilitation of a patient with MS, but that were not covered in this review. I would like to stress the principle that we need to adapt rehabilitation strategies to a progressive neurologic disease with an uncertain future course. That means we need to "overrehabilitate" MS patients with exacerbating and remitting unstable disease. As an example of what this means, consider a patient who has an EDSS of 4.5 and has a certain level of function. Suppose the patient receives a rehabilitative course and functions well. However the patient may have an exacerbation and become worse, going to an EDSS of 6.5, which may or may not improve. During this period, this patient needs to be able to function at his or her more impaired level. Therefore, it is important to train patients in therapeutic strategies they can use if they become temporarily worse. We need to remember that all organ system problems exist in a singular patient. Consequently, we must coordinate all of the treatments together, because the whole system must work for the patient as a whole.

Cerebral N-acetylaspartate is low in patients with multiple sclerosis and abnormal visual evoked potentials.

PURPOSE: Our purpose was to compare cerebral proton MR metabolite changes in patients with multiple sclerosis (MS) and abnormal visual evoked potentials (VEPs) with those in MS patients with normal VEPs. METHODS: Seventeen subjects with clinically definite MS were studied with VEPs and MR spectroscopic imaging. Proton MR metabolites were measured using a fast spectroscopic imaging technique called proton echo-planar spectroscopic imaging (PEPSI). Kurtzke's Expanded Disability Status Scale (EDSS) score was also ascertained for each subject to obtain a clinical rating. Twelve regions of interest within the visual pathway of the cerebrum were evaluated for levels of N-acetylaspartate (NAA), choline, creatine, and the presence or absence of MR-detectable lesions. RESULTS: PEPSI NAA values (water-normalized, CSF-corrected) were significantly lower in MS subjects with abnormal VEPs than in subjects with normal VEPs. MR-detectable lesion fractions and EDSS scores were also significantly different between the two VEP groups, but NAA comparison had a P value 100 times less than either of these measures. CONCLUSION: In patients with MS, NAA measurements in the optic pathways of the brain were sensitive to VEP abnormalities. NAA was more sensitive to VEP changes than were choline, creatine, MR-detectable lesions, and EDSS score.