High false-positive rate of questionnaire-based restless legs syndrome diagnosis in multiple sclerosis.

BACKGROUND/OBJECTIVES: Restless legs syndrome (RLS) is diagnosed by self-reported symptoms. Multiple sclerosis (MS) patients have disease-related symptoms which could mimic RLS. This study assessed the: (1) false-positive rate for questionnaire-based RLS diagnosis in MS patients and (2) utility of periodic leg movements during wakefulness (PLMW) on overnight polysomnography (PSG) in identifying true-positive RLS patients. METHODS: Ambulatory MS patients without known sleep disorders were recruited. Subjects completed the International RLS Study Group (IRLSG) diagnostic questionnaire (IRLDQ) and underwent full overnight PSG. IRLDQ-positive patients underwent clinical evaluation to confirm the diagnosis and completed the RLS severity scale (IRLS). RESULTS: Seventy-one MS patients (mean age 46.8 ± 10.4 years) were evaluated. Thirty-eight had a positive IRLDQ. RLS diagnosis was confirmed in 22, yielding a false-positive rate of 42% [95% confidence interval (CI) 26-59%], predominantly attributable to paresthesiae (n = 7), and cramps and/or muscle spasms (n = 4). IRLS scores were not significantly different between subjects with confirmed and nonconfirmed RLS. The PLMW index was significantly higher in patients with confirmed RLS (55.4 ± 41.9 vs. 29.7 ± 18.8, p = 0.03). The sensitivity of a PLMW index >70/h for true-positive IRLDQ was 8/22 = 36%, 95% CI: 17.2-59.3, and the specificity was 16/16 = 100%, 95% CI: 79.4-100. CONCLUSIONS: MS patients have a high false-positive rate of RLS diagnosis using a standardized questionnaire largely attributable to MS-related sensorimotor symptoms. While detailed clinical evaluation is essential for confirming RLS diagnosis, the PLMW index may provide useful adjunctive information.

Impact of sleep disorder treatment on fatigue in multiple sclerosis.

BACKGROUND: We recently reported that sleep disorders are significantly associated with fatigue in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to assess the effects of sleep disorder treatment on fatigue and related clinical outcomes in MS. METHODS: This was a controlled, non-randomized clinical treatment study. Sixty-two MS patients completed standardized questionnaires including the Fatigue Severity Scale (FSS), Multidimensional Fatigue Inventory (MFI), Epworth Sleepiness scale (ESS) and Pittsburgh Sleep Quality Index (PSQI), and underwent polysomnography (PSG). Patients with sleep disorders were offered standard treatment. Fifty-six subjects repeated the questionnaires after ≥ three months, and were assigned to one of three groups: sleep disorders that were treated (SD-Tx, n=21), sleep disorders remaining untreated (SD-NonTx, n=18) and no sleep disorder (NoSD, n=17). RESULTS: FSS and MFI general and mental fatigue scores improved significantly from baseline to follow-up in SD-Tx (p <0.03), but not SD-NonTx or NoSD subjects. ESS and PSQI scores also improved significantly in SD-Tx subjects (p <0.001). Adjusted multivariate analyses confirmed significant effects of sleep disorder treatment on FSS (-0.87, p = 0.005), MFI general fatigue score (p = 0.034), ESS (p = 0.042) and PSQI (p = 0.023). CONCLUSION: Treatment of sleep disorders can improve fatigue and other clinical outcomes in MS.

Obstructive sleep apnea is associated with fatigue in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) patients often suffer from fatigue. OBJECTIVE: We evaluated the relationship of obstructive sleep apnea (OSA) to fatigue and sleepiness in MS patients. METHODS: Ambulatory MS patients without known sleep disorders and healthy controls underwent diagnostic polysomnography and a multiple sleep latency test (objective sleepiness measure). Fatigue was measured with the Fatigue Severity Scale (FSS) and the Multidimensional Fatigue Inventory (MFI), and subjective sleepiness by Epworth Sleepiness Scale. Covariates included age, sex, body mass index, Expanded Disability Status Scale (EDSS), depression, pain, nocturia, restless legs syndrome, and medication. RESULTS: OSA (apnea-hypopnea index ≥ 15) was found in 36 of 62 MS subjects and 15 of 32 controls. After adjusting for confounders, severe fatigue (FSS ≥ 5) and MFI-mental fatigue (>group median) were associated with OSA and respiratory-related arousals in MS, but not control subjects. Subjective and objective sleepiness were not related to OSA in either group. In a multivariate model, variables independently associated with severe fatigue in MS were severe OSA [OR 17.33, 95% CI 2.53-199.84], EDSS [OR 1.88, 95% CI 1.21-3.25], and immunomodulating treatment [OR 0.14, 95% CI 0.023-0.65]. CONCLUSIONS: OSA was frequent in MS and was associated with fatigue but not sleepiness, independent of MS-related disability and other covariates.

Sleep disorders and fatigue in multiple sclerosis: evidence for association and interaction.

Fatigue is highly prevalent in multiple sclerosis (MS). It appears to be multifactorial, with "primary" or disease-related factors involved, as well as "secondary" factors, including comorbidities. Sleep disturbances are frequent in MS as well, and often result from disease-related factors. Subjective sleep disturbances in MS have been extensively studied and have been associated with fatigue. Sleep disorders in the general population have been associated with fatigue as well. However, data on objectively diagnosed sleep disorders in MS are less conclusive. Studies of sleep in MS have often suffered from low numbers of study subjects and suboptimal methodology. We review the current knowledge on sleep disturbances in MS and the relationship to fatigue. Data from neuroimaging studies and studies of molecular consequences of sleep disorders in the general population, with particular attention to sleep-disordered breathing (SDB), are briefly reviewed. Potential biologic interactions with MS are discussed in this context. We conclude that further studies of sleep disorders in MS are needed, to objectively establish their significance in this disease, and also to document any impact of treatment of sleep disorders on biologic and clinical outcomes such as fatigue.

Fatigue in multiple sclerosis: association with disease-related, behavioural and psychosocial factors.

We determined biopsychosocial correlates of general, physical, and mental fatigue in MS patients, by evaluating the additional contribution of potentially modifiable factors after accounting for non-modifiable disease-related factors. Fifty-three ambulatory MS patients, along with 28 normal controls were recruited for a cross-sectional study. Subjects completed the Multidimensional Fatigue Inventory (MFI) and Fatigue Severity Scale. Potential correlates evaluated were: disease-related factors (disease duration and type, immunomodulating treatment, muscle strength, pain, forced vital capacity (FVC), respiratory muscle strength, body mass index, disability, fibromyalgia), behavioural factors (physical activity, sleep quality) and psychosocial factors (depression, stress, self-efficacy). Multivariate models were calculated for MFI General, Physical, and Mental Fatigue. Age-adjusted multivariate models with non-modifiable factors included the following predictors (P < or = 0.10) of 1) MFI General and Mental Fatigue: none; and 2) MFI Physical Fatigue: FVC and disability. The following potentially modifiable predictors (P < or = 0.10) made an additional contribution to the models 1) MFI General Fatigue: sleep quality, self-efficacy, pain; 2) MFI Physical Fatigue: self-efficacy, physical activity; and 3) MFI Mental Fatigue: stress, self-efficacy. Fatigue in MS is multidimensional. Correlates of general and physical fatigue are disease-related, behavioural and psychosocial factors. Correlates of mental fatigue are psychosocial factors. Potentially modifiable factors account for a considerable portion of fatigue.

Serum insulin-like growth factor-I (IGF-I) does not correlate positively with isometric strength, fatigue, and quality of life in post-polio syndrome.

OBJECTIVES AND BACKGROUND: To determine if serum insulin-like growth factor-I (IGF-I) levels are associated with strength, body mass index (BMI), fatigue, or quality of life in post-poliomyelitis syndrome (PPS). PPS is likely due to a distal disintegration of enlarged post-polio motor units as a result of terminal axonal sprouting. Age-related decline in growth hormone and IGF-I (which support terminal axonal sprouts) is proposed as a contributing factor. METHODS: As part of the North American Post-Poliomyelitis Pyridostigmine Study (NAPPS), baseline data on maximum voluntary isometric contraction (MVIC), BMI, subjective fatigue (fatigue severity scale, Hare fatigue symptom scale), health-related quality of life (short form health survey-36; SF-36), and serum IGF-I levels were gathered on 112 PPS patients. Pearson correlation coefficients were calculated to evaluate the association between serum IGF-I and MVIC in 12 muscles, BMI, two fatigue scales, and SF-36 scale scores. RESULTS: There is a significant inverse correlation of IGF-I levels with MVIC in left ankle dorsiflexors (r=-0.30, P<0.01), and left and right knee extensors (r=-0.22, -0.25, P=<0.01, 0.01), but no significant correlations in other muscles. When men and women were evaluated separately, inverse correlations of IGF-I levels with MVIC were found only in men. IGF-I correlated inversely with BMI (r=-0.32, P=0006) and age (r=-0.32, P=0.0005). IGF-I did not correlate with the fatigue or SF-36 scales. CONCLUSIONS: In this exploratory study, we found that contrary to our expectations, IGF-I did not correlate positively with strength. IGF-I correlated negatively with strength in several lower extremity muscles, BMI, and age. IGF-I is likely not an important factor in the pathogenesis of fatigue and in determining quality of life in PPS, but its role on strength should be studied further.

The gastric emptying scan as a tool for surgical management of severe bowel dysfunction in spinal cord injury: 2 case reports.

We describe 2 patients with spinal cord injury (SCI) for whom the gastric emptying scan (GES) was crucial for determining the correct surgical approach in the therapeutic management of gastrointestinal complaints. Two men, ages 45 and 51 years, were admitted to a university hospital for delayed gastric complications from SCI. Both SCIs were traumatic, and the interval since injury was 18 months for the younger man and 6 months for the older man. Both men lacked voluntary motor and sensory function below the cord level of the lesion and had quadriplegia. Using GES, we measured motility (the cutoff for normal in this laboratory is 37%) and the time at which half the gastric contents were emptied (normal values are 45 +/- 8 min). Both patients had abnormal motility: residuals at 1 hour were above 50%. Half the gastric contents were emptied at 75 and 90 minutes, respectively. The therapeutic value of the GES was demonstrated for both patients, in combination with the history, physical examination, and abdominal radiographic studies. The first patient underwent ileostomy, and the second required a gastrostomy tube and a jejunostomy tube in addition to metoclopramide. The GES is a valuable diagnostic tool with an important role in the surgical management of patients with SCI.

A multicenter, randomized, double-blinded trial of pyridostigmine in postpolio syndrome.

BACKGROUND: Postpoliomyelitis syndrome (PPS) is likely due to degeneration and dysfunction of terminal axons of enlarged postpolio motor units. Age-related decline in growth hormone and insulin-like growth factor (IGF-I) may be a contributing factor. Neuromuscular junction abnormalities and decreased IGF-I levels may respond to the anticholinesterase pyridostigmine, with consequent improvement in strength, fatigue, and quality of life. OBJECTIVES: To determine the effect of pyridostigmine in PPS on health-related quality of life, isometric muscle strength, fatigue, and serum IGF-I levels; and to assess the safety of pyridostigmine in PPS. METHODS: The study was a multicenter, randomized, double-blinded, placebo-controlled trial of a 6-month course of pyridostigmine 60 mg three times per day in 126 PPS patients. The primary data analysis compared mean changes of outcomes between treatment and control groups at 6 months using an intention to treat approach. Secondary analyses included a comparison of outcomes at 6 and 10 weeks, and in compliant patients. RESULTS: The study showed no significant differences in pyridostigmine and placebo-treated patients with regard to changes in quality of life, isometric strength, fatigue, and IGF-I serum levels at 6 months in the primary analysis and in compliant patients. There were no differences in outcomes at 6 and 10 weeks between groups. However, very weak muscles (1 to 25% predicted normal at baseline) were somewhat stronger (p = 0.10, 95% CI of difference -9.5 to 73.3%), and in compliant patients IGF-I was somewhat increased (p = 0.15, 95% CI of difference -6.4 to 44.8 ng/mL) at 6 months with the medication. Pyridostigmine was generally well tolerated. CONCLUSIONS: This study showed no significant differences between pyridostigmine and placebo-treated PPS patients on measures of quality of life, isometric strength, fatigue, and serum IGF-I.

Pathophysiology and diagnosis of post-polio syndrome.

Post-poliomyelitis syndrome is defined as a clinical syndrome of new weakness, fatigue and pain which can occur several decades following recovery from paralytic poliomyelitis. The cause of this disorder is still unclear, and many possible etiologies have been proposed. The most widely accepted etiology was first proposed by Wiechers and Hubbell, which attributes PPS to a distal degeneration of massively enlarged post-polio motor units. Other probable contributing factors to the onset of this disease are the ageing process, and overuse. Currently, there is no specific diagnostic test for PPS, which continues to be a diagnosis of exclusion in an individual with symptoms and signs of the disorder.

Management of post-polio syndrome.

Many patients with post-poliomyelitis syndrome can benefit from a management program. When a post-polio patient presents with new symptoms, it is first essential to identify and treat other medical and neurological conditions which could produce these symptoms. New weakness can be managed with exercise (stretching, strengthening, and aerobic), avoidance of muscular overuse, weight loss, orthoses, and assistive devices. Fatigue can be managed with energy conservation techniques, lifestyle changes, pacing, regular rest periods or naps during the day, amitriptyline to improve sleep, and possibly pyridostigmine (trial in progress). The management of pain is dependent upon its cause. The treatment of post-polio muscular pain can include activity reduction, pacing (rest periods during activity), moist heat, ice, and stretching, use of assistive devices, and life style modifications. Fibromylagia can be treated with amitriptyline, cyclobenzaprine, and aerobic exercise. Joint and soft tissue abnormalities can be managed with modification of extremity use, physiotherapy, orthoses, assistive devices, non-steroidal anti-inflammatory medications, and rarely steroid injections and surgery. Superimposed neurological disorders may produce pain, and should be identified and treated. The identification and treatment of pulmonary dysfunction in a post-polio patient is an important aspect of management, and is discussed elsewhere in this issue. Dysphagia can be managed with diet changes, use of special breathing and swallowing techniques, monitoring fatigue and taking larger meals earlier and smaller meals later, and avoiding eating when fatigued. The management of psychosocial difficulties usually requires an interdisciplinary approach, and may include a post-polio support group, social worker, psychologist, and psychiatrist.

An open trial of pyridostigmine in post-poliomyelitis syndrome.

BACKGROUND: One of the major symptoms of postpoliomyelitis syndrome (PPS) is disabling generalized fatigue. Subjects with PPS also report muscle fatiguability and display electrophysiologic evidence of anticholinesterase-responsive neuromuscular junction transmission defects, suggesting that anticholinesterase therapy may be useful in the management of disabling fatigue. METHODS: We initiated an open trial of the oral anticholinesterase pyridostigmine, up to 180 mg per day, in 27 PPS patients with generalized fatigue and muscle fatiguability. Response to pyridostigmine was assessed with the Hare fatigue scale, the modified Barthel index for activities of daily living, and a modified Klingman mobility index. RESULTS: Two patients could not tolerate the medication. After one month of therapy, 16 patients (64%) reported a reduction in fatigue on the Hare fatigue scale; three of 16 showed improvement on the modified Barthel index for activities of daily living, and two of 16 experienced improvement on a modified Klingman mobility index. Pyridostigmine responders were significantly more fatigued than non-responders on the pre-treatment Hare score, but were not significantly different with regard to age, sex, age at acute poliomyelitis, or severity of acute poliomyelitis. CONCLUSIONS: Pyridostigmine may be useful in the management of fatigue in selected patients with PPS. Response to pyridostigmine may be predicted by severity of pre-treatment fatigue.

Fibromyalgia is common in a postpoliomyelitis clinic.

OBJECTIVE: To determine prospectively the occurrence and clinical characteristics of fibromyalgia in patients serially presenting to a postpolio clinic. Fibromyalgia may mimic some of the symptoms of postpoliomyelitis syndrome, a disorder characterized by new weakness, fatigue, and pain decades after paralytic poliomyelitis. DESIGN: Case series. SETTING: A university-affiliated hospital clinic. PATIENTS: One hundred five patients were evaluated with a standardized history and physical examination during an 18-month period. Ten patients were excluded because of the absence of past paralytic poliomyelitis. INTERVENTIONS: Patients with fibromyalgia were treated with low-dose, nighttime amitriptyline hydrochloride or other conservative measures. MAIN OUTCOME MEASURES: Patients with fibromyalgia had diffuse pain and 11 or more of 18 specific tender points on examination (American College of Rheumatology criteria, 1990). Patients with borderline fibromyalgia had muscle pain and five to 10 tender points on physical examination. RESULTS: Ten (10.5%) of 95 postpolio patients met the criteria for fibromyalgia, and another 10 patients had borderline fibromyalgia. All patients with fibromyalgia complained of new weakness, fatigue, and pain. Patients with fibromyalgia were more likely than patients without fibromyalgia to be female (80% vs 40%, P < .04) and to complain of generalized fatigue (100% vs 71%, P = .057), but were not distinguishable in terms of age at presentation to clinic, age at polio, length of time since polio, physical activity, weakness at polio, motor strength scores on examination, and the presence of new weakness, muscle fatigue, or joint pain. Approximately 50% of patients in both the fibromyalgia and borderline fibromyalgia groups responded to low-dose, nighttime amitriptyline therapy. CONCLUSIONS: (1) Fibromyalgia occurs frequently in a postpolio clinic. (2) Fibromyalgia can mimic some symptoms of postpoliomyelitis syndrome. (3) Fibromyalgia in postpolio patients can respond to specific treatment.

Predictive factors for post-poliomyelitis syndrome.

Post-poliomyelitis syndrome (PPS) is generally defined as a clinical syndrome of new weakness, fatigue, and pain in individuals who have previously recovered from acute paralytic poliomyelitis. The purpose of this study was to identify, through a case-control study design, factors that predict subsequent PPS in patients with prior paralytic poliomyelitis. Among patients attending a university-affiliated hospital post-polio clinic, "cases" were patients with new weakness and fatigue, and "controls" were patients without these complaints. A chart review of 353 patients identified 127 cases and 39 controls. Logistic regression modeling was used to calculate adjusted and unadjusted odds ratios. In univariate analyses, significant risk factors for PPS were a greater age at time of presentation to clinic (p = 0.01), a longer time since acute polio (p = 0.01), and more weakness at acute polio (p = 0.02). Other significant associated, but not necessarily causal factors were a recent weight gain (p = 0.005), muscle pain (p = 0.01) particularly that associated with exercise (p = 0.005), and joint pain (p = 0.04). Multivariate analyses revealed that a model containing age at presentation to clinic, severity of weakness at acute polio, muscle pain with exercise, recent weight gain, and joint pain best distinguished cases from controls. Age at acute polio, degree of recovery after polio, weakness at best point after polio, physical activity, and sex were not contributing factors. These findings suggest that the degree of initial motor unit involvement as measured by weakness at acute polio, and possibly the aging process and overuse are important in predicting PPS.

Stimulation frequency-dependent neuromuscular junction transmission defects in patients with prior poliomyelitis.

Generalized fatigue and muscle fatiguability are major symptoms of post-poliomyelitis syndrome (PPS), and may be due to neuromuscular junction transmission defects, as suggested by increased jitter on single fiber electromyography (SFEMG). To determine the etiology of this defect, we studied jitter at low (1, 5 Hz) and high (10, 15, 20 Hz) frequency stimulation with stimulation SFEMG in 17 post-polio patients with muscle fatiguability, and in 9 normal controls. In 5 of 17 PPS patients and in 1 of 9 controls, jitter was significantly higher (unpaired t-test, P < 0.05) at high frequency stimulation (HFS). In the remaining PPS patients and controls there was no significant difference in jitter at high and low stimulation frequencies. PPS patients with increased jitter at HFS had a significantly longer time interval since acute polio (mean 48.5 years) than PPS patients without increased jitter at HFS (mean 40 years; P < 0.05), but were not distinguished by other historical or clinical criteria. We conclude that the neuromuscular junction defect in post-polio patients is similar to that observed in amyotrophic lateral sclerosis, and is probably due to ineffective conduction along immature nerve sprouts and exhaustion of acetylcholine stores. The appearance of an increase in jitter with HFS in post-polio patients may be dependent upon time after acute polio.

Anticholinesterase-responsive neuromuscular junction transmission defects in post-poliomyelitis fatigue.

Disabling generalized fatigue and muscle fatiguability are common features of post-poliomyelitis syndrome (PPS). In 17 fatigued PPS patients, we measured jitter on stimulation single-fiber electromyography (S-SFEMG) for at least 3.5 min before and after i.v. injection of 10 mg edrophonium. We observed reduction in jitter (defined as a significant difference in jitter means before and after edrophonium, unpaired t-test P < 0.05) in 7 patients, no change in 8, and a significant increase in 2 patients. Blinded to their edrophonium results, the 17 patients were treated with pyridostigmine 180 mg/day for 1 month, with a subjective improvement of fatigue in 9 patients, and with a significant reduction in mean Hare fatigue scores in the entire group of 17 patients (pre = 2.71, and post = 1.71; Wilcoxan signed rank sum test, P < 0.05). Edrophonium-induced reduction of jitter on S-SFEMG was significantly associated with pyridostigmine-induced subjective improvement of fatigue (Fisher's exact test, P < 0.04). A significant reduction in fatigue with pyridostigmine was observed only in the 7 patients who experienced a significant reduction in jitter with edrophonium (Wilcoxan signed rank sum test, P = 0.03). In addition, the 9 pyridostigmine responders experienced a significant reduction in jitter means pre- and post-edrophonium (100% vs. 88%, Bonferroni corrected, P < 0.01). We conclude that neuromuscular transmission as measured by jitter on S-SFEMG can improve with edrophonium in a proportion of PPS patients, and that generalized fatigue and muscle fatiguability in some patients with PPS may be due to anticholinesterase-responsive NMJ transmission defects.

Diagnosis and treatment of ossification of the posterior longitudinal ligament of the spine: report of eight cases and literature review.

PURPOSE: Ossification of the posterior longitudinal ligament (OPLL) is a common, well-recognized cause of spinal stenosis and myelopathy in Japan. Although also common in whites, especially among the elderly, it has received little scientific attention. We wish to increase awareness of this important cause of myelopathy, and to determine if the clinical characteristics of OPLL are similar in non-Japanese and Japanese patients. PATIENTS AND METHODS: The clinical and radiologic features of eight cases of OPLL are presented. These cases combined with 73 non-Japanese cases gathered from the English literature are contrasted with 2,125 Japanese cases of OPLL. RESULTS: Similarities among non-Japanese and Japanese cases included: (1) male predominance; (2) peak age at onset of symptoms in the sixth decade; (3) clinical presentation, which ranged from asymptomatic to quadriplegia, with progressive or acute onset of neurologic deterioration; (4) greater than 95% localization to the cervical spine, spastic quadriparesis being the most common neurologic presentation; (5) an association with several rheumatic conditions including diffuse idiopathic skeletal hyperostosis (DISH), spondylosis, and ankylosing spondylitis; and (6) neurologic improvement with either conservative or surgical treatment in a significant proportion of patients. Differences between the two groups were minimal and included a higher mean age at onset (although onset in both groups occurred within the sixth decade) and a greater proportion of patients with DISH and with the continuous type of OPLL in the non-Japanese group. CONCLUSION: The clinical characteristics of OPLL are similar in Japanese and non-Japanese patient populations. Increased awareness of this condition, which has potentially devastating neurologic complications, will favorably influence diagnosis, treatment, and outcome.