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Case Report |
Program in Integrative Medicine, Department of Obstetrics and Gynecology, School of Medicine, University of Kansas Medical Center, Kansas City, Kansas
Address reprint requests to: Jeanne A. Drisko, MD, University of Kansas Medical Center Program in Integrative Medicine, 3901 Rainbow Blvd., Kansas City, KA 66160. E-mail: jdrisko{at}kumc.edu.
ABSTRACT
Background: Transmissible spongiform encephalopathies (TSE), which include Creutzfeldt-Jakob disease and new variant Creutzfeldt-Jakob disease, are diseases characterized by progressive deterioration in the central nervous system with neuronal degeneration, vacuolatization of the neuropil, and gliosis. Little is known about the pathogenic mechanisms of infection, and controversy exits around the inciting infective agent. It has been shown that an important factor in pathogenesis is the immune system.
Case: The reported case points to beneficial effects when antioxidant therapies are used in transmissible spongiform encephalopathies. The case revealed an early reversal in cognitive decline and subsequent improvements in myoclonus, apnea and rigidity. Although death was the ultimate outcome, the patient succumbed to the illness over 22 months after the onset of symptoms when the early rapid decline predicted demise within a few months.
Conclusion: It is possible that strategies blocking the effect of proinflammatory cytokines and the resulting oxidative damage may stem the progressive damage to the neuropil that occurs in spongiform encephalopathies. Further investigation into the use of antioxidants and other types of agents quelling inflammation needs to be undertaken. If antioxidants could be combined with treatments for the inciting infective agent, a new direction could be taken in the outcome of transmissible spongiform encephalopathies including CJD and vCJD.
Key words: transmissible spongiform encephalopathies, prion, antioxidants, brain inflammation, neurodegeneration, oxidative stress
INTRODUCTION
Transmissible spongiform encephalopathies (TSE) are diseases characterized by progressive deterioration in the central nervous system, which includes neuronal degeneration, vacuolatization of the neuropil and gliosis [1–3]. In humans, TSE have been reported as sporadic, infectious or familial disorders [4,5]. Human TSE include Kuru, Creutzfeldt-Jakob disease (CJD), new variant CJD (vCJD), Gerstmann-Straussler-Scheinker disease (GSS) and Fatal Familial Insomnia (FFI) [4,6]. GSS and FFI are related to chromosomal abnormalities in the gene that codes for the prion protein [1,4,6]. The animal forms of TSE include scrapie, bovine spongiform encephalitis (mad cow disease), elk and deer wasting disease or chronic wasting disease, mink encephalopathy and others.
Little is known about the pathogenic mechanisms of infection. Controversy exits around the inciting infective agent that produces the onset of TSE including CJD and vCJD [1,4,6–15]. On the other hand, it has been shown that an important factor in this pathogenesis is the immune system.
Evaluation of patients with documented CJD demonstrates that there are significantly higher levels of tumor necrosis factor alpha (TNF-
) and Interleukin (IL)-1ß in the intrathecal compartments when compared to the systemic compartments [16]. Because the spongiform encephalopathies are not usually associated with inflammatory cell infiltration in the brain, investigators have suggested that resident CNS cells are primarily responsible for the increased intrathecal release of these inflammatory cytokines [16]. Proinflammatory cytokines are over expressed in spongiform encephalopathies [16,17]. Proinflammatory cytokines and their attendant reactive oxygen species (ROS) appear to serve as mediators of the neurodegeneration [16,18].
There is cumulative evidence that ROS or free radicals are important in a variety of neurodegenerative disorders including TSE both in animal models and in human disease [18–22]. Neuronal labeling for markers of oxidative stress in brains of scrapie-infected mice found widespread neuronal labeling for oxidative mediated neuronal degeneration [20]. In addition, evidence for increased ROS was found in scrapie-infected rodents [18]. Reported here is the use of antioxidants in a clinical case of Creutzfeldt-Jakob disease.
CASE REPORT
The 69-year-old female patient complained of pressure in her cranium for approximately two months with rapid onset of insomnia, anxiety and ataxia. She was hospitalized where a tentative diagnosis of Creutzfeldt-Jakob disease (CJD) was made after EEG analysis. There was no family history of transmissible spongiform encephalopathies. Of note, the patient had had recent cataract surgery. Spinal tap was unremarkable at this admission with a normal protein level. All other laboratory values were within normal limits. CAT scan and MRI were normal for the patient’s age. Because of the rapid deterioration of cognitive and motor function, the patient was transferred to the Neurology Service at the University of Kansas Medical Center for second opinion.
On admission, the patient appeared to be alert but nonverbal. She responded to verbal and physical stimuli with a startle response. There was a right lateral gaze preference, but all cranial nerves appeared intact otherwise. There was no facial asymmetry, and there was equal movement of all four extremities. She had increased spasticity and rigidity of the extremities but without Babinski. Her repeat EEG was consistent with Creutzfeldt-Jakob disease. Neurologic imaging was normal for the patient’s age, and repeat spinal tap was negative. Because of the rapid cognitive and physical decline, the diagnosis of Creutzfeldt-Jakob disease was considered appropriate.
During the course of her hospitalization, the family administered a mixture of antioxidants including NADH, vitamin E (mixed tocopherols), alpha lipoic acid, multivitamin and a fresh fruit and vegetable puree, which was taken over several days. After this administration, the patient became more responsive and began to speak in appropriate although short sentences. The patient also demonstrated less rigidity and stated that she felt better. Because of the improvement, the family decided to continue antioxidant and nutrient treatment at home after discharge. Appropriate dialogue with palliative care was initiated, and the family was made aware of the severity of her diagnosis.
After the discharge to a rehabilitation hospital, the patient remained alert and responsive although somewhat lethargic. Dilantin was given to control what was most likely the onset of myoclonus but was interpreted as seizure activity. After the dilantin administration, the patient became comatose for three days. The dilantin was discontinued immediately, and the patient appeared to become responsive again but unable to verbalize. The patient was perceived to be in a persistent vegetative state at this time.
The improvement after antioxidant administration influenced the caretakers to continue aggressive antioxidant and nutrient therapy after discharge to home. This therapy was given over the course of the patient’s remaining life in an effort to lessen the effects of the advancing Creutzfeldt-Jakob disease. The antioxidant and nutrient therapy was administered by gastric feeding tube and included Coenzyme Q-10, alpha lipoic acid, NADH, vitamin C, vitamin E, B complex, a multivitamin-mineral mixture, L-glutamine, omega 3 fatty acids, magnesium and a pureed mixture of fruit and vegetables. In addition, parenteral glutathione and ascorbate were given, all of which resulted in reduction of apneic episodes, myoclonus and rigidity. The rigidity was not abolished entirely.
The patient expired 19 months after diagnosis and 22 months after onset of symptoms. Autopsy performed at the University of Kansas Medical Center confirmed extensive spongiform changes consistent with transmissible spongiform encephalitis/Creutzfeldt-Jakob disease. The findings at autopsy excluded Alzheimer’s type dementia.
INFLAMMATION AND REACTIVE OXYGEN SPECIES IN TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES
The immune system has been largely ignored in transmissible spongiform encephalopathies (TSE), although the spleen, lymph nodes and leukocytes have been known to harbor the infectious agent [7,13,23]. In fact, importance of host inflammatory responses to the infective agent that causes TSE has been dismissed [4,24]. Recent animal studies with CJD agents have shown that the antigen presenting cells of the myeloid lineage—the microglia—are activated early after infection is introduced [25]. This is further confirmed by vaccination studies in CJD, which implicate inflammatory cells [14]. In addition, agents that affect macrophage replication have been shown to prolong or even abolish the onset of scrapie infection [25].
Stimulation of the immune system, with the subsequent production of inflammatory mediators including cytokines, is known to stimulate the release of reactive oxidant species or oxidants [22,26–28]. The stimulated neutrophils and monocytes and their counterparts in the brain, the microglia, through the release of inflammatory mediators generate reactive oxidant species [18,22,29]. A free radical chain of events is triggered, which results in increased oxygen radical production and increased free radical damage in the brain [18,22]. The brain is particularly vulnerable because of its abundant content of peroxidizable fatty acids and minerals involved in the formation of reactive oxygen species [18]. In addition, antioxidants and protective enzymes are relatively deficient in the brain.
It has been shown that resident immune cells of the brain, astrocytes and microglia, proliferate in transmissible spongiform encephalopathies [7,25,30]. Gliosis in general, with astrogliosis in particular, is one of the major pathologic findings of the spongiform encephalopathies, and it occurs early in the disease course [3]. However, at the present time it is not clear if increased proliferation of the astrocytes and microglia is in response to the presence of the infective agent or a result of the neuronal damage. Nonetheless, development of pathologic changes in CJD is mediated by the types of cells that are recruited during the infection such as the glial cells [3,7].
Further confirmation of the role of the immune system is seen in experimental CJD infection in rats treated with dapsone [31]. Dapsone is known to affect infectious organisms that are in residence in macrophages. Dapsone also seems to decrease amyloid formation. Treatment of the CJD infected rats with dapsone revealed a delay in onset of clinical signs of infection [31]. This report suggested that dapsone alters macrophage processing of the infectious agent and modulates inflammatory factors that compromise neuronal function, further confirming the role of the immune system in TSE.
After neuroinvasion, accumulation of the infective agent initiates a cascade of events that leads to release of proinflammatory cytokines and reactive oxidant species, which induce tissue damage [3,16]. Proinflammatory cytokines also produce secondary astrocytosis and microglial proliferation leading in turn to additional release of cytokines and reactive oxidant species and ultimately widespread neuronal degeneration [16]. Tumor necrosis factor alpha (TNF-), a proinflammatory cytokine synthesized in many locations including microglia and astrocytes, stimulates astrogliosis and induces vacuolation and neuronal loss [16]. The typical sources of proinflammatory cytokines including Interleukin (IL)-1ß and TNF- are activated macrophages and monocytes circulating systemically [16,28,32]. Localized production of proinflammatory cytokines within the brain is from astrocytes and microglia [2,16,33]. Experimental studies in CJD have shown that TNF- and IL-1ß are involved directly in astrogliosis, neuronal degeneration and myelin vacuolation [2]. Investigators also found that transforming growth factor ß might be an essential signal for amyloid deposition [7].
High expression of proinflammatory cytokines TNF- and IL-1ß have been detected in brains of mice with experimental CJD and scrapie suggesting that spongiform changes in experimental animals could be mediated by cytokines and reactive oxygen species [16,18]. Serum and CSF concentrations of inflammatory cytokines were measured in patients with CJD and compared to controls. There were significant elevations of TNF- and IL-1ß of the CJD infected patients when compared to controls [16]. The pattern suggests intrathecal release.
Inflammatory mediators such as cytokines and associated ROS are responsible for the pathologic changes related to TSE [16,18]. Confirmatory evidence comes from a report that demonstrated accelerated disease in scrapie infected mice after hyberbaric oxygen use [34]. A similar finding was described with accelerated neuronal damage after hyperbaric oxygen therapy in suckling rats with experimental spiroplasma encephalitis [35]. Increases in ROS are known to occur with hyberbaric oxygen therapy [19,36–38]. It is in the light of these findings that the use of antioxidants would play an important role in quenching ROS involved in transmissible spongiform encephalopathies.
It is possible that strategies blocking the effect of proinflammatory cytokines and the resulting oxidative damage may stem the progressive damage to the neuropil that occurs in spongiform encephalopathies. In fact, similar benefits have been described when antioxidants are used adjunctively in Alzheimer’s disease [22]. The reported case points to beneficial effects when antioxidant therapies are used in transmissible spongiform encephalopathies. The case revealed an early reversal in cognitive decline and subsequent improvements in myoclonus, apnea and rigidity. Although death was the ultimate outcome, the patient succumbed to the illness over 22 months after the onset of symptoms when the early rapid decline predicted demise within a few months. Further investigation into the use of antioxidants and other types of agents quelling inflammation needs to be undertaken. If antioxidants could be combined with treatments for the inciting infective agent, a new direction could be taken in the outcome of transmissible spongiform encephalopathies including CJD and vCJD.
Received August 1, 2001. Accepted October 25, 2001.
REFERENCES
: a comparison with experimental Creutzfeldt-Jakob disease.
Acta Neurobiol Exp
54:
209–218,
1994.[Medline]
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