HBOT THERAPY FOR HEAD, NECK, AND BRAIN TISSUE NECROSIS

    HEAD AND NECK

    When the head and neck are treated with radiation, either through radioactive implants or stereotactic radiosurgery, the inside of the mouth can become dry and inflamed, with loss of taste, increased susceptibility to dental cavities, and bone damage leading to tooth loss. Treating the nose and throat can damage the brain, the optic nerve, soft neck tissue, and the pituitary gland. Incidental damage to the thyroid gland, or the effects of intentional internal or external radiation, have not yet been fully evaluated.

    Brandt and Balinoff reported the immediate successful placement of dental implants and appliance in a 45-year-old male with a history of squamous cell cancer of the floor of the mouth. After a course of pre- and post-surgical hyperbaric treatment, the patient was symptom-free after 39 months of his implantation with no sign of rejection.

    Radiation therapy can also be associated with bone damage and bone death. The study of Micas,Rodriguez, Fortez and Desota from Spain showed statistically significant positive results in preventing osteoradionecrosis (radiation-induced bone death) when using HBOT for several months before tooth extraction.

    Donovan, Huynh, Purdom, Johnson, and Sniezek reported the difficulties for patients who suffer damage to the cervical spine following radiation treatment of the head and neck. Two of three patients studied had osteomyelitis (bone inflammation) which required surgery to reconstruct the spine, followed by HBOT. The spine was stabilized, and neurological function resolved. In a third, less severe case, HBOT was used alone, with improved symptoms and imaging.

    Although retinal nerves in the eye are resistant to radiation damage, retinal blood vessel damage can cause visual disturbances or blindness in up to 63% of patients whose eyes are treated.

When patients with optical neuropathy received HBOT, different studies showed improvement in 27%, 54%, and 68%. Quick treatment of visual symptoms is often critical in determining the success of HBOT.

When the larynx (voice box), head, neck, or chest wall have been treated with radiation, HBOT can result in significant or total resolution of pain, swelling, and tissue death and often enable speech.

     MANDIBULAR NECROSIS

    In the past, hyperbaric oxygen has been very successful in the treatment of delayed radiation-induced soft tissue and bony necrosis (tissue death). Although it seems least successful in the treatment of neurologic (central nervous system injuries), other treatments are also ineffective. The application which has had the earliest and most extensive study is for mandibular osteonecrosis, the death of jawbone tissue subsequent to irradiation and/or tooth extraction.

    In the 1970s, the results of using HBOT for treating mandibular radiation necrosis were mixed. It wasn’t until the development of an individualized response-driven staging system integrated with surgery that HBOT became the unexcelled leader in effective mandibular reconstructive treatment.

Stage	Symptoms	Treatments	Surgery	Response(good)
1	Mandibular necrosis	30 HBOT treatments at 2.4 ATA for 90 minutes each	Minor debridement	10 additional HBOT treatments
2	Non-response to stage 1 treatment	Debridement plus 10 additional HBOT treatments	-	-
3	Non-response to stage 1 treatment with fistulae, fracture, or resorption of jawbone	Resection, reconstruction plus 10 post-reconstructive HBOT sessions	8 weeks external jaw fixation	-

Studies show hyperbaric is an effective post-surgery treatment for existing osteoradionecrosis (delayed bone tissue death resulting from radiation), providing improvement in up to 83.6% of cases where surgical intervention may or may not have accompanied the treatment. These studies include earlier cases where necrotic tissue was not aggressively removed and misaligned bone was not corrected. In studies including surgical support, Marx reported 100% success, which included not only healing of the bone, but the functional ability to support dentures and chew food.

    In comparing the use of penicillin to HBOT before extractions to prevent necrosis in heavily radiated jaws (greater than 6800 cGy), Marx found that 29.9% of penicillin group patients suffered necrosis, compared to only 5.5% of the HBOT group

    Hyperbaric oxygen treatment has been used to minimize and reverse blood vessel and supportive tissue damage by reducing swelling and scar tissue formation and encouraging the body to develop new capillaries into the radiated tissues. When proper levels of oxygen and nutrients are delivered, tissues heal more effectively, and necrosis can be avoided.

Patients studied	Protocol	# of osteoradionecrosis cases	%
37	1 million units of penicillin prior to surgery and 500 mg. daily for 10 days	11	29.9%
37	20 HBOT treatments prior to surgery and 10 after extractions	2	5.5%

    Further studies supported these findings.

     LARYNGEAL NECROSIS

    Radiation-induced laryngeal necrosis is not a common complication, occurring less than 1% of the time in a well-designed radiation treatment program. Higher treatment-fraction doses, higher total doses, and the use of neutron irradiation increase its incidence. When subsequent tissue swelling persists, laryngectomy (removal of the voice box) has often been the only choice. This has been selected for two reasons: 1) persistent swelling suggested the presence of cancerous tissue; and 2) an effective way to reverse chondronecrosis (the death of the cartilaginous tissues of the larynx) was not known. The result of either of these conditions can be swelling, constriction of the airway, foul breath, and the continued production of dead tissue.

    Biopsy is often inaccurate and may further aggravate the necrotic process, although it may be required to rule out tumor recurrence. Studies have shown that laryngectomy may not be required to resolve this problem. In three trials, only six of thirty-five patients treated with hyperbaric oxygen required laryngectomy—the remainder maintained their voice box, often with good voice quality.

     OTHER HEAD AND NECK SOFT-TISSUE NECROSIS

    In Hyperbaric Medicine Practice, Marx reported his experience using hyperbaric oxygen in a controlled, but not randomized treatment of head and neck soft-tissue radionecrosis. In this instance, some patients lived too far away, could not afford, or refused hyperbaric treatment. Except for HBOT, all other aspects of treatment for the two heavily irradiated surgical resection or flap reconstruction groups was identical.

Group	Treatment	Wound infection	Wound dehiscence (rupture)	Delayed wound healing
HBOT (160 patients)	20 pre-operative HBOT treatments at 2.4 ATA followed by 10 post-operative HBOT treatments	6%	11%	11%
No HBOT		24%	48%	55%

    A case series by Davis using HBOT for resolution of the necrosis reported success in fifteen of sixteen patients. A 1997 study by Neovius reported that twelve of fifteen experienced total healing, two improved, and one had no benefit from hyperbaric oxygen treatment. In the control group, only seven healed completely and two hemorrhaged, one of those bleeding to death as a result of the wound eroding into a major blood vessel.

    Clearly, HBOT is worth considering to resolve head and neck soft-tissue necrosis.

     TREATMENT OF BRAIN TUMORS AND AVMS

    In the United States, approximately 35,000 new intracranial tumor cases are diagnosed each year—15,000 are primary brain tumors, the remainder metastasize from tumors in other locations. Many of the brain tumors diagnosed each year are treated with radiation therapy to destroy or shrink the tumor.

    Radiation is also used to eliminate arteriovenous malformations (AVMs), defective blood vessel formations. Lynn and Friedman reported successgul treatment of a man with post radiosurgical swelling. After 25 hyperbaric oxygen treatments, he was able to successfully reduce his steroid usage. A year kater, the arteriovenous malformations was healed and the patient suffered minimal neurological impact.

    Feldmeier outlines six published reports about the application of HBOT to brain necrosis. Hart and Mainous reported that a single HBOT-treated patient improved. Chuba mentioned that all ten patients experienced temporary improvement of symptoms, although four later died from their malignancy. Long term, five of the six survivors maintained their gains. Lever reported the results for two patients with radiation-induced necrosis resulting from the treatment of arteriovenous malformations (misformed blood vessels). Both improved; one showed complete resolution according to serial MRI studies. Cirafisi and Verderamac presented the case of a patient who did not respond to hyperbaric oxygen—nor did the patient respond to steroids and anticoagulants.

    Gesell presented comprehensive results at the 2002 Meeting of the Undersea and Hyperbaric Medical Society, showing improvement in seventeen of twenty-nine patients, with 20 able to reduce steroid use. Dear’s research showed the comparative effectiveness dependent on the type of tumor—only one of eleven with gioblastoma multiforme, an extremely malignant, fast-spreading, and often recurring cancer, improved. Of note is that seven of those eleven died shortly after HBOT treatment due to a recurrence or the growth of previously undetected tumors. In those patients that Dear researched who did not have gioblastoma multiforme, eight of nine had subjective improvement, three of these had improvement which could be medically confirmed.

    Four publications Feldmeier reviewed reported the results of HBOT applied to radiation-induced optic neuritis. Guy and Schatz emphasized the importance of prompt treatment—two of their patients had complete restoration of their sight, but were treated within seventy-two hours of the start of their symptoms. Two other patients who began hyperbaric treatments at two weeks and six weeks after vision loss had no improvement. Borruat noted that one patient with bilateral optic neuritis (inflammation of the optic nerve) recovered complete vision in the most recently affected eye, but not in the eye which had been injured in the past. In the case of radiation-induced optic neuritis, it is apparent that there is a limited time window where hyperbaric oxygen treatment can restore sight.

    Pritchard completed a randomized controlled investigating the effect of hyperbaric oxygen treatment on radiation-induced brachial plexopathy, where delayed radiation damage results in reduced sensory and motor function in the arms. In this study, the median time between onset of symptoms and hyperbaric treatment was eleven years. Patients failed to demonstrate a therapeutic improvement in neuropathic function, although the patients who were treated showed a statistically significant reduction in the rate of deterioration and six showed reduced swelling in the affected arm as compared with the control group.

    Radiation therapy may be a critical component of intracranial tumor management. While it is invaluable in treating malignancies, the potential for long term side effects raises questions for benign (non-cancerous) tumors, with the incidence of visual, pituitary and brain tissue damage as high as 38%. For malignant tumors, new or continuing symptoms may be the result of the original tumor spreading (metastasis), radiation damage, or the development of new cancer. Chemotherapy seems to aggravate the deleterious effects of radiation.

     DANGERS OF BRAIN IRRADIATION

    Radiation treatment of large brain areas can result in memory loss, impaired thinking ability (cognition), reduced sexual desire, hormonal changes, personality disturbance, sleep disruption, poor cold tolerance, nausea, unsteadiness, and visual changes. Half of these patients will show brain shrinkage or increase in the non-tissue (ventricle) space. Radiation necrosis, an area of dead cells within the radiation site in the brain, may occur months or years after radiation.

    The actual damage can be very focused (focal necrosis), or throughout the white matter of the brain. Demyelination (the stripping away of the protective nerve covering), reactive gliosis (brain-specific inflammatory reactions), and coagulation necrosis (the clumping of body proteins into an inert, non-functioning mass) are observed responses.

    Both chromosomal cell damage (probably the cause of new cancers) and blood vessel damage (leading to tissue death and atrophy) may result from treatment. Less predictable is the deterioration that occurs over time, affecting not just localized brain tissue, but the death of a larger area than originally treated. Treatment-caused lesions increase from 3 to 23 months after radiation has ended—the lesions may regress, but then re-occur. Often the radiation-damaged brain shrinks in size. One theory for the continuing damage notes its similarity to the brain death cascade seen in stroke victims, where the death of cells in the brain triggers the death of adjacent cells.

    Radiation treatment of the brain inflames and damages the protective blood-brain barrier, allowing more fluid into the brain than is normal. The imbalance and presence of the fluid triggers more swelling in the enclosed skull space, building pressure. With increased pressure, blood flow is restricted, starving the portion of the brain served by the restricted blood vessels of oxygen. Without adequate oxygen, that portion of the brain begins to die.

    Most commonly, brain radionecrosis is attributed to damage within the cells lining blood vessels. Arteries narrow and become blocked—the lining thickens, loses elasticity, atrophies, and dies. The result is increased swelling and pressure, the obliteration of blood vessels, and blood supply interruption. This post-treatment blood vessel shrinking and scarring has been observed, and by itself would account for symptoms—it is the most devastating side effect of radiation therapy. Over time (post treatment!), it often causes enough damage to result in death.

    Whole brain irradiation is not a preferred treatment for patients with a single brain metastasis, because its side effects—neurological deterioration and dementia—are devastating, particularly in patients over age 60, where it affects up to 90% of radiation-treated patients. Journal of the American Medical Association researchers reported that patients receiving whole brain radiation do not remain functionally independent longer, nor do they live longer than those that have surgery alone. Cognition and hormone production abnormalities can be debilitating, potentially life threatening, and an increasingly frequent problem in brain tumor patients. These symptoms can be from progression of cancer or caused by the side effects of whole brain radiation.

    When permanent Iodine-125 seeds are implanted, up to 50% of patients suffer delayed radiation damage and radiation necrosis. Rapid tumor shrinkage can result in a greater amount of non-tumor tissue being exposed to radiation.

    In current clinical practice, focused radiation (Radiotherapy), which extends only 2-3cm beyond the periphery of the tumor site, begins immediately after surgical incision healing. Radiosurgery techniques, including Stereotatic, Gamma-Knife, Brachyradiation, and IMRT, access most areas of the brain and because of their precision, are quite suitable for treatment of metastases. Precisely targeted radiation (stereotactic therapy), supported by constantly updated CT scans, enables physicians to deliver high-dose, non-invasive, relatively well-tolerated irradiation. Boron neutron capture therapy may also be effective, but only when conventional radiotherapy has not already been used.

    Radiation of structures outside the brain may result in brain exposure. Treatment of cancers of the facial skin, nose, mouth, ears, and eyes may lead to late-onset brain effects, dementia, and death.

     SYMPTOMS OF RADIATION-INDUCED BRAIN NECROSIS

    There is extreme difficulty in determining whether a patient’s symptoms are the result of tumor recurrence, metastasis (spreading outside of the original site), or radiation necrosis. Identifiable radiation-induced necrosis occurs in 20% to 25% of patients treated for cancerous brain tumors. For large volume tumors or whole brain radiation, 40% of patients, and for localized irradiation, 3% to 9% of patients, may suffer such necrosis, seen 3 months to years after completion of treatment. Significant neurological damage can result even when treatment is not extensive.

    The extent of brain radionecrosis symptoms depends on the location of the brain which required radiation, the size of the treatment area, the total radiation dose the person was exposed to, the period of time over which treatment was administered, whether the treatment was concurrent with other treatments (e.g., chemotherapy), and individual response to therapy. The most affected areas of the brain are in the white matter. The individual response component is probably the contributing factor to the difficulty of predetermining optimal treatment.

Risk is of necrosis is increased when:

• The total radiation dose to the brain exceeds 6500-7000 cGy, with a total dose of 5500 cGy correlating with a 3-5% occurrence of radiation necrosis

• Fractionation daily dose exceeding 200 cGy also increases risk.

• Other predisposing circulatory risks including diabetes and elevated cholesterol

    Long-term radiation damage is most common in children less than 2 years of age and adults over 50. Treatment-induced destruction of the myelin sheath, cancer of the central nervous lymph system, compromise of the blood-brain barrier, and chemotherapeutic damage of the blood vessels may be seen in more than 90% of combination chemotherapy and whole-brain radiation patients older than 60 years.

Symptoms of brain radionecrosis include:
• Fatigue	• Motor, strength, coordination, or sensory loss
• Headaches	• Amnesia, dementia, seizures
• Hemorrhage	• Cerebral atrophy/Decreased cognitive function
• Difficulty with balance	• Visual or gait disturbances
• Loss of the ability to speak	• Personality, libido, thirst, appetite, or sleep changes
• Urinary incontinence	• Hypothalamus/pituitary hormonal disruption (sex hormones, thyroid hormone, cortisol)

    Acute brain dysfunction occurs during and up to 1 month after radiotherapy due to blood-brain barrier disruption. Chemicals in blood are extremely toxic to brain tissue. The blood-brain barrier is a protective membrane (blood vessel endothelial cells) which allows the transfer of oxygen and nutrients from the blood to the brain without intermingling blood and cerebral-spinal fluid.

    One to 4 months after radiotherapy, early delayed complications may occur. These are caused by white matter injury, nerve demyelination, and the accumulation of fluid in the brain. Symptoms include drowsiness in children, the reappearance of the initial tumor's symptoms, a temporary long-term memory deficit, and overall brain dysfunction. Both the acute and early delayed complications are steroid responsive.

    Up until 6 months after the initiation of radiation therapy, acute organ damage, often clinically silent, accumulates.

    During the second six months, the sub-acute period, permanent damage may start to become evident. In the chronic period, 2 to 5 years after treatment, residual damage continues and 5 years after treatment, in the late clinical period, premature aging and the development of new cancers becomes evident.

    DIAGNOSIS OF RADIATION-INDUCED BRAIN NECROSIS

    It is often difficult to determine if the symptoms are caused by recurrence of the tumor, spreading of the cancer from the original site (metastasis), or the death of otherwise healthy tissue (necrosis). Because the site where necrosis most frequently occurs is where radiation was used to destroy tumor tissue, the symptoms often mimic those previously experienced before tumor treatment. Whether there is an autoimmune component to the necrosis process is unknown.

    A radiation-induced necrosis diagnosis is difficult to confirm without surgical tissue sampling (craniotomy or biopsy). Even more complex is that fact that symptoms may not be caused by tumor or necrosis alone, but often by a combination of active tumor tissue and radiation necrosis together. CT and MRI scans are inconclusive. Although patients who show radiographic changes may have no symptoms, the converse is not true. For patients who suffer impairments, MRIs mirror the severity of symptoms.

    Sometimes a FDG-PET Scan or T1-SPECT studies can tell the difference by measuring metabolic levels (higher than normal for tumor, lower than normal for necrotic tissue), but again, if both types of tissue are present, they may provide a metabolic profile very close to normal. Also, the increased metabolic activity in inflammatory “edges” surrounding necrotic tissue may give a false positive for the presence of tumor tissue. A PET scan can provide useful targeting information for further biopsy, the appropiateness and scope of further surgery, and quickly monitor patient response to a particular course of treatment.

    Magnetic resonance spectroscopy (MRS) measures metabolic markers, including creatine (cellular bioenergetics), choline (membrane metabolism), lactate (anaerobic metabolism), and N-acetylaspartate (neuron function). Cancerous gliomas have very high creatine and choline levels. Necrotic tissue has low creatine, choline, and N-acetylaspartate, which could be expected since necrotic cells are not functioning. MRS may be particularly useful in distinguishing pure tumor from pure necrosis.

    TREATMENT OF RADIATION-INDUCED BRAIN NECROSIS

    Traditional treatments (usually corticosteroids) for radionecrosis are also dangerous, and typically not administered until the patient complains of symptoms, with dosage increased as required to stabilize the condition. How corticosteroids actually work is uncertain, but doctors believe they reduce the response of the body to injury and thus diminish the flow of fluid into tissues. When corticosteroids are used to control swelling, only about 35% of patients respond. Long term usage of corticosteroids results most notably in osteoporosis, the thinning and weakening of bones.

Additional side effects are:
• internal bleeding	• glucose intolerance
• suppression of the immune system
• weakness	• weight gain

    If steroids fail, surgical removal of the damaged portion of the brain may be an option. This not only allows diagnostic verification, but the reduction in tumor size can relieve intracranial pressure and improve disability. Surgery itself carries a high risk of complications and the potential for further neurological deficit. Even then, surgery is not always possible due to injury size or location or the presence of tumors in multiple sites.

    If steroids are not effective, and surgery is not a choice, treating symptoms used to be the only choice—and one that did not stop the underlying damage process. The objective of any treatment has to be evaluated—success, often described as the ‘not having the tumor recur,’ is probably more accurately described in terms of longevity and quality of life.

    HYPERBARIC OXYGEN TREATMENT FOR RADIATION-INDUCED BRAIN NECROSIS

    Traditional radiation injury treatment has focused on control of intracranial swelling, treating the symptoms rather than the underlying cause.

    There is a difference between normal tissue injuries and those caused by radiation. In radiation, the injury is concentrated in the center of the wound, and “fades” into the surrounding tissue, becoming gradually less pronounced. Because there is no abrupt difference in oxygen levels, the body does not recognize the need to grow new blood vessels (revascularization) into the injured area and bring the necessary oxygen and nutrients to promote healing.

HBOT TREATMENT RESULTS FOR RADIATION-INDUCED BRAIN NECROSIS

• Studies have shown that the growth of new blood vessels, both within and around bone and soft tissue, is stimulated by the artificial oxygen level difference created by hyperbaric oxygen therapy.

• HBOT raises arterial oxygen levels 10 to 15 times higher than that produced by normal atmospheric pressure.

• HBOT returns blood flow to the injured portions of the brain, decreasing swelling, and often, completely healing the patient.

• Hyperbaric oxygen treatment shows a 90% success rate in controlling and reversing radiation-induced brain necrosis.

    Although the direct bacteriocidal effects of HBOT fight infection, HBOT is by no means a cure for tumors, but can be recommended as part of an integrated, personally tailored treatment for a difficult condition. What is interesting is that HBOT does not only treat the underlying cause of post-radiation symptoms; it is the only known treatment potentially capable of reversing brain radiation necrosis.

    When tissues have received dosage totaling more than 5000 cGy (SI unit of absorbed dose I Rad = 0.01 Gy), the response to HBOT is the regeneration of blood capillaries in the affected region, tissue healing, and increased tissue oxygenation. Most patients with chronic radiation injuries and no underlying tumor activity can be cured.

©2008 Florida Oxygen