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Hyperbaric Oxygen Therapy for Multiple Sclerosis
CNS Neuroscience & Therapeutics
Abstract
Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative neurological illness with no cure. It has been suggested that Hyperbaric Oxygen Therapy (HBO(2)T) may slow or reverse the progress of the disease. This article summarizes the clinical evidence for the use of HBO(2)T in the treatment of MS. We conducted a literature review focused on the interaction of hyperbaric oxygenation and MS. In particular, we appraised the clinical data regarding treatment and performed a meta-analysis of the randomized evidence using the methodology of the Cochrane Collaboration. We found 12 randomized studies in the area, all of which were performed between 1983 and 1987. A meta-analysis of this evidence suggests there is no clinically significant benefit from the administration of HBO(2)T. The great majority of randomized trials investigated a course of 20 treatments at pressures between 1.75ATA and 2.5ATA daily for 60-120 min over 4 weeks against a placebo regimen. None have tested the efficacy of HBO(2)T against alternative current best practice. No plausible benefit of HBO(2)T on the clinical course of MS was identified in this review. It remains possible that HBO(2)T is effective in a subgroup of individuals not clearly identified in the trials to date, but any benefit is unlikely to be of great clinical significance. There is some case for further human trials in selected subgroups and for prolonged courses of HBO(2)T at modest pressures, but the case is not strong. At this time, the routine treatment of MS with HBO(2)T is not recommended.
... Instead, HBOT in MS was taken in consideration in part because some MS lesions share similarities, including perivenular location of the lesions and vessel reactivity, with lesions caused by gas embolism and decompression illness in which HBOT has therapeutic beneficial effects (Bennett and Heard, 2010), and in part because HBOT has been shown to have an immunosuppressive effect in rats with active EAE (Warren et al., 1978). ...
... Recently, Bennett and Heard (2010) performed a critical meta-analysis of all the data arising from these trials in order to establish whether HBOT is a valid treatment for MS, or not. They did not identify plausible benefits of HBOT on the clinical course of MS, concluding that the routine treatment of MS with HBOT is not recommended (Bennett and Heard, 2010), despite that some neurologists and MS patients claimed a beneficial effect of HBOT in ameliorating the neurological deficits. ...
... The advanced stage of disease may have reduced the efficacy of the therapy given that in patients with chronic MS, it is unlikely to achieve an amelioration of the neurological deficits. In support to these hypotheses, a recent trial with HBOT, that included a large cohort of patients with MS, was performed in the 2000s and the results were recently published (2009) exclusively online (no authors formally recognized; reviewed in Bennett and Heard, 2010). In this trial, 703 patients with MS were examined, of which: 417 with chronic-progressive, 43 with chronic-static and 167 with relapsing-remitting MS (Bennett and Heard, 2010). ...
Multiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS). Pathological studies have revealed that MS lesions can have hypoxia- like properties, raising the possibility that the inflamed CNS may suffer an energy deficit. We recently demonstrated that the spinal cord of rats with active experimental autoimmune encephalomyelitis (EAE, a model of MS) is hypoxic, and that hypoxia can be reversed by inspiring oxygen-enriched air. This thesis examines the contribution of hypoxia to the neurological deficits, and the use of oxygen as a therapy. Demyelinating and non-demyelinating models of EAE in rats were evaluated, namely active and passive EAE respectively. Room air controls were used for comparison. Assessment of neurological deficits in active EAE revealed that oxygen (95%) promptly improved neurological function in paralysed rats, within only 1 hour of exposure. Furthermore, prolonged administration of oxygen (75%) applied either prophylactically (from the day of immunisation for 23 days) or therapeutically from the onset of disease (for 24, 48 or 72 hours) produced a greater and long-lasting amelioration of disease severity. Interestingly, oxygen treatment from disease onset reduced oligodendrocyte cell-stress and death, demyelination, microglial activation and macrophage infiltration in the spinal cord, without exacerbating oxidative damage. The protective effect was proportional to the duration of the treatment and significant in rats treated for 72 hours. Other experiments have revealed that the spinal cord of rats with passive EAE is also hypoxic and oxygen treatment significantly ameliorated disease progression when administered prophylactically. We also tested polynitroxylated pegylated hemoglobin (PNPH) as an alternative oxygen-based treatment in active EAE, revealing an acute improvement of the neurological function 1 hour after the injection of PNPH. We conclude that hypoxia contributes to neurological deficits and demyelination in inflammatory autoimmune demyelinating disease, and that oxygen therapy can reduce both the deficits and the demyelination.
... Bennett and Heard (2004) performed a systematic meta-analysis review of 12 clinical trials, concluding that there was little evidence of a significant beneficial effect of HBOT, although they raised the possibility that 'it still remains possible that HBOT is effective in a subgroup of individuals not clearly identified in the trials to date' (Bennett and Heard, 2004). Based on the conflicting outcomes of these studies, the use of HBOT is not currently recommended for treating multiple sclerosis (Bennett and Heard, 2010). ...
... Is there any therapeutic potential in manipulating oxygen supply to the multiple sclerosis patient? Unsurprisingly, for a disease with heterogeneous clinical presentation and pathogenesis, to date, this has not provided a simple answer, with HBOT trials providing inconclusive results (Bennett and Heard, 2010). Recent animal studies have further muddied the waters by showing that enhanced and diminished oxygen both provide therapeutic benefit in EAE (Desai et al., 2016;Halder and Milner, 2020). ...
Over the past 50 years, intense research effort has taught us a great deal about multiple sclerosis. We know that it is the most common neurological disease affecting the young-middle aged, that it affects two to three times more females than males, and that it is characterized as an autoimmune disease, in which autoreactive T lymphocytes cross the blood–brain barrier, resulting in demyelinating lesions. But despite all the knowledge gained, a key question still remains; what is the initial event that triggers the inflammatory demyelinating process? While most research effort to date has focused on the immune system, more recently, another potential candidate has emerged: hypoxia. Specifically, a growing number of studies have described the presence of hypoxia (both ‘virtual’ and real) at an early stage of demyelinating lesions, and several groups, including our own, have begun to investigate how manipulation of inspired oxygen levels impacts disease progression. In this review we summarize the findings of these hypoxia studies, and in particular, address three main questions: (i) is the hypoxia found in demyelinating lesions ‘virtual’ or real; (ii) what causes this hypoxia; and (iii) how does manipulation of inspired oxygen impact disease progression?
... The following 12 clinical trials failed to allow comparisons of efficacy between trials as patients were not stratified according to disease severity (which is difficult to do), age/sex or consistency of exposure time to oxygen or pressure regime. Not surprisingly, Bennett and Heard (Bennett and Heard, 2010) concluded that oxygen treatment was ineffective, based on the data available from their meta-analysis of randomized trials using a course of 20 oxygen treatments with non-stratified MS subjects exposed to oxygen at pressures between 1.75 ATA and 2.5 ATA daily for 60-120 min over 4 weeks against a placebo regimen. ...
... Researchers from the University of Exeter Medical School (PE, LM) and the Research Director of a local Hyperbaric Medical Centre (GS) met with a group of members from an MS Centre where two barochambers provide oxygen therapy. Given that oxygen therapy is not prescribed by clinicians as a treatment for MS (Bennett and Heard, 2010) and is not approved by the National Institute for Health and Care Excellence (NICE) (The Guideline Development Group, 2014) pwMS at this centre attend on a private basis and describe themselves as 'members' rather than patients. Some members travel long distances to access treatment. ...
Background
Thousands of people with multiple sclerosis (MS) have used self-administered oxygen therapy in the UK. Clinical trials have been performed, with scant evidence that people with MS have been consulted to explore how they benefit from or how to optimise this treatment. The conventional MS disease disability scores used in trials seldom reflect the effects individuals report when using oxygen therapy to treat their symptoms.
Methods
Three people with MS and the manager of an MS Centre formed a public involvement group and collaborated with clinicians and scientists to inform a lab-based study to investigate the physiological effects of oxygen therapy on microvascular brain endothelial cells.
Results
People with MS often use oxygen therapy at a later stage when their symptoms worsen and only after using other treatments. The frequency of oxygen therapy sessions and hyperbaric pressure is individualised and varies for people with MS. Despite direct comparisons of efficacy proving difficult, most individuals are exposed to 100% O2 at 1.5 atmosphere absolute (ATA; 1140 mmHg absolute) for 60 min. In a laboratory-based study human brain endothelial cells were exposed in vitro to 152 mmHg O2 for 60 min with and without pressure, as this equates to 20% O2 achievable via hyperbarics, which was then replicated at atmospheric pressure. A significant reduction in endothelial cells ICAM-1 (CD54) implicated in inflammatory cell margination across the blood brain barrier was observed under oxygen treatment.
Conclusions
By collaborating with people living with MS, we were able to design laboratory-based experimental protocols that replicate their treatment regimens to advance our understanding of the physiological effects of hyperbaric oxygen treatment on brain cells and their role in neuroinflammation.
... Some claims exist about the efficacy of HBOT in MS patients. Fisher et al. [9][10][11], in a double-blind controlled study, showed significant but transient improvements in mobility, fatigability, and walking in MS patients receiving HBOT. Warren et al., showed that HBOT resulted in an augmentation of experimental allergic encephalomyelitis, an animal model of MS [12]. ...
... Kindwall et al. didn't show any benefit from HBOT in MS patients compared to the control group, except for a temporary improvement in bladder control which was reported by some patients [38]. Furthermore, two other main studies did not demonstrate a beneficiary from HBOT in MS patients [9,38]. ...
Background
The present study was carried out to evaluate cerebral perfusion in multiple sclerosis (MS) patients with a moderate to severe stage of disease. Some patients underwent hyperbaric oxygen therapy (HBOT) and brain perfusion between before and after that was compared.
Methods
We retrospectively reviewed 25 secondary progressive (SP)-MS patients from the hospital database. Neurological disability evaluated by Expanded Disability Status Scale Score (EDSS). Brain perfusion was performed by (99 m) Tc-labeled bicisate (ECD) brain SPECT and the data were compared using statistical parametric mapping (SPM). In total, 16 patients underwent HBOT. Before HBOT and at the end of 20 sessions of oxygen treatment, 99mTc-ECD brain perfusion single photon emission computed tomography (SPECT) was performed again then the results were evaluated and compared. Brain perfusion was performed by (99 m) Tc-labeled bicisate (ECD) brain SPECT and the data were compared using statistical parametric mapping (SPM).
Results
A total of 25 SP-MS patients, 14 females (56 %) and 11 males (44 %) with a mean age of 38.92 ± 11.28 years included in the study. The mean disease duration was 8.70 ± 5.30 years. Of the 25 patients, 2 (8 %) had a normal SPECT and 23 (92 %) had abnormal brain perfusion SPECT studies. The study showed a significant association between severity of perfusion impairment with disease duration and also with EDSS (P <0.05). There was a significant improvement in pre- and post-treatment perfusion scans (P <0.05), but this did not demonstrate a significant improvement in the clinical subjective and objective evaluation of patients (P >0.05).
Conclusions
This study depicted decreased cerebral perfusion in SP-MS patients with a moderate to severe disability score and its association with clinical parameters. Because of its accessibility, rather low price, practical ease, and being objective quantitative information, brain perfusion SPECT can be complementing to other diagnostic modalities such as MRI and clinical examinations in disease surveillance and monitoring. The literature on this important issue is extremely scarce, and follow up studies are required to assess these preliminary results.
... [1][2][3][4][5] The antinociceptive effects may implicate both supraspinal and spinal mechanisms. 6,7 While a considerable number of clinical HBO2 studies have been published, [8][9][10][11][12][13] there is a paucity of basal pathophysiological understanding of the anti-inflammatory effects of HBO2 therapy in humans. The objective of this study was therefore to investigate the effects of HBO2 therapy in a validated thermal injury model in healthy volunteers. ...
... 1,2,5,8,9,13,16,18,19) and the HBO2 session (nos. 3,4,6,11,12,14,15,17), respectively. In regard to baseline comparisons, between the two sequences, no significant differences were observed for PPT (P = 0.57), WDT (P = 0.35), CDT (P = 0.44) or HPT (P = 0.61). ...
Hyperbaric oxygen (HBO2 ) treatment has in animal experiments demonstrated antinociceptive effects. It was hypothesized that these effects would attenuate secondary hyperalgesia areas (SHAs), an expression of central sensitization, after a first-degree thermal injury in humans.
Seventeen healthy volunteers were examined during two sessions using a randomized crossover design. Volunteers were studied during control conditions (ambient pressure, FI O2 = 0.21) and during HBO2 (2.4 standard atmosphere, FI O2 = 1.0, 90 min) conditions in a pressure chamber. Quantitative sensory testing, including assessment of SHAs was performed.
A statistically significant overall attenuation of SHAs was seen during the HBO2 sessions compared with the control-sessions (P = 0.011). In the eight volunteers starting with the HBO2 session, no difference in SHAs compared with control was demonstrated. However, in the nine volunteers starting with the control session, a statistical significant attenuation of SHAs was demonstrated in the HBO2 session (P = 0.004).
The results indicate that HBO2 therapy in humans attenuates central sensitization induced by a thermal skin injury, compared with control. These new and original findings in humans corroborate animal experimental data. The thermal injury model may give impetus to future human neurophysiological studies exploring the central effects of hyperbaric oxygen treatment.
© 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
... Their data support the idea of tissue hypoxia as risk factor for neuroaxonal damage formation in the very acute onset of inflammatory lesions. Several hyperbaric oxygen treatment trials in human MS have been performed; however, these results showed rather anecdotal, transient improvements, and did not support a longterm effect in comparative trials (Bennett & Heard, 2010;Fischer et al., 1983;Wood et al., 1985). . Nonetheless, neuronal damage in chronic neuroinflammation is not only dependent on neurotoxic mediators, but also on the capability to counterbalance neuroaxonal damage formation (Schwartz et al., 1999). ...
Astrocytes constitute the parenchymal border of the blood-brain barrier (BBB), modulate the exchange of soluble and cellular elements, and are essential for neuronal metabolic support. Thus, astrocytes critically influence neuronal network integrity. In hypoxia, astrocytes upregulate a transcriptional program that has been shown to boost neuroprotection in several models of neurological diseases. We investigated transgenic mice with astrocyte-specific activation of the hypoxia-response program by deleting the oxygen sensors, HIF prolyl-hydroxylase domains 2 and 3 (Phd2/3). We induced astrocytic Phd2/3 deletion after onset of clinical signs in experimental autoimmune encephalomyelitis (EAE) that led to an exacerbation of the disease mediated by massive immune cell infiltration. We found that Phd2/3-ko astrocytes, though expressing a neuroprotective signature, exhibited a gradual loss of gap-junctional Connexin-43 (Cx43), which was induced by vascular endothelial growth factor-alpha (Vegf-a) expression. These results provide mechanistic insights into astrocyte biology, their critical role in hypoxic states, and in chronic inflammatory CNS diseases.
... Previous preclinical research has shown HBO to be effective in decreasing symptoms associated with animal models of neuropathic pain, arthritis, and inflammatory pain, among others 7-11 while other preclinical research has shown NBO to be useful in decreasing symptoms associated with carbon monoxide poisoning and cerebral ischemia. [12][13][14][15][16] Clinical studies have also demonstrated a degree of therapeutic benefit with HBO treatment in selected subgroups of patients with MS. 17 Considering these findings, it may be possible that NBO or HBO could alleviate the symptoms of EAE through regularpressure or high-pressure oxygen. If shown to be successful, NBO or HBO could provide relatively safer alternatives to current pharmacotherapies that are administered to human patients with MS and might lead to further understanding of the mechanisms of this disease. ...
Background Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model of MS. Oxygen therapy, such as hyperbaric oxygen (HBO) or normobaric oxygen (NBO), has been advanced as a potential treatment option to allay the motor and sensory deficits associated with MS. However, it is unclear whether any therapeutic benefits derived from treatment are a result of pressurized oxygen or simply pure oxygen administration. This study aimed to explore whether pressurized oxygen (HBO) or sea-level oxygen (NBO) would attenuate the motor and sensory deficits associated with EAE. Methods Forty-two male Harlan Lewis rats were randomly assigned to one of four conditions: MBP/HBO, MBP/NBO, MBP/no treatment, or a vehicle group. Injections of MBP or vehicle were administered on day 1, and animals were allowed one-week to recover. Following recovery, animals were administered HBO at 2.0 atmospheres absolute (ATA) or sea-level oxygen for 60-minutes daily. Mechanical paw withdrawal threshold (MPWT) testing was conducted on the first day and every alternate day after the start of treatment to assess the development of tactile allodynia. Motor impairment tests were performed twice daily (immediately prior to and after oxygen treatment) to assess for the presence of motor deficits or paralysis. Results On days 14 through 18, animals injected with MBP had a greater level of motor impairment compared to the vehicle control group. Interestingly, results also indicated that NBO was as effective as HBO in attenuating EAE symptoms. Conclusion In conclusion, these results underscore the need for further research to determine the ideal parameters of oxygen treatment, particularly whether pressurization is necessary to attenuate symptoms of EAE.
... The current findings raise the long and vexed history of oxygen as a therapy in MS. While many patients report that oxygen therapy reliably provides a temporary (days) reduction in symptoms such as fatigue and bladder dysfunction, such therapy is discounted by many neurologists, who are supported by Cochrane and other assessment of clinical trials [70][71][72] . The sceptical opinion has been bolstered by a belief that any beneficial effects of oxygen therapy are "difficult to ascribe with biological plausibility" 63 , but we believe that such plausibility is now provided by both the findings of tissue hypoxia in neuroinflammatory disease 4,5,[32][33][34]57 , and the clearly beneficial effects of oxygen therapy in experimental models (current study and 4,5,57 ). ...
Aims:
To explore the importance of tissue hypoxia in causing neurological deficits and demyelination in the inflamed CNS, and the value of inspiratory oxygen treatment, using both active and passive experimental autoimmune encephalomyelitis (EAE).
Methods:
Normobaric oxygen treatment was administered to Dark Agouti rats with either active or passive EAE, compared with room air-treated, and naïve, controls.
Results:
Severe neurological deficits in active EAE were significantly improved after just 1 hour of breathing ~95% oxygen. The improvement was greater and more persistent when oxygen was applied either prophylactically (from immunization for 23 days), or therapeutically from the onset of neurological deficits for 24, 48, or 72 hours. Therapeutic oxygen for 72 hours significantly reduced demyelination and the integrated stress response in oligodendrocytes at the peak of disease, and protected from oligodendrocyte loss, without evidence of increased oxidative damage. T-cell infiltration and cytokine expression in the spinal cord remained similar to that in untreated animals. The severe neurological deficit of animals with passive EAE occurred in conjunction with spinal hypoxia and was significantly reduced by oxygen treatment initiated before their onset.
Conclusions:
Severe neurological deficits in both active and passive EAE can be caused by hypoxia and reduced by oxygen treatment. Oxygen treatment also reduces demyelination in active EAE, despite the autoimmune origin of the disease.
... This intervention can definitively increase the oxygen carrying capacity of blood to the brain. Efficacious use was reported in transient cerebral ischemia and in multiple sclerosis 35,36 . Efrati et al. 37 found that hyperbaric oxygen treatment could activate neuroplasticity in patients with chronic neurologic deficiencies due to stroke. ...
Oxygen enriched air may increase oxygen pressure in brain tissue and have biochemical effects even in subjects without lung disease. Consistently, several studies demonstrated that normobaric oxygen treatment has clinical benefits in some neurological conditions. This study examined the efficacy of normobaric oxygen treatment in subjects with depression. In a randomized, double-blind trial, 55 participants aged 18-65 years with mild to moderate depression (had a Hamilton Rating Scale for Depression [HRSD] score of ≥ 8) were recruited to the study from the Southern district in Israel. Participants underwent a psychiatric inclusion assessment at baseline and then were randomly assigned to either normobaric oxygen treatment of 35% fraction of inspired oxygen or 21% fraction of inspired oxygen (room air) through a nasal tube, for 4 weeks, during the night. Evaluations were performed at baseline, 2 and 4 weeks after commencement of study interventions, using the following tools: HRSD; Clinical Global Impression (CGI) questionnaire; World Health Organization-5 questionnaire for the estimation of Quality of Life (WHO-5-QOL); Sense of Coherence (SOC) 13-item questionnaire; and, Sheehan Disability Scale (SDS). A multivariate regression analysis showed that the mean ± standard deviation [SD] changes in the HRSD scores from baseline to week four were − 4.2 ± 0.3 points in the oxygen-treated group and − 0.7 ± 0.6 in the control group, for a between-group difference of 3.5 points (95% confidence interval [CI] − 5.95 to − 1.0; P = 0.007). Similarly, at week four there was a between-group difference of 0.71 points in the CGI score (95% CI − 1.00 to − 0.29; P = 0.001). On the other hand, the analysis revealed that there were no significant differences in WHO-5-QOL, SOC-13 or SDS scores between the groups. This study showed a significant beneficial effect of oxygen treatment on some symptoms of depression.
Trial registration: NCT02149563 (29/05/2014).
... [9] The effect of HBO 2 on multiple sclerosis (MS) as an autoimmune disease was evaluated in several studies. [10] However, these studies did not prove the beneficial effect of HBO 2 on MS. Furthermore, HBO 2 may have beneficial effects in refractory inflammatory bowel diseases with lowering the levels of inflammatory cytokines. ...
... HBOT provided significant improvement of visual acuity and field in patients with non-arteritic anterior ischemic optic neuropathy [42]. HBOT also temporarily improves visual symptoms in patients with multiple sclerosis [43]. Nevertheless, HBOT can not be recommended in these patients until more advanced and well-designed studies are reported. ...
Purpose:
To evaluate the effect of hyperbaric oxygen therapy (HBOT) on central corneal thickness (CCT), intraocular pressure (IOP) and the retinal nerve fiber layer (RNFL) thickness in patients with type 2 diabetes mellitus (DM).
Materials and methods:
This prospective non-randomized cohort study consisted of type 2 DM patients who received 30 sessions of HBOT for diabetic foot ulcer (DFU). The CCT, IOP and RNFL measured at base-line (CCT-b, IOP-b, RNFL-b), after the 10th session of HBOT (CCT-1, IOP-1, RNFL-1), after the 20th session of HBOT (CCT-2, IOP-2, RNFL-2), after the 30th session of HBOT (CCT-3, IOP-3, RNFL-3) and after the three months of the last session of HBOT (CCT-4, IOP-4, RNFL-4). We gained the superior-nasal, superior-temporal, inferior-nasal, inferior-temporal, nasal and temporal quadrant RNFL values with a spectral-domain optical coharence tomography (SD-OCT).
Results:
Forty-six eyes of 46 patients included in the study. During the study period, a statistically significant increase in mean IOP values compared to baseline was observed (p< 0.001). We found no significant changes at CCT and all quadrants of RNFL values during HBOT and after three month of the treatment (p>0.05). During the study period, the IOP levels increased over 21 mmHg (between 22-28 mm-Hg) in 7 eyes (15.2%).The mean HbA1c values of these patients with IOP > 21 mmHg were 8.2 ± 0.9 mg / dl, and there was significant differences compared with those of patients with IOP values ≤ 21 mmHg (7.4 ±2.8 mg/dl) (p=0.001).
Conclusions:
HBOT increase intraocular pressure in type 2 diabetic patients especially in ones with impaired blood glucose regulation. However, it does not cause any changes in central corneal thickness and retinal nerve fiber layer. As diabetic retinopathy and DFU are in common pathologies, thus this brief report concludes a need for further studies with longer follow up periods to explore the potential interaction of HBOT on CCT, IOP and RNFL.
... Moreover, some studies have displayed HBOTs favorable impact on radiation-induced injuries where fibrotic deposition, diminished vascularity, and tissue hypoxia play role in the disease pathogenesis. 18,[28][29][30][31][32] Although there appears to be a correlation between the use of HBOT and an improved outcome, causation has yet to be definitively established. Conditions such as diabetic foot ulcers, ischemic stroke, sports injuries, and multiple sclerosis are common diseases that are treated with HBOT but a lack of strong support from peer-reviewed research, with many studies being underpowered. ...
Hyperbaric oxygen therapy (HBOT) serves as "primary" or "adjunctive" therapy in a wide range of pathologies. It is considered the mainstay of management for potentially life-threatening conditions such as carbon monoxide poisoning, decompression illness, and gas embolisms. Moreover, HBOT has been utilized for decades as an adjunctive therapy in a variety of medical disciplines, including chronic wounds, which affect approximately 6.5 million Americans annually. In general, chronic wounds are characterized by hypoxia, impaired angiogenesis, and prolonged inflammation, all of which may theoretically be ameliorated by HBOT. Nonetheless, the cellular, biochemical, and physiological mechanisms by which HBOT achieves beneficial results in chronic wounds are not fully understood, and there remains significant skepticism regarding its efficacy. This review article provides a comprehensive overview of HBOT, and discusses its history, mechanisms of action, and its implications in management of chronic wounds. In particular, we discuss the current evidence regarding the use of HBOT in diabetic foot ulcers, while digging deeply into the roots of controversy surrounding its efficacy. We discuss how the paucity of high-quality research is a tremendous challenge, and offer future direction to address existing obstacles.
... weekly) sessions ('dives'), base their opinion on the benefit they experience in the days following a dive, often commenting on acute, temporary improvements in fatigue and bladder function in particular. Clinicians base their scepticism on a number of clinical trials, mainly conducted in the 1980s and now the subject of a Cochrane review [230,231] which noted, "For example, the mean Expanded Disability Status Scale (EDSS) at 12 months was improved in the HBOT group (group mean reduction in EDSS compared to sham -0.85 of a point, 95% confidence interval: -1.28 to -0.42, P =0.0001). " but which concluded, "At this time, the routine treatment of MS with (HBO) is not recommended. ...
The deep and periventricular white matter is preferentially affected in several neurological disorders, including cerebral small vessel disease (SVD) and multiple sclerosis (MS), suggesting that common pathogenic mechanisms may be involved in this injury. Here we consider the potential pathogenic role of tissue hypoxia in lesion development, arising partly from the vascular anatomy of the affected white matter. Specifically, these regions are supplied by a sparse vasculature fed by long, narrow end arteries/arterioles that are vulnerable to oxygen desaturation if perfusion is reduced (as in SVD, MS and diabetes) or if the surrounding tissue is hypoxic (as in MS, at least). The oxygen crisis is exacerbated by a local preponderance of veins, as these can become highly desaturated 'sinks' for oxygen that deplete it from surrounding tissues. Additional haemodynamic deficiencies, including sluggish flow and impaired vasomotor reactivity and vessel compliance, further exacerbate oxygen insufficiency. The cells most vulnerable to hypoxic damage, including oligodendrocytes, die first, resulting in demyelination. Indeed, in preclinical models, demyelination is prevented if adequate oxygenation is maintained by raising inspired oxygen concentrations. In agreement with this interpretation, there is a predilection of lesions for the anterior and occipital horns of the lateral ventricles, namely regions located at arterial watersheds, or border zones, known to be especially susceptible to hypoperfusion and hypoxia. Finally, mitochondrial dysfunction due to genetic causes, as occurs in leucodystrophies or due to free radical damage, as occurs in MS, will compound any energy insufficiency resulting from hypoxia. Viewing lesion formation from the standpoint of tissue oxygenation not only reveals that lesion distribution is partly predictable, but may also inform new therapeutic strategies.
... HBO therapy is a noninvasive treatment that was developed at the turn of the nineteenth century for the treatment of decompression sickness, and it has been used in a variety of neurologic disorders with satisfactory outcomes, such as in multiple sclerosis, 21 acute ischemic stroke, 22 decompression sickness, 23 traumatic brain injury, 14 and even brain tumors. 24 It was considered to be safe and well tolerated in most conditions with few adverse effects, such as oxygen poisoning, ear injury, seizures, temporary myopia, muscle twitching, and pulmonary fibrosis. ...
Purpose:
The aim of the study was to examine the clinical effect of postoperative hyperbaric oxygen (HBO) therapy on symptoms and signs in the ventriculoperitoneal (VP) shunt insertion treatment of idiopathic normal pressure hydrocephalus (iNPH).
Materials and methods:
We conducted a retrospective analysis of 61 patients treated at our institution for iNPH since 2007. Patients were stratified into 2 groups according to undergoing pure VP shunt with gravitational valves (Group 1) or combined with postoperative HBO therapy (Group 2). Clinical improvements as well as complications were compared between the two groups.
Results:
There is no significant difference between two groups regarding age, sexual proportion, body mass index (BMI), education years and the average NPH scale score before the surgery, as well as the complication rate after the surgery (P＞0.05). On average, the total NPH scale scores were both increased in the 2 groups at 1, 3 and 6 months after shunting, with no significant differences (P＞0.05). However, the group 2 tended to increase more compared with group 1, especially 6 months later after shunting. And the increasing of cognitive functions (CF) was more significant in group 2 (P＜0.05).
Conclusions:
HBO therapy combined with VP shunt is expected to improve the effect of iNPH treatment, especially for the cognitive performance.
... Fifty percent of MS patients could use complementary treatments [117] due to lack of any side effect, but the efficiency of these treatments are weak [117,118] . These treatments include several types: vitamin D, Yoga, medicinal plants, oxygen therapy, acupuncture and reflexology [117,[119][120][121][122] . The percentage of MS female patients using complementary treatments is higher than male patients; however these females have a long MS history [117]. ...
Multiple sclerosis (MS) is the most famous autoimmune disease attacking the central nervous system. It attacks people from age 20–50 years old and the females' attacks double than males' attacks. MS is an autoimmune disease affecting principally the central nervous system that causes nerve sheath demyelination, followed by axon damage and paralysis. MS symptoms include muscle weakness, weak reflexes, muscle spasm, difficulties in movement and unbalance. Many factors may be responsible for MS: microorganism, virus, smoking, stress, environmental toxins, contaminated diet and gout. MS is widely spread in the population in North Europe and this is related to lack of vitamin D due to decrease of sunlight exposure. MS biomarkers include nitric oxide, interleukin-6, nitric oxide synthase, fetuin-A and osteopontin. MS is not a genetic disease (not transferred from parents into next generations) but MS appears when leukocyte antigen system-related genes are changed in human chromosome 6. The physiology of MS patients is controlled by numbers of biological processes such as activation of immune-inflammatory, oxidative and nitrosative stress pathways. MS includes two main steps: (1) myelin sheath destruction and formation of lesions and, (2) inflammation. Four types of MS can be distinguished: relapsing-remitting, primary progressive, secondary progressive and progressive relapsing. Nine treatments have been accepted for relapsing-remitting MS type: interferon β-1a, interferon β-1b, mitoxantrone, natalizumab, glatiramer acetate, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. However, the only treatment used is mitoxantrone for progressive MS with many side effects. Complementary treatments are also used in MS treatments such as vitamin D, Yoga, medicinal plants, oxygen therapy, acupuncture and reflexology.
... The same authors revaluated the use of HBOT in 2010, in trials they had previously analyzed between 1983 and 1987 and came to the same conclusions that HBOT for MS was ineffective. They suggested that 'only staunch advocates would be willing to pursue such investigations', (Bennett and Heard 2010). ...
Multiple sclerosis (MS) is normally considered a chronic inflammatory disease of the central nervous system (CNS), where T-cells breaching the blood brain barrier react against proteins of the axonal myelin sheaths, leading to focal plaques and demyelination in the brain and spinal cord. Many current therapies are immunosuppressive in nature and are designed to target the immune system at an early stage of the disease. But there is no cure and MS may evolve into a neurodegenerative disease, where immunomodulatory treatments appear less effective. Neurodegeneration is influenced by oxidative and endoplasmic reticulum (ER) mediated stress which can be induced independently of immune processes. Since 1970, MS patients have been self-managing their long term symptoms using hyperbaric oxygen and reporting improvement in their symptoms, especially bladder control. In contrast, the majority of clinical trial evidence does not support the views of patients. Therefore does oxygen under pressure affect brain tissue by modulating oxidative or ER stress at the cellular level resulting in CNS tissue repair or deterioration? This chapter reviews our understanding and the role of oxidative and ER stress in the context of employing hyperoxia treatments to treat MS and evaluate its effects on neural cells.
... Public pressure caused the National Multiple Sclerosis Society of the U.S.A. to fund a proper placebo-controlled, double-blinded study where 40 patients were enrolled. Both sets of patients were subjected to 2 atmospheres of pressure, one group was exposed to a 100% oxygen atmosphere while the other group was exposed to an atmosphere comprised of 10% oxygen with the remainder nitrogen [47]. The exposure was for a period of 90 min, 5 days a week for 4 weeks. ...
... Numerous websites advertise off-label HBOT for a wide variety of other conditions including multiple sclerosis, dementia, stroke and ALS (4,5). Metaanalyses conclude that there is insufficient evidence to support the use of HBOT in multiple sclerosis (6), dementia (7) and stroke (8). The FDA has warned patients against such off-label use (9). ...
... Fifty percent of MS patients could be use complementary treatments [117] , due to lack of any side effect but the efficiency of these treatments are weak [117,118] . These treatments include several types: vitamin D, Yoga, medicinal plants, oxygen therapy, acupuncture and reflexology [117,[119][120][121][122] . The percentage of MS females patients using complementary treatments are higher than males patients however these females have a long MS history, more disable, in-satisfaction with MS health programs [117]. ...
Multiple sclerosis (MS) is the most famous autoimmune disease attacking the central nervous system. It attacks people from age 20–50 years old and the females' attacks double than males' attacks. MS is an autoimmune disease affecting principally the central nervous system that cause nerve sheath demyelination followed by axon damage and paralysis. MS symptoms include muscle weakness, weak reflexes, muscle spasm, difficult in move, miss-coordination and unbalance with others. There are many factors may be responsible for MS: microbial, viral, smoking, stress, environmental toxins, contaminated diet, and gout. MS is wide spread in the populations in North Europe and this related to lack of vitamin D due to decrease of sunlight exposure. MS biomarkers include nitric oxide, interleukin-6, nitric oxide synthase, fetuin-A and osteopontin. MS is not a genetic disease where MS occurs when human leukocyte antigen system related genes are changed in chromosome 6. The physiology of MS is monitored by activation of immune-inflammatory, oxidative, and nitrosative stress pathways. MS is including two main steps: (1) myelin sheath destruction and formation of lesions and, (2) inflammation. Four types of MS can be distinguished: relapsing-remitting, primary progressive, secondary progressive and progressive relapsing. Nine treatments have been accepted for relapsing-remitting MS type: interferon β-1a, interferon β-1b, mitoxantrone, natalizumab, glatiramer acetate, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab, however, the only treatment used is mitoxantrone for progressive MS but many of MS treatments side effects are recorded. Complementary treatments also used in MS treatments such as: vitamin D, Yoga, medicinal plants, oxygen therapy, acupuncture and reflexology.
... When used as a therapy of multiple sclerosis, HBOT is seen to create a temporary improement in the sufeffers symptoms, however thus far no long-term results have been confirmed [43,44]. The ineffectiveness of HBOT is explained by an increased oxidative stress which, according to some authors, may occur in such conditions [45]. ...
Hyperbaric oxygen therapy (HBOT) is found among the interests of researchers who seek new methods of treatment of diseases of the nervous system. An increase of the partial pressure of oxygen in arterial blood within the appropriate range leads to numerous changes in the cells of the brain tissue. In this paper we analyse the results of selected articles describing HBOT used on pathologies of the nervous system such as stroke, autism, multiple sclerosis and cerebral palsy as well as in the course of research on animal models. The results are promising, although some studies struggled with numerous methodological problems and differences in the applied protocols, which resulted in conflicting results in individual interventions. In consequence, the need for further studies in randomised control trials and determination of the protocol by an international group of researchers dedicated to the use of HBOT was emphasised.
... Hypoperfusion 40 patients were enrolled. Both sets of patients were subjected to 2 atmospheres of pressure, one group was exposed to a 100% oxygen atmosphere while the other group was exposed to an atmosphere comprised of 10% oxygen with the remainder nitrogen [47]. The exposure was for a period of 90 min, 5 days a week for 4 weeks. ...
Background: The current pharmacotherapies longest in use to treat multiple sclerosis (MS) do not slow progression to disability. The aim of this commentary is to stimulate interest in looking at MS from a new perspective. There is an abundance of evidence that MS is not primarily an autoimmune disease but is a disease where there is first damage to the blood-brain barrier as well as the oligodendrocyte-myelin unit; this damage then elicits an immune response in a subset of people that have an immune system predisposed to attacking myelin-associated antigens. A brief overview is given of the evidence for arterial compliance problems, intracranial compliance problems, venous return problems and hypoperfusion problems in MS.
... Drugs such as histamine and amyl nitrite, which increase perfusion and thus may counteract energy failure, provided only temporary beneficial effects [129]. Similarly, hyperbaric oxygen has highly significant transient effects in the treatment of patients with multiple sclerosis but failed to show any lasting results (e.g., 100% oxygen at 2 atmospheres for 90 min once daily, for a total of 20 exposures) [130,131]. The failure of hyperbaric oxygen therapy in patients with multiple sclerosis may be related to oxidative stress, which can increase in such conditions, similar to reperfusion injury [132] and the temporal timing of oxygen delivery in oxygen-sensitive periods [113]. ...
Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Different trigger pathologies have been suggested by the primary cytodegenerative “inside-out” and primary inflammation-driven “outside-in” hypotheses. Recent data indicate that mitochondrial injury and subsequent energy failure are key factors in the induction of demyelination and neurodegeneration. The brain weighs only a few percent of the body mass but accounts for approximately 20% of the total basal oxygen consumption of mitochondria. Oxidative stress induces mitochondrial injury in patients with multiple sclerosis and energy failure in the central nervous system of susceptible individuals. The interconnected mechanisms responsible for free radical production in patients with multiple sclerosis are as follows: (i) inflammation-induced production of free radicals by activated immune cells, (ii) liberation of iron from the myelin sheets during demyelination, and (iii) mitochondrial injury and thus energy failure-related free radical production. In the present review, the different sources of oxidative stress and their relationships to patients with multiple sclerosis considering tissue injury mechanisms and clinical aspects have been discussed.
... However, some studies showed no significant improvement. [19,71,72] Art and dance therapy could be effective in the emotional state of MS patients and could improve their well-being. ...
Multiple sclerosis (MS) is a chronic, disabling, recurrent demyelination of the central nervous system (CNS). It could affect different regions in the brain and spinal cord, and according to the domain which is affected, it could cause different symptoms such as motor, sensory, or visual impairment; fatigue; bowel, bladder, and sexual dysfunction; cognitive impairment; and depression. MS patients also face reduced quality of life. Drugs that are used in MS are not fully efficient and patients suffer from many symptoms and adverse effects. Today there is an increasing trend of using complementary and alternative medicine (CAM). People are more likely to use this type of treatment. Using appropriate lifestyle and CAM therapy can subside some of the symptoms and could improve the quality of life in these patients. Many people with MS explore CAM therapies for their symptoms. This review is aimed to introduce CAM therapies that could be used in MS patients.
... Although HBO is usually well tolerated, it may produce mild visual symptoms and some rare adverse effects like cataracts, seizures, pressure injury to the ear, and pneumothorax 6 . Because of its high cost and no therapeutic effects in MS, at this time, routine treatment of MS with HBO is not recommended 35 . ...
The National Center for Complementary and Alternative Medicine defines complementary and alternative medicine as a group of diverse medical and health care systems, practices and products that are not generally considered part of conventional medicine. Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system that affects people during early adulthood. In spite of many approved medications, the treatment options in MS are limited. Many people with MS explore complementary and alternative medicine (CAM) treatments to help control their MS and treat their symptoms. Surveys suggest that up to 70% of people with MS have tried one or more CAM treatment for their MS. People with MS using CAM generally report deriving some benefit from therapies. The CAM therapies most frequently used include diet, omega-3 fatty acids and antioxidants. The therapies with highest potential among CAM therapies that warrant further investigation are low-fat diet, omega-3 fatty acids, lipoic acid, and vitamin D supplementation as potential anti-inflammatory and neuroprotective agents in both relapsing and progressive forms of MS. There are very limited researches evaluating the safety and efficacy of CAM in MS. However, in recent years, the USA National Institutes of Health and the National Multiple Sclerosis Society have been actively supporting the researches in this very important area.
Purpose of Review
Multiple sclerosis (MS) is a complex neurodegenerative disease characterized by inflammation, demyelination, and neurodegeneration. Significant hypoxia exists in brain of people with MS (pwMS), likely contributing to inflammatory, neurodegenerative, and vascular impairments. In this review, we explore the concept of a negative feedback loop between hypoxia and inflammation, discussing its potential role in disease progression based on evidence of hypoxia, and its implications for therapeutic targets.
Recent Findings
In the experimental autoimmune encephalomyelitis (EAE) model, hypoxia has been detected in gray matter (GM) using histological stains, susceptibility MRI and implanted oxygen sensitive probes. In pwMS, hypoxia has been quantified using near-infrared spectroscopy (NIRS) to measure cortical tissue oxygen saturation (StO2), as well as through blood-based biomarkers such as Glucose Transporter-1 (GLUT-1). We outline the potential for the hypoxia-inflammation cycle to drive tissue damage even in the absence of plaques. Inflammation can drive hypoxia through blood–brain barrier (BBB) disruption and edema, mitochondrial dysfunction, oxidative stress, vessel blockage and vascular abnormalities. The hypoxia can, in turn, drive more inflammation.
Summary
The hypoxia-inflammation cycle could exacerbate neuroinflammation and disease progression. We explore therapeutic approaches that target this cycle, providing information about potential treatments in MS. There are many therapeutic approaches that could block this cycle, including inhibiting hypoxia-inducible factor 1-α (HIF-1α), blocking cell adhesion or using vasodilators or oxygen, which could reduce either inflammation or hypoxia. This review highlights the potential significance of the hypoxia-inflammation pathway in MS and suggests strategies to break the cycle. Such treatments could improve quality of life or reduce rates of progression.
Introduction
Insomnia stands as a frequent consequence of a cerebrovascular event, afflicting a substantial fraction of those who endure the aftermath of stroke. The ramifications of insomnia following a stroke can further exacerbate cognitive and behavioural anomalies while hindering the process of neurological convalescence. While several randomised controlled trials (RCTs) have scrutinised the effects of hyperbaric oxygen therapy (HBOT) on poststroke insomnia, the advantages and drawbacks persist in a state of ambiguity. We advocate for a systematic review and meta-analysis of randomised clinical trials to comprehensively evaluate the effectiveness and safety of HBOT in the context of poststroke insomnia.
Methods and analysis
A systematic search will be conducted from nine major databases (PubMed, Web of Science, EMBASE, VIP Information Database, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, China Biomedical Literature Database and Wanfang Database, Physiotherapy Evidence Database (PEDro)) for HBOT for poststroke insomnia of RCTs. The search procedures will adhere to a rigorous approach, commencing from the inception date of each database and continuing until 1 November 2023, with inquiries conducted exclusively in English and Chinese. The primary outcome will focus on the alteration in the quality of sleep while secondary outcomes will encompass the evaluation of adverse events and the rate of reoccurrence. The process of selecting studies, extracting data and evaluating the quality of research will be carried out independently by two reviewers. The quality of the included literature will be assessed using the tools of the Cochrane Collaboration. Meta-analysis will be performed by using RevMan V.5.4 and STATA V.16.0.b software. Finally, the quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation method.
Ethics and dissemination
As all data are derived from published investigations via databases without direct patient contact, ethical approval is obviated in this study. The scientific studies will be published in professional academic publications.
PROSPERO registration number
CRD42023468442.
Hiperbarik Oksijen Tedavisi, basınç odası adı verilen kapalı bir sızdırmaz kabin içerisinde, artırılmış atmosferik basınç altında, %100 oranında oksijenin, hastalara maske, başlık ya da entübasyon tüpü vasıtasıyla solutulması prensibine dayanan bir tedavi yöntemidir. Hiperbarik Oksijen Tedavisi’nin uygulandığı kabinler, tek kişilik olabildiği gibi, aynı anda birden fazla hastanın tedavi edilebildiği çok kişilik basınç odaları da bulunmaktadır. Tedavi edici oksijen basıncının, çevre basıncının üzerinde bir basınçta uygulanması gerekmektedir. Tedavi süreleri de, her seans için ortalama 90 dakika veya vakanın tıbbi durumuna göre daha uzundur. 1955 yılından beri tıp pratiğinde aktif olarak kullanılmakta olan Hiperbarik Oksijen Tedavisi, temelde iki fizyolojik mekanizma ile etki göstermektedir. Bunlar, yüksek basıncın doğrudan fiziksel etkisi ve parsiyel oksijen basıncının yükselmesi ile oluşan fizyolojik etkilerdir. Bu temel etki mekanizmaları aracılığıyla, dolaşım sisteminde ve dokularda patolojik olarak oluşan gaz kabarcıklarının hacmini azaltır, doku oksijenasyonunu artırır, yara iyileşmesini hızlandırır, iyileşmeyen yaralarda bakteriyel enfeksiyon riskini azaltır, anjiogenezi uyarır ve immün yanıtı düzenler. Hiperbarik oksijen tedavisi bu etkileri sayesinde, dekompresyon hastalığı, karbon monoksit zehirlenmesi, hava ve gaz embolisi, gazlı gangren, crush yaralanması, kompartman sendromu, retinal arter oklüzyonu, diabetik ayak gibi iyileşmeyen yaralar, yumuşak dokunun nekrotizan enfeksiyonları, ani işitme kaybı ve kronik osteomiyelit gibi birçok tıbbi durumda endikedir. Bunlara ek olarak, son yıllarda yapılan deneysel ve klinik çalışmalarda, yangısal ve sistemik hastalıklar, maligniteler, COVID-19 enfeksiyonu, erektil disfonksiyon, yaşlanma, iskemik kalp ve beyin hastalıkları gibi durumlarda da etkinliği araştırılmaktadır. Bu derlemenin amacı, Hiperbarik Oksijen Tedavisi’nin etki mekanizmalarını, yangı üzerine etkilerini ve son yıllarda yapılan birçok yeni çalışmaya konu olan yangısal hastalıklar üzerindeki etkinliğini gözden geçirmektir.
Traumatic brain injury (TBI) impacts about 42 million people per year and is especially common among veterans and individuals experiencing homelessness. In fact, TBI is two to seven times more prevalent among those experiencing homelessness than the general population. Despite this significant clinical burden, effective treatments for TBI remain a major unmet clinical need among this unique patient population. Although neuroinflammation has been recognized as a key contributing factor to TBI pathology, we hypothesize that individuals experiencing homelessness likely display even greater neuroinflammation following TBI due to exacerbated stress of daily living. Thus, we explain the pathophysiology of neuroinflammation in TBI and homelessness and propose the necessity of including this unique population in novel therapy developments, such as stem cell transplantation.
This literature review focuses on the underlying pathophysiology of TBI and PTSD symptoms, while also examining the plethora of stem cell treatment options to ameliorate these neuronal and functional changes. As more veterans return suffering from TBI and/or PTSD, it is vital that researchers discover novel therapies to mitigate the detrimental symptoms of both diagnoses. A variety of stem cell treatments have been studied and offer hopeful options for TBI and PTSD recovery.
Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the ‘real MS’ is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of ‘no evident inflammatory disease activity’ (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.
Introduction:
Hyperbaric oxygen (HBO) has been used for the treatment of cerebral palsy for more than 20 years, but its efficacy and safety are still controversial. In this systematic review and meta-analysis, we evaluated the currently promulgated data related to the efficacy of HBO for patients with cerebral palsy.
Methods:
We searched the PubMed/Medline, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases (from their inception to April 2020) for randomized controlled trials published in English or Chinese. Two researchers used the Cochrane Collaboration tool for data extraction and an independent quality assessment. The extracted data were analyzed by Review Manager 5.3 software.
Results:
A total of 25 studies consistent with the inclusion criteria were included, with a total of 2,146 people, which included 1,185 participants in the HBO group and 961 in the control group. This meta-analysis showed that when compared with the controls, HBO therapy can improve the gross motor functions evaluated by the Gross Motor Function Measure (n = 696, SMD 0.29, 95% CI [0.07-0.51], Z = 2.62, p = 0.009) and Gross Motor Function Classification System (n = 248, MD -0.40, 95% CI [-0.52 to -0.27], Z = 6.28, p < 0.00001), global developmental level evaluated by Gesell (n = 560, RR 1.30, 95% CI [1.19-1.42], Z = 6.03, p < 0.00001) and developmental quotient (n = 374, MD 8.25, 95% CI [6.48-10.01], Z = 9.15, p < 0.00001) and language expression (n = 270, MD 4.34, 95% CI [2.30-6.38], Z = 4.17, p < 0.00001) and comprehension (n = 270, MD 4.87, 95% CI [2.87-6.88], Z = 4.76, p < 0.00001). HBO therapy only caused mild ear pain. However, the quality of the data for all outcomes evaluated by the Grading of Recommendations Assessment, Development, and Evaluation analysis was very low.
Conclusions:
HBO therapy may produce a much more efficient clinical experiment result than the control group with cerebral palsy patients, and HBO therapy is well tolerated and relatively safe for the included participants.
In-vivo measurement of CNS tissue oxygenation and metabolism is critical in health and disease. Broadband-near infrared spectroscopy is a non-invasive optical technique which measures tissue oxygenation, haemodynamics and metabolism through in-vivo quantification of concentration changes of oxy- and deoxy-haemoglobin (Δ[HbO2] and Δ[HHb]) and oxidised cytochrome-c-oxidase (Δ[oxCCO]). Current commercially available NIRS systems only use a few wavelengths to measure concentration change that fails to provide accurate Δ[oxCCO] measurement. Broadband-NIRS instruments however, use more than 100 wavelengths which enables quantification of change in [oxCCO], an important marker of cellular oxidative metabolism. These systems tend to be bulky, requiring extensive calibrations and trained staff to operate them; making them less versatile and difficult to be adapted in the clinical environment. Furthermore, existing broadband-NIRS systems quantify chromophore concentration changes assuming a fixed optical pathlength across all the subjects using a previously measured DPF (differential pathlength factor) with time or frequency domain systems. This thesis describes the development of a portable broadband-NIRS system called mini-CYRIL “CYtochrome Research Instrument and appLication”, based on easily sourced components. A miniature white light source (HL-2000-HP) and miniature spectrometers (QE65pro and Ventana VIS-NIR) by Ocean Optics were customised for measuring CNS tissue oxygenation and metabolism. While having the features of commercially available NIRS systems in terms of portability, ease of use and no need for wavelength calibration, in terms of performance mini-CYRIL is comparable to broadband-NIRS instruments providing reliable Δ[oxCCO] measurements that have been validated and assessed through in-vivo tissue studies in (a) preclinical model of: (i) neonatal hypoxic-ischaemic (HI) encephalopathy, (ii) multiple sclerosis (MS) and (iii) low-light level therapy in the aged retina; (b) infants during brain functional activation. Mini-CYRIL is furthermore novel in offering calculation of absolute change in the concentration of chromophores based on real-time measurement of the optical path of light traversing the tissue. None of the current NIRS systems offer this feature which is crucial in case of changing pathology following an injury.
Multiple sclerosis is an autoimmune disease of the central nervous system that can develop at any age. Multiple sclersis (MS) affects women more than men. The disorder is most commonly diagnosed between ages 20 and 40, but can be seen at any age. The aim of our study is to represent how is some CAM methods in treatment of MS are effective, and how to organizing them in community based rehabilitation programs. Material and Method: We are interested in findings one model to educate medical staff for implementation of some CAM methods in our society on science way. We have concluded 429 studies about last medical and complementary methods for the treatment, classification, assessment and effects of them on increase QOL by patients with MS. Results: We have analyzed 14 methods who had effect on MS patients (Yoga, Tai Chi, Nutrition, Supplements, Cry therapy, Hydro therapy, Art therapy, Meditation, Hyperbaric oxygen therapy, Acupuncture, Herbal therapy, Music therapy and Kinesiotajping. All were representing like effects on QOL, dose, application and assessment. Discussion: During the past decade, there have been initiatives across Europe, North America, and Australia/New Zealand to identify the needs of people with MS and the services and expertise required to meet those needs. Many programs have been raised for a more patient-centered and to optimize and safeguard modern patients' treatment decisions and treatment outcomes. They are managed to realize community based rehabilitation models. Conclusions: Rehabilitation is most important and aims at leading individuals with MS to adapt their lifestyle. Implementation of CAM methods in Community based rehabilitation programs has purpose to increase QOL by those patients.
Multiple sclerosis is one of the most common neurological disorders and causes of disability among young people. Although some people with MS have some disability in their lifetime, up to 60% or more of the patients have major implications for their quality of life and financial cost to society. Most people with MS have a normal or near-normal life expectancy. In rare cases, MS is so malignant, progressive and ends quickly. Despite our awareness of the significant impact of MS, there is a serious lack of information on resources which are available to deal in the health system with the disease. Significant findings: Globally, the average estimated prevalence of MS was 30 per 100,000 (range: 5-80); Regionally, the average estimated prevalence of MS is the largest in Europe (80 per 100,000), followed by the Eastern Mediterranean (14.9), America (8.3) in the Western Pacific (5), Southeast Asia (2.8) and Africa (0.3); Globally, the average estimated incidence of MS would be 2.5 per 100 000 (ranging from 1.1 to 4). There is globally a major gap in the provision of essential and more specific forms of information about this disease.
The position of WHO publication regarding the application of CAM is:
- The five most prevalent alternative or complementary approaches used in more than 50% of countries are diet and nutrition (88.3%), acupuncture (86.7%), herbal medicine (81.7%), massage (78.3 %) and homeopathy (73.3%).
- Other alternative or complementary approaches used in some countries, chiropractic and osteopathy (41.7%), aromatherapy (40%), hyperbaric oxygen (40%), cannabis (38.3%), ayurvedic medicine (36.7%), pilates (36.7%), dentistry (replacement of seals) (36.7%), biofeedback (35%), macrobiotic diet (31.7%), naturopathy (28.3%), hypnotherapy (21,7%), hypnosis (18.3%) and iridology (18.3%).
Our training program for non-pharmacological treatment of Multiple sclerosis is made according to the latest findings from the search of the medical database pubmed. The data on the effectiveness of treatment are mostly cited publications published in the last 5-10 years, while CAM methods are mostly in the last 5 years
Background:
Coma after acute head injury is always alarming. Depending on the type of injury, immediate treatment may be life-saving. About a quarter of a million patients are treated for traumatic brain injury in Germany each year. Treatment recommendations must be updated continually in the light of advancing knowledge.
Methods:
This review of treatment recommendations, prognostic factors, and the pathophysiology of coma after acute head injury is based on a 2015 German guideline for the treatment of head injury in adults and on pertinent publications retrieved by a selective search in PubMed for literature on post-traumatic coma.
Results:
As soon as the vital functions have been secured, patients with acute head injury should undergo cranial computed tomography, which is the method of choice for identifying intracranial injuries needing immediate treatment. Patients who have an intracranial hematoma with mass effect should be taken to surgery at once. The prognosis is significantly correlated with the patient's age, the duration of coma, accompanying neurological manifestations, and the site of brain injury. The case fatality rate of patients who have been comatose for 24 hours and who have accompanying lateralizing signs, a unilaterally absent pupillary light reflex, or hemiparesis lies between 30% and 50%. This figure rises to 50-60% in patients with abnormal extensor reflexes and to over 90% in those with bilaterally absent pupillary light reflexes. Current neuropathological and neuroradiological studies indicate that coma after acute head injury is due to reversible or irreversible dysfunction of the brainstem.
Conclusion:
Brain tissue can tolerate ischemia and elevated pressure only for a very limited time. Comatose head-injured patients must therefore be evaluated urgently to determine whether they can be helped by the surgical removal of a hematoma or by a decompressive hemicraniectomy.
Traumatic brain injury (TBI) describes the presence of physical damage to the brain as a consequence of an insult and frequently possesses psychological and neurological symptoms depending on the severity of the injury. The recent increased military presence of US troops in Iraq and Afghanistan has coincided with greater use of improvised exploding devices, resulting in many returning soldiers suffering from some degree of TBI. A biphasic response is observed which is first directly injury-related, and second due to hypoxia, increased oxidative stress, and inflammation. A proportion of the returning soldiers also suffer from post-traumatic stress disorder (PTSD), and in some cases, this may be a consequence of TBI. Effective treatments are still being identified, and a possible therapeutic candidate is hyperbaric oxygen therapy (HBOT). Some clinical trials have been performed which suggest benefits with regard to survival and disease severity of TBI and/or PTSD, while several other studies do not see any improvement compared to a possibly poorly controlled sham. HBOT has been shown to reduce apoptosis, upregulate growth factors, promote antioxidant levels, and inhibit inflammatory cytokines in animal models, and hence, it is likely that HBOT could be advantageous in treating at least the secondary phase of TBI and PTSD. There is some evidence of a putative prophylactic or preconditioning benefit of HBOT exposure in animal models of brain injury, and the optimal time frame for treatment is yet to be determined. HBOT has potential side effects such as acute cerebral toxicity and more reactive oxygen species with long-term use, and therefore, optimizing exposure duration to maximize the reward and decrease the detrimental effects of HBOT is necessary. This review provides a summary of the current understanding of HBOT as well as suggests future directions including prophylactic use and chronic treatment.
Th e use of complementary and alternative medicine (CAM) is common in multiple sclerosis (MS). It includes approaches to MS that are not generally considered as part of conventional medicine. Th ere is very limited research evaluating the safety and effectiveness of CAM in MS. CAM therapies in MS exhibit a broad range of risk-benefit profiles; some of these therapies are low risk and possibly beneficial, whereas others are ineffective, dangerous, or unstudied. However, in recent years, much effort has been invested in research in this very important area. Health professionals who provide objective, evidence based and practical information about the risks and benefits of CAM therapies may improve the quality of care for those with MS.
Abstract The role of nitrosative stress in the early pathogenesis of neuroinflammation and demyelination is undoubtedly wide. This review summarizes and integrates the results, found in previously performed studies, which have evaluated nitrosative stress participation in neuroinflammation. The largest number of studies indicates that the supply of nitrosative stress inhibitors has led to the opposite clinical effects in experimental studies. Some results claim that attributing the protective role to nitric oxide, outside the total changes of redox oxidative processes and without following the clinical and paraclinical correlates of neuroinflammation, is an overrated role of this mediator. The fact is that the use of nitrosative stress inhibitors would be justified in the earlier phases of neuroinflammation. The ideal choice would be a specific inducible nitric oxide synthase (iNOS) inhibitor, because its use would preserve the physiological features of nitric oxide produced by the effects of constitutive NOS. This review discusses the antinitrosative therapy as a potential mode of therapy that aims to control neuroinflammation in early phases, delaying its later phases, which are accompanied with irreversible neurological disabilities. Some parameters of nitrosative stress might serve as surrogate biomarkers for neuroinflammation intensity and its radiological and clinical correlates.
Multiple sclerosis (MS) is a potentially life-changing immune mediated disease of the central nervous system. Until recently, treatment has been largely confined to acute treatment of relapses, symptomatic therapies and rehabilitation. Through persistent efforts of dedicated physicians and scientists around the globe for 160 years, a number of therapies that have an impact on the long term outcome of the disease have emerged over the past 20 years. In this three part series we review the practicalities, benefits and potential hazards of each of the currently available and emerging treatment options for MS. We pay particular attention to ways of abrogating the risks of these therapies and provide advice on the most appropriate indications for using individual therapies. In Part 1 we review the history of the development of MS therapies and its connection with the underlying immunobiology of the disease. The established therapies for MS are reviewed in detail and their current availability and indications in Australia and New Zealand are summarised. We examine the evidence to support their use in the treatment of MS.
In this third and final part of our review of multiple sclerosis (MS) treatment we look at the practical day-to-day management issues that are likely to influence individual treatment decisions. Whilst efficacy is clearly of considerable importance, tolerability and the potential for adverse effects often play a significant role in informing individual patient decisions. Here we review the issues surrounding switching between therapies, and the evidence to assist guiding the choice of therapy to change to and when to change. We review the current level of evidence with regards to the management of women in their child-bearing years with regards to recommendations about treatment during pregnancy and whilst breast feeding. We provide a summary of recommended pre- and post-treatment monitoring for the available therapies and review the evidence with regards to the value of testing for antibodies which are known to be neutralising for some therapies. We review the occurrence of adverse events, both the more common and troublesome effects and those that are less common but have potentially much more serious outcomes. Ways of mitigating these risks and managing the more troublesome adverse effects are also reviewed. Finally, we make specific recommendations with regards to the treatment of MS. It is an exciting time in the world of MS neurology and the prospects for further advances in coming years are high.
Abstract Experimental autoimmune encephalomyelitis (EAE) is a model for human multiple sclerosis (MS) in rodents. Static magnetic field (SMF)-exposure was shown to be beneficial in specific cases of inflammatory background, where it suppresses symptoms. The null-hypothesis was that animals with induced EAE exposed to SMF would show different seriousness of symptoms, than those in the sham-exposed control group. Three replicated series of repetitive, 30 min/day whole-body exposure to SMF with 477 mT peak-to-peak magnetic induction and 48 T/m lateral induction gradient was tested on female CSJLF1 mice with a mild, mouse spinal cord homogenate emulsion-induced EAE. Conventional scores of the animal response to EAE were compared between sham- and SMF-exposed groups of animals. Following pilot test we used 18 animals per group. Primary outcome measure was the daily group average of standard EAE scores. Results show that SMF-exposure has a strong, reproducible, and significantly beneficial effect up to 51.82% (p<0.001) over sham-exposure on the symptoms of EAE in the course of the 25 days of the experiment. This study aimed to build experimental research foundation for a later therapy option by applying SMF-exposure in the clinical management of MS.
Major advances are taking place in the development of therapeutics for multiple sclerosis (MS), with a move past traditional immunomodulatory/immunosuppressive therapies toward medications aimed at promoting remyelination or neuroprotection. With an increase in diversity of MS therapies comes the need to assess the effectiveness of such therapies. Magnetic resonance imaging (MRI) is one of the main tools used to evaluate the effectiveness of MS therapeutics in clinical trials. As all new therapeutics for MS are tested in animal models first, it is logical that MRI be incorporated into preclinical studies assessing therapeutics. Here, we review key papers showing how MR imaging has been combined with a range of animal models to evaluate potential therapeutics for MS. We also advise on how to maximize the potential for incorporating MRI into preclinical studies evaluating possible therapeutics for MS, which should improve the likelihood of discovering new medications for the condition.
Oxygen treatment has been a cornerstone of acute medical care for numerous pathological states. Initially, this was supported by the assumed need to avoid hypoxaemia and tissue hypoxia. Most acute treatment algorithms, therefore, recommended the liberal use of a high fraction of inspired oxygen, often without first confirming the presence of a hypoxic insult. However, recent physiological research has underlined the vasoconstrictor effects of hyperoxia on normal vasculature and, consequently, the risk of significant blood flow reduction to the at-risk tissue. Positive effects may be claimed simply by relief of an assumed local tissue hypoxia, such as in acute cardiovascular disease, brain ischaemia due to, for example, stroke or shock or carbon monoxide intoxication. However, in most situations, a generalized hypoxia is not the problem and a risk of negative hyperoxaemia-induced local vasoconstriction effects may instead be the reality. In preclinical studies, many important positive anti-inflammatory effects of both normobaric and hyperbaric oxygen have been repeatedly shown, often as surrogate end-points such as increases in gluthatione levels, reduced lipid peroxidation and neutrophil activation thus modifying ischaemia-reperfusion injury and also causing anti-apoptotic effects. However, in parallel, toxic effects of oxygen are also well known, including induced mucosal inflammation, pneumonitis and retrolental fibroplasia. Examining the available 'strong' clinical evidence, such as usually claimed for randomized controlled trials, few positive studies stand up to scrutiny and a number of trials have shown no effect or even been terminated early due to worse outcomes in the oxygen treatment arm. Recently, this has led to less aggressive approaches, even to not providing any supplemental oxygen, in several acute care settings, such as resuscitation of asphyxiated newborns, during acute myocardial infarction or after stroke or cardiac arrest. The safety of more advanced attempts to deliver increased oxygen levels to hypoxic or ischaemic tissues, such as with hyperbaric oxygen therapy, is therefore also being questioned. Here, we provide an overview of the present knowledge of the physiological effects of oxygen in relation to its therapeutic potential for different medical conditions, as well as considering the potential for harm. We conclude that the medical use of oxygen needs to be further examined in search of solid evidence of benefit in many of the current clinical settings in which it is routinely used.
We need formal economic analyses in the field of hyperbaric medicine. As the first step in a staged approach to full cost-effectiveness analysis for major indications, we present an analysis of the true cost of treatment and the cost of treatment per diagnosis in our unit. Following explicit definitions of cost, accounting cost objects, cost objectives and cost categories, we calculated all costs involving the treatment of patients during the financial year 2003-2004. Dollar costs were taken from a detailed examination of itemised spending provided through the hospital accounting system. Patients were classified into diagnostic groups and included both those who did and those who did not receive hyperbaric oxygen therapy (HBOT). The latter were mainly wound care patients. We then calculated the individual cost for each diagnosis. All costs are expressed in Australian dollars. We treated a total of 304 patients with 1,333 compression cycles using both monoplace and multiplace compression vessels. The total number of individual patient compressions was 3,446. The overall cost for the year of operation was 4,159, while for those having only wound care the average cost was 325. These figures will assist us in accurately representing the likely costs of future therapy and in discussions with third-party payers. It is our intention to use these data to inform cost-effectiveness studies currently under way in our facility.
The long term results are reported of a trial involving 120 patients with chronic multiple sclerosis who were randomised to receive either 100% oxygen at 2 atmospheres absolute (ATA) for 90 minutes daily for 20 sessions or placebo therapy with air using a simulated compression procedure. The previous finding of subjective improvement in bowel/bladder function at the end of treatment was not confirmed by objective urodynamic assessment. The treatment did not alter disease progression as measured by the Kurtzke disability status scale nor did it alter the rate of acute relapse. There was less deterioration in cerebellar function at one year in the treated patients as measured by the Kurtzke functional systems scale. No other differences were found between the two groups. Psychometric tests and measurements of lymphocyte sub-populations showed no treatment related effects. Evoked potential studies showed no improvements but there was a significant reduction in amplitude of the visual evoked potential in the treated patients at the end of therapy. This might indicate a reversible degree of retinal damage induced by oxygen toxicity.
The effects of hyperbaric oxygen at a pressure of two atmospheres absolute were studied in a group of patients with chronic progressive multiple sclerosis. A slight but statistically insignificant shortening of the visual evoked potential latencies was seen after treatment with hyperbaric oxygen as compared with placebo treatment. The treatment did not appreciably halt the progression of the disease and deferioration occurred more often among the patients in the treatment group than in the control group.
Multiple sclerosis (MS) is a commonly occurring inflammatory and demyelinating neurological disease. It has been considered to be an autoimmune disorder mediated by CD4+ type 1 T helper cells, but recent studies have challenged this idea by indicating a role for other immune cells. So, T- and B-cell responses in the brain of patients with MS involve the clonal expansion of lymphocytes and the antigen-driven maturation of the B-cell receptors, indicating that the immune response in MS engages a broad range of immune cells that target a limited number of brain antigens. At variance with the classical view, axons are not spared during the inflammatory process. Indeed, axonal damage determines clinical outcome to a large extent. Studies of the mechanisms of axonal damage and neurodegeneration in MS are in their infancy. Here, we summarize recent advances in our understanding of the pathogenesis of MS, and conclude with an outlook on how to capitalize on this knowledge to develop new therapeutic approaches.
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Selected References
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Schumacher GA. Critique of experimental trials of therapy in multiple sclerosis. Neurology. 1974 Nov;24(11):1010–1014. [PubMed]
Objective:
To compare efficacy of interferon beta-1a, 22 microg or 44 microg weekly, with placebo in relapsing MS.
Background:
Uncertainty exists concerning the optimal dose regimen for interferon beta in relapsing-remitting MS. Many patients and physicians prefer the convenience and lesser side effects of an injection given once weekly (qw) as opposed to three times weekly. Pharmacokinetic data and information on biologic markers suggest that this frequency may be suboptimal.
Methods:
Randomized, double-blind study of interferon beta-1a 22 microg, 44 microg, or placebo administered by weekly subcutaneous injection for 48 weeks. Proton density (PD)/T2-weighted and T1-weighted-gadolinium MRI scans during 24 weeks of therapy were analyzed for the number of combined unique (CU) lesions (primary outcome). Biannual PD/T2 scans were analyzed for T2 activity and burden of disease (BOD).
Results:
CU lesions at 24 weeks had a median of 0.71/scan with placebo, 0.5/scan with 22 microg (not significant), and 0.33/scan with 44 microg (p = 0.002). T2 new lesion count/scan (mean/median) at 48 weeks was 3.2/1.5 for placebo, 2.4/1.0 for 22 microg (p = 0.03), and 1.5/1.0 for 44 microg (p = 0.0005). BOD at 48 weeks showed a median increase of 5.9% for placebo compared with a decrease of 1.4% in the 44 microg group (p = 0.0058) and 2% in the 22 microg group (p = 0.0018). No clinical variable, apart from steroid use in the 44 microg qw group (p = 0.014), showed significance.
Conclusions:
These data confirm an MRI benefit of interferon beta-1a at low dose in MS, but highlight the limited clinical effect. Taken together with other studies, the data demonstrate a dose-effect relationship for both clinical and MRI variables.
The theory of a relation between the cerebrovascular system and the lesions of multiple sclerosis has been advanced by many workers. The first of many to assign a primary role to vascular lesions was Rindfleisch.1 Ribbert2 early maintained that the demyelinated areas were related to a primary disseminated thrombosis. He described a congested central vessel in all the sclerotic patches. In two small patches cut in serial section he found white blood cells in the lumen of the vessel, partly adherent to the vessel wall and partly filling the vessel as an embolus. He stated that these changes in the vessel were multiple thrombi and expressed the belief that they had an important causative role in multiple sclerosis. The most recent adherents to the idea that vascular lesions play a primary role in the pathogenesis of the lesions of multiple sclerosis have been Putnam and his collaborators.3
Background Previous trials of interferon beta in multiple sclerosis (MS) have shown efficacy, but the degree of clinical benefit remains uncertain, and the optimum dose is not known. We undertook a double-blind, placebo-controlled study in relapsing/remitting MS to investigate the effects of subcutaneous interferon beta-1a. Methods 560 patients with Kurtzke expanded disability status scale (EDSS) scores of 0-5.0, from 22 centres in nine countries, were randomly assigned subcutaneous recombinant interferon beta-1a 22 mu g (n=189), or 44 mu g (n=184), or placebo (n=187) three times a week for 2 years. Neurological examinations were done every 3 months. All patients had MRI twice yearly and 205 had monthly scans in the first 9 months of treatment. Analysis was by intention to treat. Findings Clinical data on 533 (95%) patients were available at 2 years. The relapse rate was significantly lower at 1 and 2 years with both doses of interferon beta-1a than with placebo (mean number per patient 1.82 for 22 mu g group, 1.73 for 44 mu g group vs 2.56 for placebo group: risk reductions 27% [95% CI 14-39] and 33 [21-44]). Time to first relapse was prolonged by 3 and 5 months in the 22 mu g and 44 mu g groups respectively, and the proportion of relapse-free patients was significantly increased (p < 0.05). Interferon beta-1a delayed progression in disability, and decreased accumulated disability during the study. The accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group. Interpretation Subcutaneous interferon beta-1a is an effective treatment for relapsing/remitting MS in terms of relapse rate, defined disability, and all MRI outcome measures in a dose-related manner, and it is well tolerated. Longer-term benefits may become clearer with further follow-up and investigation.
• Three hundred twelve patients were entered into a long-term study of effects of hyperbaric oxygen on multiple sclerosis. The protocol called for an initial 20 treatments in either the monoplace or multiplace chamber on a daily basis followed by monthly booster treatments for 2 years. One hundred seventy neurologists and 22 institutions provided data for this study. There was no control group, but the study was based on Schumacher's postulation that a scientifically valid study to test the efficacy of a new therapy was possible by choosing patients who were definitively diagnosed with multiple sclerosis and following them up for 2 years after the imposed treatment. If the overwhelming majority of the subjects failed to get worse over the 2-year observation period, the efficacy of the treatment would be manifest. The expanded Kurtzke Disability Status Scale (EDSS) was used to assess the severity of the disease state. The dropout rate was high with only 76% (237 of 312 patients) finishing the initial 20 treatments. Twenty-two percent (69 of 312) finished 1 year of booster therapy, and 9% (28 of 312) completed 2 years of monthly boosters. The mean deterioration on the Kurtzke EDSS score was 0.93 or almost a full step from the beginning of treatment until the last evaluation. There was no difference in outcome between those who had the shortest and longest periods of time between onset of symptoms and hyperbaric oxygen treatment. Treatment pressure made no difference in outcome. Changes in the Kurtzke EDSS score bore no relationship to the use of booster treatment. Patients who were reasonably well off at the onset of treatment with initial Kurtzke EDSS scores of 1 or 2 (n = 21) deteriorated by an average of 1.7 Kurtzke points. Those patients whose initial Kurtzke EDSS scores were greater than 2 (n = 164) deteriorated on an average of 0.82 points. Of interest was that 19.5% (39 of 200) of the patients reported a temporary improvement in bladder function, but improvement was maintained in only 11 patients (5.5%) at 2-year follow-up. Fifteen patients (7.5%) indicated long-term worsening. There was no significant change in the working status of the patients following hyperbaric oxygen treatment. Although this study treated the patients in accordance with protocols reported to produce a benefit in multiple sclerosis, we were unable to substantiate any useful long-term effect of hyperbaric oxygen therapy.
Background
The beneficial effects of interferon β have only been shown for patients in the relapsing-remitting phase of multiple sclerosis (MS). The role of interferon β in the treatment of patients who are in the secondary progressive phase of the disease (SP-MS), and for whom no effective drug treatment is available, has not been assessed.
Methods
In this multicentre, double-masked, randomised, placebo-controlled trial, outpatients with SP-MS having scores of 3·0–6·5 on the Expanded Disability Status Scale (EDSS) received either 8 million IU interferon β-1b every other day subcutaneously, or placebo, for up to 3 years. The primary outcome was the time to confirmed progression in disability as measured by a 1·0 point increase on the EDSS, sustained for at least 3 months, or a 0·5 point increase if the baseline EDSS was 6·0 or 6·5. A prospectively planned interim analysis of safety and efficacy of the intention-to-treat population was done after all patients had been in the study for at least 2 years.
Findings
358 patients with SP-MS were allocated placebo and 360 were allocated interferon β-1b; 57 patients (31 placebo, 26 interferon β-1b) were lost to follow-up. There was a highly significant difference in time to confirmed progression of disability in favour of interferon β-1b (p=0·0008). Interferon β-1b delayed progression for 9–12 months in a study period of 2–3 years. The odds ratio for confirmed progression was 0·65 (95% Cl 0·52–0·83). This beneficial effect was seen in patients with superimposed relapses and in patients who had only progressive deterioration without relapses. Positive results were also obtained regarding time to becoming wheelchair-bound, relapse rate and severity, number of steroid treatments and hospital admissions, as well as on magnetic resonance imaging variables. The drug was safe and side effects were in line with previous experience with interferon β-1b. The study was stopped after the interim results gave clear evidence of efficacy.
Interpretation
Treatment with interferon β-1b delays sustained neurological deterioration in patients with SP-MS. Interferon β-1b is the first treatment to show a therapeutic effect in patients with SP-MS.
Background
Previous trials of interferon β in multiple sclerosis (MS) have shown efficacy, but the degree of clinical benefit remains uncertain, and the optimum dose is not known. We undertook a double-blind, placebo-controlled study in relapsing/remitting MS to investigate the effects of subcutaneous interferon β-1a.
Methods
560 patients with Kurtzke expanded disability status scale (EDSS) scores of 0–5·0, from 22 centres in nine countries, were randomly assigned subcutaneous recombinant interferon β-1a 22 μg (n=189), or 44 μg (n=184), or placebo (n=187) three times a week for 2 years. Neurological examinations were done every 3 months. All patients had MRI twice yearly and 205 had monthly scans in the first 9 months of treatment. Analysis was by intention to treat.
Findings
Clinical data on 533 (95%) patients were available at 2 years. The relapse rate was significantly lower at 1 and 2 years with both doses of interferon β-1a than with placebo (mean number per patient 1·82 for 22 μg group, 1·73 for 44 μg group vs 2·56 for placebo group: risk reductions 27% [95% Cl 14–39] and 33 [21–44]). Time to first relapse was prolonged by 3 and 5 months in the 22 μg and 44 μg groups respectively, and the proportion of relapse-free patients was significantly increased (p < 0·05). Interferon β-1a delayed progression in disability, and decreased accumulated disability during the study. The accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group.
Interpretation
Subcutaneous interferon β-1a is an effective treatment for relapsing/remitting MS in terms of relapse rate, defined disability, and all MRI outcome measures in a dose-related manner, and it is well tolerated. Longer-term benefits may become clearer with further follow-up and investigation.
Objectives- To evaluate clinical and MRI effects of natural interferon β treatment in both relapsing-remitting (RR) and secondary-progressive (SP) multiple sclerosis patients. Material and methods- A double-blind, randomized trial of natural interferon β (nIFN-β) in 58 ambulatory patients with RR and 40 with SP multiple sclerosis. Forty-nine patients (29 RR and 20 SP) were treated with intramuscular nIFN-β 6 MIU three times a week for 24 months and 49 control patients were treated with placebo. Results- Primary clinical endpoints were differences in exacerbation rates and proportion of patients remaining exacerbation-free. There were no significant baseline differences between the treated and placebo groups. In the treated RR group a significant reduction in exacerbation rate, an increase in the probability of remaining exacerbation-free, and an improvement in mean EDSS were found at 24 months. MRI activity and total lesion burden were significantly reduced in treated RR patients. In the SP group, nIFN-β produced a significant reduction in EDSS score, a significant reduction in active lesion number, a marginally significant favourable difference in total lesion burden but no significant effect on the number of gadolinium-enhancing lesions. Side effects were transient and mild in treated patients. Conclusions- These observations confirm that nIFN-β is a promising and well-tolerated treatment for either RR or SP MS patients.
A new hypothesis as to etiology is presented. Special emphasis is placed on the controversy surrounding the use of hyperbaric oxygen in a critical analysis of the published double-blind studies and related discussions. Emphasis placed on the predominant infective and autoimmune hypotheses cannot be supported, either from the pathology of the disease or by the response to treatment. It is concluded that the evidence of beneficial effects of hyperbaric oxygen therapy, despite the use of patients with advanced disease in trials, is very impressive, especially in chronic progressive disease. It is also concluded that there is need for further research and that such studies should examine the effects of hyperbaric oxygenation alone, and in combination with other therapeutic agents, in individual patients with the methods of real time investigation now available. Meanwhile, based on comparative efficacy and safety, hyperbaric oxygenation is recommended for treating early stages of MS, especially for treating cerebellar and bowel-bladder disorders. ACTH-cortisone, antiviral agents, co-polymer 1, double-blind studies, hyperbaric oxygen therapy, immunosuppressants, Kurtzke disability scores, MS etiology, MS pathophysiology MS therapy, multiple sclerosis (MS), plasmapheresis Introduction Multiple sclerosis (MS) is classified as a demyelinating disease of the central nervous system (1) and is the most common of the demyelinating diseases. Despite over a century of investigation MS remains one of the most frustrating diseases for patients and physicians because there is no agreed upon etiology and there is no cure or agreed upon therapy. Perhaps no other disease has had so many therapies proposed and had them fail (2, 3). The purpose of this article is to review some of the evidence for the etiology and pathophysiology of MS and match the information with current therapies. Specific attention will be directed at a critique of the basis for hyperbaric oxygen (HBO) as a new therapeutic modality for MS (summarized in Table 1). We concentrate on HBO because this therapeutic modality has generated an extremely emotional, as well as an intellectual controversy, perhaps more so than any previously proposed treatment.
This review assesses the evidence of the efficacy of hyperbaric oxygen in multiple sclerosis. Material & methods – We used a list of predefined criteria for good methodology and interpreted the results of 14 identified controlled trials with emphasis on the quality. Results – At least eight trials can be considered to have a reasonable to high quality. In one of these 8 trials the results were in favour of hyperbaric oxygen treatment; the others found no clear positive effects. The patients had chronic progressive or chronic stable multiple sclerosis. In most trials, hyperbaric oxygen was supplied at pressures of 1.75 – 2 ATA, during 20 sessions of 90 min in 4 weeks. The principle endpoint was the (Expanded) Disability Status Score [(E)DSS] and the Functional Status Score as described by Kurtzke. Also specific outcomes such as evoked potentials were frequently used, but no consistent positive effects were demonstrated. Side effects were generally minor, ear and visual problems predominated. Conclusions – The majority of controlled trials could not show positive effects. Further evidence might consist of trials in patients with disease of recent onset or with other dosing regimens but the case for such further trials is not strong. Considering the state of affairs we cannot recommend the use of hyperbaric oxygen in the treatment of multiple sclerosis.
This review gives an overview of national registries that are currently in use for patients with multiple sclerosis (MS). The large-scale registries described herein include the Danish MS Registry, the Norwegian MS Registry, the Swedish MS Registry, the Italian MS Database Network, the North-American NARCOMS Registry, and the German MS Registry. These MS registries are extremely helpful for studying disease characteristics in large populations and monitoring the long-term outcome of disease-modifying therapies. Furthermore, an almost complete ascertainment of cases provides information on the provision of treatments, services and supplies within a given area that may be used to compare different levels of health care within and between these regions. In the long-term, MS registries monitor the health care situation of MS patients over time including the implementation of guidelines relating to care and treatment, measure the improvements that have taken place, and reveal shortages and/or misalignment in health care services. The information gathered herein is not only useful for the long-term follow-up of the individual patient, but also for society as a whole by increasing understanding of and knowledge about MS and allowing national authorities and relevant parties to make informed and relevant decisions about MS.
In acute multiple sclerosis, cranial computerized tomography (CT) may show periventricular and deep white matter contrast-enhanced lesions that are easier to see using 8 mm rather than 13 mm cranial CT sections. Follow-up studies show that the lesions evolve either to areas of density similar to the surrounding white matter or to low-density lesions. We presume they represent foci of active demyelination with extravasation of iodine through an altered blood-brain barrier. Enhanced cranial CT studies may be helpful in diagnosing acute multiple sclerosis and in following the course of the white matter lesions.
Three hundred twelve patients were entered into a long-term study of effects of hyperbaric oxygen on multiple sclerosis. The protocol called for an initial 20 treatments in either the monoplace or multiplace chamber on a daily basis followed by monthly booster treatments for 2 years. One hundred seventy neurologists and 22 institutions provided data for this study. There was no control group, but the study was based on Schumacher's postulation that a scientifically valid study to test the efficacy of a new therapy was possible by choosing patients who were definitively diagnosed with multiple sclerosis and following them up for 2 years after the imposed treatment. If the overwhelming majority of the subjects failed to get worse over the 2-year observation period, the efficacy of the treatment would be manifest. The expanded Kurtzke Disability Status Scale (EDSS) was used to assess the severity of the disease state. The dropout rate was high with only 76% (237 of 312 patients) finishing the initial 20 treatments. Twenty-two percent (69 of 312) finished 1 year of booster therapy, and 9% (28 of 312) completed 2 years of monthly boosters. The mean deterioration on the Kurtzke EDSS score was 0.93 or almost a full step from the beginning of treatment until the last evaluation. There was no difference in outcome between those who had the shortest and longest periods of time between onset of symptoms and hyperbaric oxygen treatment. Treatment pressure made no difference in outcome. Changes in the Kurtzke EDSS score bore no relationship to the use of booster treatment. Patients who were reasonably well off at the onset of treatment with initial Kurtzke EDSS scores of 1 or 2 (n = 21) deteriorated by an average of 1.7 Kurtzke points. Those patients whose initial Kurtzke EDSS scores were greater than 2 (n = 164) deteriorated on an average of 0.82 points. Of interest was that 19.5% (39 of 200) of the patients reported a temporary improvement in bladder function, but improvement was maintained in only 11 patients (5.5%) at 2-year follow-up. Fifteen patients (7.5%) indicated long-term worsening. There was no significant change in the working status of the patients following hyperbaric oxygen treatment. Although this study treated the patients in accordance with protocols reported to produce a benefit in multiple sclerosis, we were unable to substantiate any useful long-term effect of hyperbaric oxygen therapy.
The outcome of multiple sclerosis (MS), assessed according to the Kurtzke Disability Status Scale (DSS), was reviewed in 1,099 consecutive patients followed in London, Canada, between 1972 and 1984. A geographically based subgroup of 196 patients representing 90% of Middlesex County MS patients as well as a group of 197 patients seen from onset of disease were separately analysed. The clinical course was progressive from onset in 33% of the total population and in 28% of the Middlesex County subgroup. Of those with duration of 6-10 yrs, 30-40% with initially remitting disease developed progressive MS. The cross-sectional distribution of disability was bimodal with peaks at DSS 1 (no disability) and DSS 6 (assistance required for walking). Actuarial analysis showed that the median time to reach DSS 6 from onset of MS was 14.97 +/- 0.31 yrs in the total population and 9.42 +/- 0.44 yrs in the "seen from onset' subgroup. Survival was minimally altered; 87% of patients followed up to 40 yrs were still alive, although ascertainment of cases with this duration of MS was incomplete. Data describing the rate at which disability develops after the onset of a progressive phase of MS are also presented. The implications of these data in planning and interpretation of clinical therapeutic trials are discussed.
Seventeen patients with definite and progressive multiple sclerosis entered a double-blind randomized placebo-controlled therapeutic trial of hyperbaric oxygen (HBO). Exposure in monoplace chamber was 90 minutes long each time, 5 days a week, for 4 weeks. The treatment and placebo groups received 100% oxygen at 1.5 bar constant pressure or normal air at 0.1-0.2 bar, respectively. The clinical status of the patients in both groups were compared until one year after treatment. There was no benefit of HBO versus placebo according to the Kurtzke disability status scale. A lesser proportion of patients with deterioration of bowel/bladder function 12 months after therapy was the only benefit of HBO versus placebo according to Kurtzke functional systems scales. On the whole however, HBO is useless in the management of progressive forms of multiple sclerosis.
Eighty four patients with multiple sclerosis were treated in monoplace chambers with either hyperbaric oxygen at 2 atmospheres absolute or placebo. Comprehensive double blind assessment was carried out before, immediately after, and one month after treatment. There was no clinically important or significant benefit in any of the four major criteria of outcome--namely, the patient's subjective opinion, the examiner's opinion, the score on the Kurtzke disability status scale, or the time taken to walk 50 m. Out of 40 other clinical variables assessed, two (the sensory scale and timed writing with the left hand) showed a significant improvement without any subjective clinical correlate or change in any of seven other tests of left hand function. No group of symptoms was perceived by the patients as having improved more after treatment with hyperbaric oxygen than placebo. It is concluded that there is no basis for recommending hyperbaric oxygen in the treatment of multiple sclerosis.
We carried out a randomized, double-blind, placebo-controlled trial of hyperbaric oxygen therapy (HBO) in patients with chronic stable MS. Eighty-two patients were treated in a multiplace hyperbaric chamber with gas supplied by mask. Forty-one patients received 20 consecutive daily treatments of 100% O2 followed by 7 "booster" treatments in the next 6 months; 41 control patients received "air" (12.5% O2 at 1.75 atmospheres absolute). There was no significant difference in treatment and control groups in the Extended Kurtzke Disability scores, Kurtzke Functional scores, magnetic resonance imaging, or evoked potentials after the initial 20 treatments or after the boosters. HBO is not effective in treating chronic stable MS.
A randomized double-blind trial of hyperbaric oxygen (2 atmospheres absolute for 20 sessions of 90 minutes, over a period of one month) demonstrated no advantage over a placebo gas mixture in the treatment of multiple sclerosis. Of 41 patients completing the trial, 21 had been treated with oxygen, eight of whom reported improvement (two confirmed objectively). Of 20 patients in the placebo group, seven claimed improvement (four confirmed objectively). Even when patients with mild disease were considered separately, or when functional systems were assessed individually, no benefit could be shown to result from hyperbaric oxygen therapy.
The neurological features of decompression sickness, which is thought to be due to gas embolism, are similar to those of multiple sclerosis (MS). This similarity suggested the re-examination of a concept, first proposed in 1882, that the demyelination in MS is due to venous thrombosis. Unfortunately, although the plaques of MS are often perivenular, thromboses are not always present. Nevertheless, vascular theories can explain the topography of the lesions in MS. Embolism is generally associated with arterial rather than venous damage, and with neuronal infarction rather than loss of myelin. However, the intra-arterial injection of a range of substances can cause venous damage and perivenous demyelination in the brain, although it does not exactly reproduce the plaques seen in man. There is also evidence in man that fat may lodge in the microcirculation of the nervous system and cause distal perivenous oedema with the loss of myelin from axons. Since acute fat embolism may produce lesions not only in the white matter of the brain, but also in the cord, the retina, the meninges, and the skin, and since all these have been described in MS, subacute fat embolism may be the cause of MS.
Several uncontrolled studies have suggested a beneficial effect of hyperbaric oxygen on multiple sclerosis. We studied 40 patients with advanced chronic multiple sclerosis who were randomly divided into two matching groups. The experimental group received pure oxygen, and the placebo group received a mixture of 10 per cent oxygen and 90 per cent nitrogen; both groups were treated at a pressure of 2 atmospheres absolute for 90 minutes once daily, for a total of 20 exposures. Objective improvement occurred in 12 of 17 patients treated with hyperbaric oxygen and in 1 of 20 patients treated with placebo (P less than 0.0001). Improvement was transient in seven of the patients treated with oxygen and long-lasting in five. Those with less severe forms of the disease had a more favorable and lasting response. At one year of follow-up, deterioration was noticed in 2 patients (12 per cent) in the oxygen group, neither of whom had had an initial response, and in 11 patients (55 per cent) in the placebo group, one of whom had had a positive initial response (P less than 0.0008). Minor ear problems and reversible myopia were the only side effects observed. These preliminary results suggest a positive, though transient, effect of hyperbaric oxygen on advanced multiple sclerosis, warranting further study. This therapy cannot be generally recommended without longer follow-up periods and additional confirmatory experience.
One method of evaluating the degree of neurologic impairment in MS has been the combination of grades (0 = normal to 5 or 6 = maximal impairment) within 8 Functional Systems (FS) and an overall Disability Status Scale (DSS) that had steps from 0 (normal) to 10 (death due to MS). A new Expanded Disability Status Scale (EDSS) is presented, with each of the former steps (1,2,3 . . . 9) now divided into two (1.0, 1.5, 2.0 . . . 9.5). The lower portion is obligatorily defined by Functional System grades. The FS are Pyramidal, Cerebellar, Brain Stem, Sensory, Bowel & Bladder, Visual, Cerebral, and Other; the Sensory and Bowel & Bladder Systems have been revised. Patterns of FS and relations of FS by type and grade to the DSS are demonstrated.
After a review of theories on the aetiopathogenesis of multiple sclerosis and the theoretical basis of present day therapy of the disease, the known results of general hyperbaric oxygen treatment are listed. A detailed description of the therapeutic action of hyperbaric oxygen therapy (HOT) in multiple sclerosis and the biological theory behind the treatment follows. Finally the results obtained on 1000 patients treated in the 1977-81 period are reported.
This review assesses the evidence of the efficacy of hyperbaric oxygen in multiple sclerosis. Material & methods - We used a list of predefined criteria for good methodology and interpreted the results of 14 identified controlled trials with emphasis on the quality. Results - At least eight trials can be considered to have a reasonable to high quality. In one of these 8 trials the results were in favour of hyperbaric oxygen treatment; the others found no clear positive effects. The patients had chronic progressive or chronic stable multiple sclerosis. In most trials, hyperbaric oxygen was supplied at pressures of 1.75-2 ATA, during 20 sessions of 90 min in 4 weeks. The principle endpoint was the (Expanded) Disability Status Score [(E)DSS] and the Functional Status Score as described by Kurtzke. Also specific outcomes such as evoked potentials were frequently used, but no consistent positive effects were demonstrated. Side effects were generally minor, ear and visual problems predominated. Conclusions - The majority of controlled trials could not show positive effects. Further evidence might consist of trials in patients with disease of recent onset or with other dosing regimens but the case for such further trials is not strong. Considering the state of affairs we cannot recommend the use of hyperbaric oxygen in the treatment of multiple sclerosis.
To evaluate clinical and MRI effects of natural interferon beta treatment in both relapsing-remitting (RR) and secondary-progressive (SP) multiple sclerosis patients.
A double-blind, randomized trial of natural interferon beta (nIFN-beta) in 58 ambulatory patients with RR and 40 with SP multiple sclerosis. Forty-nine patients (29 RR and 20 SP) were treated with intramuscular nIFN-beta6 MIU three times a week for 24 months and 49 control patients were treated with placebo.
Primary clinical endpoints were differences in exacerbation rates and proportion of patients remaining exacerbation-free. There were no significant baseline differences between the treated and placebo groups. In the treated RR group a significant reduction in exacerbation rate, an increase in the probability of remaining exacerbation-free, and an improvement in mean EDSS were found at 24 months. MRI activity and total lesion burden were significantly reduced in treated RR patients. In the SP group, nIFN-beta produced a significant reduction in EDSS score, a significant reduction in active lesion number, a marginally significant favourable difference in total lesion burden but no significant effect on the number of gadolinium-enhancing lesions. Side effects were transient and mild in treated patients.
These observations confirm that nIFN-beta is a promising and well-tolerated treatment for either RR or SP MS patients.
Recent phase III clinical trials of immunomodulatory therapies in relapsing-remitting multiple sclerosis have shown significant benefits of active treatment on relapse related end points, but effects on disability outcomes have been inconsistent. These apparent discrepancies could be due to differences in the clinical end points employed, the behaviour of placebo cohorts, or both.
Disability data from the placebo cohorts of two large phase III studies, the United States glatiramer acetate trial (Copolymer 1 Multiple Sclerosis Study Group) and the multinational interferon beta-1a trial (PRISMS Study Group) were combined and masked (n = 313). Two groups of disability outcome measures were assessed. Firstly, measures of disability change (2 year EDSS difference and area under the EDSS/time curve, AUC) were calculated. Secondly, conventional disease progression end points ("confirmed progression" and "worsening to EDSS 6.0") were evaluated by using Kaplan-Meier analysis and compared with a categorical classification based on EDSS trends.
The average increase in disability for the entire cohort as assessed by mean 2 year EDSS change (<0.5 EDSS point) or mean AUC (+0.57 EDSS-years) was small. For the "confirmed progression" end points, increasing the stringency of the definition lowered their incidence (from 32% with 1.0 point at 3 months, to 9% with 2.0 points at 6 months), but did not improve the positive predictive accuracy for "sustained progression" maintained to the end of the study. The error rate for this outcome was about 50%. Worsening to EDSS 6.0 was a more reliable end point, but had even lower sensitivity (incidence <10%). EDSS trend analysis showed markedly heterogeneous disease courses, which were then categorised into "stable" (26%), "relapsing-remitting" (59%), and "progressive" (15%) courses. Patients with the last course had deteriorated considerably by the end of 2 years (mean worsening of 2.0 EDSS points).
In relapsing-remitting multiple sclerosis treatment trials, the conventional measure of mean EDSS change has low sensitivity, whereas the widely applied confirmed progression end points have high error rates regardless of their definition stringency. Alternative methods with better data utilisation include AUC summary measures and categorical disease trend analysis. The heterogeneity of disability outcomes in short trials, combined with unreliable clinical end points, diminishes the credibility of therapeutic claims aimed at reducing irreversible neurological deficits. The behaviour of patients treated with placebo should be carefully analysed before conclusions are drawn on the efficacy of putative treatments.
Multiple sclerosis is currently an incurable disease and there is much interest in developing new disease-modifying treatments and testing them in clinical trials. Because therapies are essentially partially effective, neurologists have to develop ways to assess whether the medication they test slows down the course of the disease. Promising treatments selected for Phase III clinical trials are first tested in Phase I/II studies, where preliminary evidence of efficacy is demonstrated in the absence of severe adverse events. Phase III clinical trials are designed to detect significant differences between responses to active therapies and a placebo or a marketed drug. The selection and usage of instruments to detect changes in patients is probably the most important issue in their design. The purpose of this paper is to discuss methodological problems of evaluating drug efficacy in phase III MS trials, including the characteristics of the ideal instrument to measure progression of the disease, the strengths and limitations of existing clinical, radiologic and laboratory outcome measures.
T1 hypointense lesions (T1 black holes) are focal areas of relatively severe CNS tissue damage detected by MRI in patients with MS.
To determine the natural history of T1 hypointense lesions in relapsing MS and the utility of T1 hypointense lesions as outcome measures in MS clinical trials.
MR studies were from the Multiple Sclerosis Collaborative Research Group trial. Longitudinal results are reported in 80 placebo- and 80 interferon beta-1a (IFNbeta-1a)-treated patients with mild to moderate disability relapsing-remitting MS.
There was a small but significant correlation between T1 hypointense lesion volume and disability at baseline and on trial (r = 0.22, r = 0.28). In placebo patients there was a 29.2% increase in the mean volume of T1 hypointense lesions (median 124.5 mm3) over 2 years (p < 0.001 for change from baseline), as compared to an 11.8% increase (median 40 mm3) in the IFNbeta-1a-treated patients (change from baseline not significant). These treatment group comparisons did not quite reach significance. The most significant contributor to change in T1 hypointense lesions was the baseline number of enhancing lesions (model r2 = 0.554). Placebo patients with more active disease, defined by enhancing lesions at baseline, were the only group to show a significant increase in T1 hypointense lesion volume from baseline.
The development of T1 hypointense lesions is strongly influenced by prior inflammatory disease activity, as indicated by enhancing lesions. These results suggest that treatment with once weekly IM IFNbeta-1a (30 mcg) slows the 2-year accumulation of these lesions in the brain.
To examine MRI changes resulting from treatment of secondary progressive MS (SPMS) with two doses of interferon-beta-1a (Rebif).
Interferon-beta (IFN-beta) reduces relapses and delays progression in relapsing-remitting MS, but there are conflicting results on its clinical benefit in SPMS.
In a double-blind, randomized, multicenter, placebo-controlled study (SPECTRIMS), 618 patients received IFN-beta-1a 22 microg, 44 microg, or placebo subcutaneously three times weekly for 3 years. T2 activity and burden of disease (BOD) were measured in 617 patients by using semiannual proton density/T2-weighted (PD/T2) MRI scans. A cohort of 283 patients also had 11 monthly PD/T2 and T1-weighted gadolinium-enhanced (T1-Gd) scans at study start.
Treatment reduced median numbers of active lesions per patient per scan (semiannual T2 activity: 0.17, 0.20 and 0.67 for the high dose, low dose, and placebo, p < 0.0001; monthly combined unique activity [T1+T2]: 0.11, 0.22, and 1.00, p < 0.0001) and accumulation of BOD (percent change from baseline to month 36: -1.3, -0.5, and 10.0 for the high dose, low dose, and placebo, respectively; p = 0.0001). MRI benefit was most evident in the subgroup of patients who reported relapses in the 2 years before the study. Neutralizing antibody development was associated with reduction in treatment effect: antibody-positive patients did not show significant differences from placebo at either dose.
Interferon-beta-1a used in SPMS showed significant effects on all MRI measures, particularly in patients with relapses in the 2 years before the study.
Glucocorticoids: 1. On the basis of several and generally consistent Class I and Class II studies, glucocorticoid treatment has been demonstrated to have a short-term benefit on the speed of functional recovery in patients with acute attacks of MS. It is appropriate, therefore, to consider for treatment with glucocorticoids any patient with an acute attack of MS (Type A recommendation). 2. There does not appear, however, to be any long-term functional benefit after the brief use of glucocorticoids in this clinical setting (Type B recommendation). 3. Currently, there is not compelling evidence to indicate that these clinical benefits are influenced by the route of glucocorticoid administration, the particular glucocorticoid prescribed, or the dosage of glucocorticoid, at least at the doses that have been studied to date (Type C recommendation). 4. On the basis of a single Class II study, it is considered possible that regular pulse glucocorticoids may be useful in the long-term management of patients with RRMS (Type C recommendation). Interferon beta: 1. On the basis of several consistent Class I studies, IFNβ has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with MS or with clinically isolated syndromes who are at high risk for developing MS (Type A recommendation). Treatment of MS with IFNβ produces a beneficial effect on MRI measures of disease severity such as T2 disease burden and probably also slows sustained disability progression (Type B recommendation). 2. As a result, it is appropriate to consider IFNβ for treatment in any patient who is at high risk for developing CDMS, or who already has either RRMS or SPMS and is still experiencing relapses (Type A recommendation). The effectiveness of IFNβ in patients with SPMS but without relapses is uncertain (Type U recommendation). 3. It is possible that certain populations of MS patients (e.g., those with more attacks or at earlier disease stages) may be better candidates for therapy than others, although, at the moment, there is insufficient evidence regarding these issues (Type U Recommendation). 4. On the basis of Class I and II studies and several pieces of consistent Class III evidence, it is considered probable that there is a dose-response curve associated with the use of IFNβ for the treatment of MS (Type B recommendation). It is possible, however, that a portion of this apparent dose-effect instead may be due to differences in the frequency of IFNβ administration (rather than dose) between studies. 5. On the basis of several Class II studies, the route of administration of IFNβ is probably not of clinical importance, at least with regard to efficacy (Type B recommendation). The side-effect profile, however, does differ between routes of administration. There is no known clinical difference between the different types of IFNβ, although this has not been thoroughly studied (Type U recommendation). 6. On the basis of several Class I studies, treatment of patients with MS with IFNβ is associated with the production of NAb (Type A recommendation). The rate of NAb production, however, is probably less with IFNβ-1a treatment than with IFNβ-1b treatment (Type B recommendation). The biologic effect of NAb is uncertain, although their presence may be associated with a reduction in clinical effectiveness of IFNβ treatment (Type C recommendation). Whether there is a difference in immunogenicity between subcutaneous and intramuscular routes of administration is unknown (Type U recommendation). The clinical utility of measuring NAb in an individual on IFNβ therapy is uncertain (Type U recommendation). Glatiramer acetate: 1. On the basis of Class I evidence, glatiramer acetate has been demonstrated to reduce the attack rate (whether measured clinically or by MRI) in patients with RRMS (Type A recommendation). Treatment with glatiramer acetate produces a beneficial effect on MRI measures of disease severity, such as T2 disease burden, and possibly also slows sustained disability progression in patients with RRMS (Type C recommendation). 2. As a result, it is appropriate to consider glatiramer acetate for treatment in any patient who has RRMS (Type A recommendation). Although it may be that glatiramer acetate also is helpful in patients with progressive disease, there is no convincing evidence to support this hypothesis (Type U Recommendation). Cyclophosphamide: 1. Based on consistent Class I evidence, pulse cyclophosphamide treatment does not seem to alter the course of progressive MS (Type B recommendation). 2. Based on a single Class III study, it is possible that younger patients with progressive MS might derive some benefit from pulse plus booster cyclophosphamide treatment (Type U recommendation). Methotrexate: 1. Based on limited and somewhat ambiguous Class I evidence from a single trial, it is considered possible that methotrexate favorably alters the disease course in patients with progressive MS (Type C recommendation). Azathioprine: 1. On the basis of several, but somewhat conflicting, Class I and II studies, it is considered possible that azathioprine reduces the relapse rate in patients with MS (Type C recommendation). 2. Its effect on disability progression has not been demonstrated (Type U recommendation). Cladribine: 1. On the basis of consistent Class I evidence, it is concluded that cladribine reduces Gd enhancement in patients with both relapsing and progressive forms of MS (Type A recommendation). 2. Cladribine treatment does not, however, appear to alter favorably the course of the disease, either in terms of attack rate or disease progression (Type C recommendation). Cyclosporine: 1. Based on this Class I study, it is considered possible that cyclosporine provides some therapeutic benefit in progressive MS (Type C recommendation). 2. However, the frequent occurrence of adverse reactions to treatment, especially nephrotoxicity, together with the small magnitude of the potential benefit, makes the risk/benefit of this therapeutic approach unacceptable (Type B recommendation). Mitoxantrone: 1. On the basis of generally consistent Class II and III studies, it is concluded that mitoxantrone probably reduces the attack rate in patients with relapsing forms of MS (Type B recommendation). The potential toxicity of mitoxantrone, however, may outweigh the clinical benefits early in the course of disease. 2. On the basis of several Class II and III observations, it is considered possible that mitoxantrone has a beneficial effect on disease progression in MS, although, at the moment, this clinical benefit has not been established (Type C recommendation). Intravenous immunoglobulin: 1. The studies of intravenous immunoglobulin (IVIg), to date, have generally involved small numbers of patients, have lacked complete data on clinical and MRI outcomes, or have used methods that have been questioned. It is, therefore, only possible that IVIg reduces the attack rate in RRMS (Type C recommendation). 2. The current evidence suggests that IVIg is of little benefit with regard to slowing disease progression (Type C recommendation). Plasma exchange: 1. On the basis of consistent Class I, II, and III studies, plasma exchange is of little or no value in the treatment of progressive MS (Type A recommendation). 2. On the basis of a single small Class I study, it is considered possible that plasma exchange may be helpful in the treatment of severe acute episodes of demyelination in previously nondisabled individuals (Type C recommendation). Sulfasalazine: 1. Based on a single Class I study, it is concluded that treatment of MS with sulfasalazine provides no therapeutic benefit in MS (Type B recommendation).
In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.
In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.
There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).
In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
Multiple sclerosis is a chronic inflammatory and demyelinating disease of the central nervous system. Although the immune system seems to play an important role in its pathogenesis, target antigens are still uncertain and pathways leading to tissue destruction have not been fully elucidated. Recent studies have significantly contributed to better understanding of the disease process and broadened our view on possible scenarios of disease initiation and progression. Here, we review the role of the immune system in the manifestation and evolution of MS and discuss different pathogenetic concepts. We conclude with an outlook on future strategies for identifying the cause of MS.