User:Philip B. James

Monosclerosis or Mono Sclerosis and Multiple Sclerosis

Summary The current emphasis on the use of drugs to manage the chronic disease known as multiple sclerosis has diverted attention from improving the treatment of patients with the first episode. This is clearly important because it may lead to permanent disability and a treatment that is successful at this stage may prevent progression of the scarring known as sclerosis. Magnetic Resonance Imaging (MRI), has shown that the sclerosis begins as a Micro-vascular Syndrome with oedema from failure of the blood-brain barrier and evidence in real time that brain cells lack the oxygen essential for remission, has been overlooked. However, the research awarded the 2019 Nobel prize for physiology or medicine shows that this oxygen deficiency, known as 'hypoxia', up-regulates the genes that promote inflammation, which is the immune response involved in the tissue damage in multiple sclerosis. As oxygen, is the only agent to show benefit in patients with the chronic disease it should be prescribed to treat the hypoxia present in the first attack. The equipment to provide 100% oxygen has already been commissioned for a neurological disease by NHS Trusts in the UK.

History The first mention of the typical changes that precede sclerosis in the nervous system was by Dr. R. Clutterbuck in the Lancet in 18261 and pathologists in the early 20th century expanded on his observations using the term 'Disseminated Sclerosis' because they was felt that a blood-borne agent is involved. Imaging in the 1980s confirmed that the first event in the underlying disease does involve the small blood vessels of the nervous system but, nevertheless the disease is now known as Multiple Sclerosis (MS). By 1942 a typical lesion surrounding a vein had been reconstructed by serial sections by pathologists Dow and Berglund.2 Since the 1980s, imaging has been used to follow the sequence of events of attacks in the disease underlying the development of MS and the key information it has provided offers the possibility of reducing or even preventing the sclerosis. Computed Tomography (CT) has shown the reduction of tissue density in a typical lesion that follows the replacement of structural elements, such as myelin by water.3 Using the injection of dye, CT has also shown that leakage from a blood vessel begins an attack and may even precede the development of symptoms.4

MRI: MS is a Micro-vascular Syndrome Magnetic resonance techniques were first used in chemical analysis and scanners used the computer programmes developed for CT to gain much greater resolutions. Magnetic Resonance Imaging (MRI) has confirmed the microscopic observation made by Rindfleisch in Zürich in 1863,5 that the bright spots seen on MRI black and white images that begin the formation of sclerosis surround a small vein.6 The events demonstrated by imaging in the living patient clearly indicate that the disease underlying the development of both multiple and mono sclerosis7 are a 'Micro-vascular Syndrome' and the immune changes are secondary: They are found at the same level as multiple sclerosis in stroke8 and even after a head injury. Vascular damage, associated with failure of the Blood-brain Barrier, seen as bright spots on MRI is consistent with fluid micro-embolism which is a well-established mechanism that can account for single and multiple lesions.9,10 MRI has also shown that opening of the barrier initiates the animal model adopted for MS research, Experimental Allergic Encephalomyelitis (EAE), which uses mineral oil micro-embolism.11

Pathologists identified single lesions in the nervous system at autopsy many years ago and MRI has been used to image patients with a single symptom, said to be suffering from a 'Clinically Isolated Syndrome'. Examples are the changes of vision known as 'optic neuritis' and the paraplegia that follows damage across the spinal cord called 'transverse myelitis.' MRI has shown that many such patients already have multiple areas affected12 but, despite this, a diagnosis of multiple sclerosis is not possible for three reasons: First; the diagnostic criteria13 require at least two attacks to be multiple with the lesions disseminated in space, that is, located in two places in the nervous system. Second, they must be separated by a minimum interval of a month and third; there must be objective evidence of disability on clinical examination. Unfortunately, these entirely arbitrary stipulations ensure that multiple lesions are present and chronic illness has developed before treatment is considered and the delays introduced by the so-called diagnosis are usually measured in years.

MRI: 'Bright Spots' in the Brain are Common

Serial brain MR imaging has been used over several months to follow multiple sclerosis patients said to be in remission and found disease activity still present14 with the typical 'bright spots' coming and going over the months of the study: Clearly the blood vessel damage can heal. A dramatic increase in the use of MRI and improvements in resolution have shown that ‘bright spots’ are actually common in the general population: In fact, they are seen so frequently that some doctors have been tempted to say they are normal. They are not being associated with many brain diseases and injuries and their numbers increase with age. They are found in the dementia attributed to thrombo-embolism from arterial atheroma.15 The bright spots are usually in the deep white matter of the brain and are either referred to as 'Unidentified Bright Objects', UBOs (a pun on UFOs), or 'White Matter Hyperintensities' (WMHs). The changes may heal or cause pathology i.e. sclerosis.

Although the reasons for the localisation of the bright spots in the white matter have recently been discussed,16 it has yet to be recognised that material carried in blood may cause them by damaging the Blood-brain Barrier.17 If the damage to the complex mechanisms maintaining the barrier18 do not recover, patients are left vulnerable to a wide variety of the agents carried in blood which may cause symptoms to recurr.19 However, this localisation to white matter does not apply to the spinal cord, where grey and white matter are equally affected.20  Objective evidence of disability by an "expert neurologist" is - a requirement for the diagnosis of multiple sclerosis - is rarely produced by lesions in the white matter of the hemispheres of the brain. However, damage to the optic nerves, the brain stem and the spinal cord is associated with disability that can usually be detected on clinical examination.

Oxygen and Gene Regulation

A remarkable development of MRI, Magnetic Resonance Spectroscopy (MRS), was used as long ago as 199321 to follow the biochemical changes in a new 'bright spot' in a patient already labelled as having multiple sclerosis. It identified a 'Lactate peak' and the presence of lactate, or lactic acid, is accepted as being due to the failure of oxygen delivery known as 'hypoxia'. This has since been confirmed but has not led to patients being treated with additional oxygen for attacks: Healing is not yet understood to be oxygen-dependent.

However, the latest research has shown that a fall in the oxygen available to cells is, paradoxically, associated with the up-regulation of a master protein, Hypoxia-inducible Factor 1 (HIF-1) which controls inflammation,22 recognised to be the cardinal feature of multiple sclerosis. As MRI has shown bright spots to be associated with hypoxia and, experimentally, the oxygen levels associated with disability and remission have been determined 23, using more oxygen in treatment may improve remission and prevent a first episode leading to disabling sclerosis. Hyperbaric oxygen treatment is used pilots, divers and astronauts.24 However, the USAF begins treatment with 100% oxygen by a tight fitting mask at ground level only using a pressure chamber if this is not successful.25 This approach has been now commissioned by the NHS in the UK for the neurological disease causing cluster headache. There is no substitute for oxygen and hyperbaric oxygen treatment is the only intervention to produce benefit in patients in a matched double-blind controlled study of patients with chronic multiple sclerosis, despite disease durations ranging from 6 to 27 years.26

Philip B. James MB ChB DIH PhD FFOM Emeritus Professor of Medicine University of Dundee Scotland UK.

References

1. Clutterbuck R. On diseases of the spinal marrow. Lancet 1826;12:648-652. 2. Dow RS, Berglund G. Vascular patterns of lesions of multiple sclerosis. Arch Neurol Psychiat 1942;47:1-18. 3. Aita JF, Bennett DR, Anderson RE, Ziter F. Cranial CT appearance of acute multiple sclerosis. Neurology 1978; 28: 251-55. 4. Sears ES, Tindall RSA, Zarnow H. Active multiple sclerosis: enhanced computerized tomographic imaging of lesions and the effect of corticosteroids. Arch Neurol 1978;35:426-434. 5. Rindfleisch E. Histologisches Detail zu der grauen Degeneration von Gehirn und Ruckenmark. Arch Pathol Anat Physiol Klin Med 1863;26:474-483. 6. Ge Y, Zohrabian VM, Grossman RI. Seven-Tesla magnetic resonance imaging: a new vision of microvascular abnormalities in multiple sclerosis. Arch Neurol 2008;65:812-816. 7. James PB. MRI, monosclerosis and multiple sclerosis. Lancet 2002;359:1436. 8. Wang WZ, Classon T, Kostulas V, et al. Myelin antigen reactive T cells in cerebrovascular disease. Clin Exp Immunol 1992;88:157-62. 9. James PB. Evidence for subacute fat embolism as the cause of multiple sclerosis. Lancet 1982;i:380-386. 10. James PB. Hyperbaric oxygenation in fluid microembolism. Neuro Res 2007;29:56-59. 11. Maggi P, Sati P, Massacesi L. Magnetic resonance imaging of experimental autoimmune encephalomyelitis in the common Marmoset. J Neuroimmunol 2017;304: 86-92 12. Ormerod IEC, Miller DH, McDonald WI, et al. The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions. Brain 1987;110:1579-616. 13. Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983;53: 227-31. 14. Harris JO, Frank JA, Patronas N, et al. Serial gadolinium-enhanced magnetic resonance imaging scans in patients with early, relapsing-remitting multiple sclerosis; implications for clinical trials and natural history. Ann Neurol 1991;29:548-555. 15. Wardlaw JM, Valdés Hernández MC, Muñoz-Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. Am J Heart Assoc 2015;4:e00140. 16. Martorella SM, Blázquezb MC, Figueredob JC, et al. Hyperintense punctiform images in the white matter: A diagnostic approach. Radiología 2012;54:321-325 17. Hills BA, James PB. Microbubble damage to the blood-brain barrier: relevance to decompression sickness. Undersea Biomed Res 1991;18:111-116. 18. Foroutan S, Brillault J, Forbush B, O'Donnell M. Moderate to severe ischemic conditions increase activity and phosphorylation of the cerebral mirovascular endothelial NA+ - K+ - Cl- cotransporter. Am J Physiol Cell Physiol 2005;289:C1492-1501. 19. James PB. Multiple sclerosis or blood-brain barrier disease. Lancet 1989;i:46. 20. Putnam TJ, Alexander. Loss of axis-cylinders in sclerotic plaques and similar lesions. Arch Neurol Psychiatry 1947;57:661-672. 21. Miller DH, Austin SJ, Connelly A, et al. Proton magnetic resonance spectroscopy of an acute and chronic lesion in multiple sclerosis. Lancet 1991;337: 58–59. 22. Eltzshig HK, Carmeliet P. Hypoxia and inflammation. N Eng J Med 2011; 364:656-665. 23. US Navy Diving Manual Revision 7. SS521-AG-PRO-010, 2016. 24. Davies AL. Desai RA, Bloomfield PS, et al. Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann Neurol 2013;74:815-825. 25. Krause KM, Pilmanis AA. The effectiveness of ground level oxygen treatment for altitude decompression sickness in human research subjects. Aviat Space Environ Med 2000;71:115-118. 26. Fischer BH, Marks M, Reich T. Hyperbaric oxygen treatment of multiple sclerosis: a randomised, placebo controlled, double-blind study. N Engl J Med 1983; 308: 181–86.