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PubMedDate not supplied

Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial.

BACKGROUND: Several double-blind placebo-controlled trials of relapsing-remitting multiple sclerosis have shown beneficial effects of intravenous immunoglobulin (IVIG) on relapse rate and disability. The European Study on Intravenous Immunoglobulin in Multiple Sclerosis set out to test IVIG in the secondary progressive phase of the disease. METHODS: 318 patients with clinically definite secondary progressive multiple sclerosis (mean age 44 years [SD 7]) were randomly assigned IVIG 1 g/kg per month (n=159) or an equivalent volume of placebo (albumin 0.1%; n=159) for 27 months. After baseline investigation, clinical assessments were made every 3 months and MRI was repeated after 12 months and 24 months. The primary outcome was confirmed worsening of disability as defined by the time to first confirmed progression on the expanded disability status scale (EDSS). Analyses were by intention to treat. FINDINGS: 19 patients in the IVIG group and 39 in the placebo group terminated study treatment prematurely but were included in the analyses. IVIG treatment had no beneficial effect on time to confirmed EDSS progression (hazard ratio 1.11 [95% CI 0.80-1.53] for IVIG versus placebo). The annual relapse rate was 0.46 in both groups. No significant differences between the treatment groups were found in any of the other clinical outcome measures or in the change of T2-lesion load over time. The treatment was generally well tolerated, although deep venous thrombosis, pulmonary embolism, or both occurred in seven patients with risk factors for thromboembolism (IVIG six, placebo one). INTERPRETATION: Treatment with IVIG in this study did not show any clinical benefit and therefore cannot be recommended for patients with secondary progressive multiple sclerosis.

Adult↗
PubMed1989

Cold-induced reversible myocardial ischaemia in systemic sclerosis.

The effect of cold provocation on myocardial perfusion was studied in 21 patients with systemic sclerosis and 8 healthy controls. The cold provocation was designed not to cause a pain reaction, and no rise in heart rate/blood pressure product occurred during provocation. Myocardial perfusion was assessed by measurement of thallium uptake by imaged single photon emission computed tomography. No patient had clinical evidence of cardiac involvement, but abnormal electrocardiographic (ECG) findings were found in 5. In 12 patients cold-induced reversible perfusion defects were found; 9 of these also had permanent defects. A further 3 patients had permanent perfusion defects but no reversible defects. The permanent and/or reversible perfusion defects were not related to age among the patients and were not seen in any of the healthy controls, whose age distribution was similar. The reversible and permanent defects were not related to other features of systemic sclerosis, nor to the ECG findings. It is concluded that abnormalities in myocardial perfusion are common in systemic sclerosis and may be present without apparent clinical myocardial involvement. A cold-induced vasopastic process in the myocardial circulation might contribute to the development of the patchy myocardial fibrosis seen in patients with systemic sclerosis.

Adult↗
PubMed1997

Offspring recurrence rates and clinical characteristics of conjugal multiple sclerosis.

BACKGROUND: There has been no previous systematic study of conjugal multiple sclerosis. This study of conjugal pairs with complex traits investigated disease transmissibility and the genetic contribution to frequency and clinical course. METHODS: We studied 45 conjugal pairs concordant for multiple sclerosis from 58 pairs recorded in a national register of familial disease, 86 offspring of the 45 pairs were individually assessed for clinical evidence of neurological disease; those over age 16 underwent cranial magnetic resonance imaging. Clinical features were compared in 33 pairs in whom neither member had symptoms before they met. FINDINGS: Of the 86 offspring, five (6%) had clinically definite multiple sclerosis. A further five children had either characteristic imaging abnormalities or clinical symptoms consistent with demyelination, but did not meet the criteria for clinically definite disease. There was no evidence of clinical concordance, clustering at year of onset, or distortion of the expected pattern of age of onset in the second affected spouse from 33 pairs. The crude recurrence in children of conjugal pairs (1 in 17) is significantly higher than previously reported population-based risk for offspring of single affected parents (1 in 200). INTERPRETATION: Taken with the low prevalence of multiple sclerosis in the spouses of affected individuals, and the lack of concordance for age at onset in these families, the disparity in crude recurrence between children of conjugal pairs and those of single affected parents shows that the recurrence risk in children is determined by genetic factors inherited from both parents.

Adolescent↗
PubMed1999

Nonvitrectomizing vitreous surgery: a strategy to prevent postoperative nuclear sclerosis.

OBJECTIVE: The development or progression of postoperative nuclear sclerosis is the most common complication of successful vitrectomy in elderly patients. The authors treated idiopathic epimacular proliferation (EMP) with nonvitrectomizing vitreous surgery in an attempt to prevent postoperative nuclear sclerosis. DESIGN: Prospective, nonrandomized, comparative case series. PARTICIPANTS: The authors surgically removed membranes from the sensory retina in 21 eyes of 21 patients with EMP. INTERVENTION: Neither intravitreal infusion nor vitrectomy of any kind was performed during the procedure. The peeled membrane was left floating in the vitreous cavity in 11 (group 1) eyes and removed in 10 eyes (group 2). Nonoperated fellow eyes served as controls. MAIN OUTCOME MEASURES: Visual acuity, slit-lamp and/or Scheimpflug photography, and refractometry were performed pre- and postoperatively to evaluate changes in the degree of lenticular opacity. RESULTS: There was no difference in the rate of development or progression of nuclear sclerosis or the degree of myopic shift between operated and control eyes during the postoperative follow-up period (mean, 9.7 months). No serious complications were noted. There was no difference in postoperative course between patients in the two operative groups. CONCLUSIONS: Although interpretation of the results of this study is limited due to its small size and short follow-up, nonvitrectomizing vitreous surgery seems to decrease the postoperative development or progression of nuclear sclerosis in patients with idiopathic EMP.

Aged↗
PubMed2002

Cannabinoids and multiple sclerosis.

There is a growing amount of evidence to suggest that cannabis and individual cannabinoids may be effective in suppressing certain symptoms of multiple sclerosis and spinal cord injury, including spasticity and pain. Anecdotal evidence is to be found in newspaper reports and also in responses to questionnaires. Clinical evidence comes from trials, albeit with rather small numbers of patients. These trials have shown that cannabis, Delta(9)-tetrahydrocannabinol, and nabilone can produce objective and/or subjective relief from spasticity, pain, tremor, and nocturia in patients with multiple sclerosis (8 trials) or spinal cord injury (1 trial). The clinical evidence is supported by results from experiments with animal models of multiple sclerosis. Some of these experiments, performed with mice with chronic relapsing experimental allergic encephalomyelitis (CREAE), have provided strong evidence that cannabinoid-induced reductions in tremor and spasticity are mediated by cannabinoid receptors, both CB(1) and CB(2). Endocannabinoid concentrations are elevated in the brains and spinal cords of CREAE mice with spasticity, and in line with this observation, spasticity exhibited by CREAE mice can be ameliorated by inhibitors of endocannabinoid membrane transport or enzymic hydrolysis. Research is now needed to establish whether increased endocannabinoid production occurs in multiple sclerosis. Future research should also be directed at obtaining more conclusive evidence about the efficacy of cannabis or individual cannabinoids against the signs and symptoms of these disorders, at devising better modes of administration for cannabinoids and at exploring strategies that maximize separation between the sought-after therapeutic effects and the unwanted effects of these drugs.

Animals↗
PubMed2001

Depression associated with multiple sclerosis. Looking beyond diagnosis to symptom expression.

BACKGROUND: While it is recognised that patients with multiple sclerosis have a high lifetime risk for major depression, less is known about sub-syndromal presentations of affective instability, i.e., irritability, sadness and tearfulness and how these symptoms of emotional dyscontrol may affect a subject's overall degree of psychological distress. METHODS: A consecutive sample of 100 out-patients with clinically definite multiple sclerosis attending their yearly neurological examination were assessed for major depression [Structured Clinical Interview for DSM-IV (SCID-1)], pathological laughing and crying [Pathological Laughing and Crying Scale (PLACS)], self report questionnaires documenting mood [Beck Depression Inventory (BDI)] and overall psychological distress [the 28 item General Health Questionnaire (GHQ)]. RESULTS: Seventeen percent of subjects received a diagnosis of major depression, 8% had pathological laughing and crying (PLC), 48% had symptoms of emotional dyscontrol without meeting criteria for a formal psychiatric diagnosis and 27% had minimal psychiatric symptoms (emotionally stable). The groups did not differ with respect to neurological variables. However, on a validated index of psychological distress (i.e., GHQ scores > or =5), there were significantly more subjects with major depression and emotional dyscontrol than those deemed emotionally stable (P<0.0001). LIMITATIONS: The small number of patients with PLC (N=8) curtailed statistical power when it came to analysing this sub-group. CONCLUSIONS: Clinicians should be sensitive to complaints such as irritability and sadness in patients with multiple sclerosis, even when symptoms do not fulfil criteria for formal, psychiatric diagnoses. Our data demonstrate that such complaints are associated with levels of psychological distress that approach those experienced by patients with major depression. Given that these sub-syndromes of affective instability respond well to pharmacotherapy, detection and treatment can significantly reduce one important aspect of morbidity associated with multiple sclerosis.

Adult↗
PubMed1997

Human leukocyte antigens and cytokine expression in cerebral inflammatory demyelinative lesions of X-linked adrenoleukodystrophy and multiple sclerosis.

The two most common forms of X-linked adrenoleukodystrophy (X-ALD) are the cerebral forms (CER) with an inflammatory demyelinating reaction that resembles multiple sclerosis, and adrenomyeloneuropathy (AMN) which involves primarily the spinal cord and in which the inflammatory reaction is mild or absent. We found no significant association between the childhood cerebral form (CCER) or AMN and the human leukocyte (HLA) class I and Class II antigens including the class II DR2 haplotypes associated with multiple sclerosis. Inflammatory cytokine (tumor necrosis factor-alpha, interleukin-1 beta, interleukin-4, interleukin-6 and interferon-gamma) gene expression was increased in multiple sclerosis brain lesions, as has been reported previously, but much less so in CER brain lesions. These findings suggest that the pathogenesis of the inflammatory response in X-ALD differs from that in multiple sclerosis.

Adrenoleukodystrophy↗
PubMed1987

Skin changes in patients with amyotrophic lateral sclerosis: light and electron microscopic observations.

Patients with amyotrophic lateral sclerosis are usually confined to bed within a few years from the onset of the disease; however, bedsores are not known to develop even at its terminal stages. In this study, skin from patients with amyotrophic lateral sclerosis, neuromuscular diseases other than amyotrophic lateral sclerosis, and nonneurologic disorders has been examined by light and electron microscopy for morphologic changes in the connective tissue. On physical examination of the skin in amyotrophic lateral sclerosis patients, the stretched fold showed a delayed relaxation phase. On light microscopy, collagen bundles in the dermis were disoriented, separated, and fragmented, especially in the papillary dermis. Ultrastructurally, extensive deposits of amorphous, fine granular material in the ground substance compartment of the dermis were observed. The preceding cutaneous changes became more apparent as the disease advanced. We speculate that the deposition of this amorphous material may play the role of pressure absorber, thus preventing the occlusion of blood vessels.

Aged↗
PubMedDate not supplied

The acoustic reflex in patients with asymptomatic multiple sclerosis.

A convenient, inexpensive test to identify multiple sclerosis during periods of symptomatic remission would be clinically advantageous. Recent studies have suggested that examination of acoustic reflex onset latency and rise time may be useful in detecting some forms of retrocochlear auditory pathology. This prospective, single-blinded study compares these features of the human acoustic reflex in a control sample, a sample with sensorineural hearing loss, and a sample with multiple sclerosis, to determine the usefulness of acoustic reflex measurements as a screening test for otherwise asymptomatic multiple sclerosis. Acoustic reflex threshold, onset latency, and rise time measurements were similar for all groups. This finding suggests that tests for abnormalities of acoustic reflex rise time and onset latency, under the conditions used in this study, may not be sufficiently sensitive to screen for the presence of otherwise asymptomatic multiple sclerosis.

Adult↗
PubMed1991

Evidence for a pathogenic linkage between glomerular hypertrophy and sclerosis.

Primary renal disease of immunologic or nonimmunologic mechanisms induces loss of substantial nephron population. It is presumed that the initial loss of functioning nephrons causes alterations of function and metabolism in remnant nephrons, which per se are self-inflictive, leading to further loss of nephrons. The ultimate outcome of this vicious cycle is the end-stage kidney. The potential role of various pathophysiologic mechanisms has been explored. These studies have shown a tight link between glomerular hypertrophy and sclerosis. Analysis of individual glomeruli show a biphasic pattern of these two parameters. Early development of glomerular sclerosis takes place along with the hypertrophy of the glomerulus, and further advancement of sclerosis occurs with shrinkage in glomerular size. Thus, we propose that, after initial nephron loss, the remnant glomeruli are exposed to increased growth-promoting factors, which are self-inflictive in nature due to their capacity to produce excessive amounts of extracellular matrix in the mesangial area. When the excessive matrix obliterates the glomerular capillary lumen, a typical sclerotic lesion appears. This is a vicious and accelerating process, since sclerosis induces further reduction in the nephron population, thereby imposing greater influence of growth-promoting factors even on glomeruli that are initially resistant.

Aging↗
PubMed1999

Pregnancy and multiple sclerosis: a 2-year experience.

OBJECTIVE: To present our experience with management of parturients with multiple sclerosis and to examine the role of intravenous immunoglobulin (IVIg) in the prevention of postpartum exacerbations of the disease. METHODS: Fifteen patients with multiple sclerosis with a relapsing-remitting course were followed during pregnancy and 6 months postpartum. To prevent postpartum exacerbations, 14 of the patients had received IVIg after delivery. RESULTS: None of the patients who received postpartum IVIg relapsed during the 6 months after delivery. None of the observed obstetric complications nor the operative deliveries could be related to the coexistence of multiple sclerosis. CONCLUSION: Postpartum IVIg treatment is beneficial in preventing acute childbirth-associated exacerbations in patients with relapsing-remitting multiple sclerosis. Furthermore, this disease does not seem to increase obstetric complications.

Adult↗
PubMed1977

Cell-mediated hypersensitivity in multiple sclerosis and other neurological diseases.

Using a direct macrophage migration inhibition test the hypersensitivity against encephalitogenic protein and phytohaemagglubinin in normal persons, multiple sclerosis patients and patients with other diseases of the central nervous system were examined. It proved that the vast majority of patients were sensitised to brain antigen. The percentage of positive tests and the percentage of migration inhibition was related to the activity of the disease. No differences were found between lymphocytes of multiple sclerosis patients and of patients with the other neurological diseases patients. Foetal calf serum was proven to depress the hypersensitivity to phytohaemagglutinin as did multiple sclerosis serum on normal lymphocytes. The results did not support the hypothesis that multiple sclerosis is caused by a cell-mediated auto-immune process.

Autoimmune Diseases↗
PubMed2003

Expression of the low affinity neurotrophin receptor p75 in spinal motoneurons in a transgenic mouse model for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a lethal neurodegenerative disorder involving motoneuron loss in the cortex, brainstem and spinal cord, resulting in progressive paralysis. Aberrant neurotrophin signalling via the low affinity neurotrophin receptor p75 has been suggested to be involved in the motoneuron death by the activation of apoptotic pathways. In order to investigate the involvement of neurotrophin receptor p75 in the amyotrophic lateral sclerosis related motoneuron degeneration process, we have studied the expression of this receptor in the spinal cord of transgenic mice carrying a mutated human Cu, Zn superoxide dismutase gene. Mutations in the superoxide dismutase gene are one of the genetic causes for familiar amyotrophic lateras sclerosis and human superoxide dismutase-1 transgenic mice develop symptoms and pathology similar to those in human amyotrophic lateras sclerosis. Our study shows that in these mice, spinal motoneurons, which normally do not contain the neurotrophin receptor p75 receptor, express this receptor during the progress of the disease. Expression of the neurotrophin receptor p75 receptor coincides with the expression of activating transcription factor 3, a member of the activating transcription factor/cyclic AMP family of stress transcription factors. Only a minority of these spinal motoneurons actually showed co-expression of neurotrophin receptor p75 with caspase-3 activity, suggesting that expression of the neurotrophin receptor p75 receptor is not directly related to the execution phase of the apoptosis process.

Amyotrophic Lateral Sclerosis↗
PubMed2002

Viral cirrhosis with chronic right heart failure and cardiac liver sclerosis: a hypothesis on the differentiation between the two diseases through pulsed Doppler sonography examination.

Chronic right heart failure determines cardiac liver sclerosis as a consequence of the hepatic venous congestion that is easily detectable with pulsed Doppler sonography measuring hepatic venous pulsatility. These Doppler parameters profoundly change on the basis of the causative agent of the liver sclerosis. In fact, on pulsed Doppler examination, we detected a flat waveform in hepatic veins of subjects with viral liver cirrhosis whereas we only observed biphasic waveforms in subjects with cardiac liver sclerosis. On the contrary, a pulsed Doppler sonography pattern in subjects with viral cirrhosis and associated chronic right heart failure is unknown. We suppose that splanchnic pulsed Doppler sonography has an important role both in differentiating cardiac liver sclerosis from viral cirrhosis with chronic right heart failure and in the follow-up of the seriousness of the right ventricular failure.

Blood Pressure↗
PubMed2004

Do hyporesponsive genetic variants of the melanocortin 1 receptor contribute to the etiology of multiple sclerosis?

Hyporesponsive genetic variants of the melanocortin 1 receptor result in pigmentary phenotypes exhibiting light skin and light color hair, including red hair. These variants are common in populations with high rates of multiple sclerosis, while rare in populations with low rates. Alpha-melanocyte stimulating hormone, the major ligand for this receptor, is responsible for phenotype determination, but is also known for its anti-inflammatory and immune modulating effects, including inhibition of factors implicated in multiple sclerosis pathology. As the melanocortin 1 receptor is expressed on various cell types involved in immune response, it is possible that carriers of hyporesponsive variants of this receptor lack the full anti-inflammatory and immune modulating effects of alpha-melanocyte stimulating hormone. It is proposed that these variants are part of a spectrum of genes involved in the etiology of multiple sclerosis. Related aspects of multiple sclerosis epidemiology are examined.

Clinical Trials as Topic↗
PubMed1997

Ascorbate availability and neurodegeneration in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease in which upper and lower motoneurons progressively deteriorate and die. Neuronal damage is most evident in the lower central nervous system, and death generally occurs following central respiratory failure. Proposed and demonstrated mechanisms for amyotrophic lateral sclerosis are diverse, and include altered superoxide dismutase and neurofilament proteins, autoimmune attack, and hyperglutamatergic activity. However, they do not account for the late onset of the disease, its earlier onset in males, and the differential vulnerability of neurons located in the brainstem and spinal cord. It is proposed here that, within the context of a specific defect such as altered superoxide dismutase, age-dependent decline in ascorbate availability triggers the disease. A role for ascorbate, which is found in millimolar levels in neurons, is suggested by a number of consistencies: 1) superoxide radicals being a common substrate for superoxide dismutase and ascorbate; 2) a close association between central nervous system ascorbate levels and injury tolerance; 3) a steady decline in ascorbate plasma levels and cellular availability with age; 4) plasma ascorbate levels being lower in males; 5) an association of ascorbate release with motor activity in central nervous system regions, in vivo; 6) the coupling of brain-cell ascorbate release with glutamate uptake; 7) possible roles for ascorbate modulation of N-methyl-D-aspartate receptor activity; 9) the ability of ascorbate to prevent peroxynitrite anion formation; and 10) evidence supporting the scorbutic guinea pig as a model for amyotrophic lateral sclerosis. Emphasis is placed on the probable competition between superoxide dismutase and ascorbate within the context of a primary defect of metal-binding or metal access in high-concentration proteins such as superoxide dismutase and human heavy neurofilaments. Finally, distinct features of alpha-motoneuronal physiology suggest that cell physiological characteristics such as high metabolic activity and extensive calcium dynamics may render neurons differentially vulnerable in amyotrophic lateral sclerosis.

Amyotrophic Lateral Sclerosis↗
PubMed1987

Long-term prognosis of tuberous sclerosis with epilepsy in children.

A follow-up study was performed on 40 children with tuberous sclerosis and epilepsy. In 68% of the patients with infantile spasms and 73% of those without them, complex partial seizures were observed. Thus, patients with tuberous sclerosis are subject to not only infantile spasms but also complex partial seizures. Patients with infantile spasms showed mental retardation more often than those without. Seizures which had evolved from infantile spasms were more difficult to control than those which had not. The prognosis of infantile spasms associated with tuberous sclerosis was better than that of prenatal group other than tuberous sclerosis. Forty percent of the 40 cases showed asymmetry on EEG, and the asymmetry tended to disappear as the patients grew up.

Adolescent↗
PubMed1998

CT and MR imaging of cerebral tuberous sclerosis.

Tuberous sclerosis is a heredofamilial neurocutaneous syndrome, or phakomatosis, with multisystem involvement including the brain, kidney, skin, retina, heart, lung, and bone. The brain is the most frequently affected organ in tuberous sclerosis. Brain lesions in tuberous sclerosis are of three kinds; cortical tubers, white matter abnormalities, and subependymal nodules. We review the computed tomography (CT) and magnetic resonance (MR) features of the brain lesions in patients with tuberous sclerosis. CT clearly demonstrates calcified subependymal nodules. MR imaging demonstrates more clearly cortical, and white matter lesions than CT, since MR imaging shows excellent image contrast between various normal structures and high sensitivity in detecting pathological states due to intrinsic differences in proton density and in particular, in proton relaxation times of tissues. Possible pathogenesis of this disorder is also discussed.

Brain↗