Research into the mechanisms of symptom development is less mature, but several lines of research have generated much interest, including the role of cytokines (Dantzer 2001; Larson and Dunn 2001; Meyers and Valentine 1995) and the impact of anaemia (Temple et al. 1995; Marsh et al. 1991). Understanding the mechanisms of cancer-related fatigue is critical for the provision of targeted interventions (see Chapter 4). The role of proinflammatory cytokines in the genesis of mental fatigue and cognitive impairment is an exciting area of research. Proinflammatory cytokines have profound effects on brain function (Meyers and Valentine 1995). For example, it is known that treatment with interferon-a increases levels of interleukin-1p (IL-1P), interleukin-6 (IL-6) and tumour necrosis factor-a (TNF-a), and that this increase is associated with the impairment of memory, motor, executive functions, and mood that are suggestive of frontal-subcortical dysfunction (Valentine et al. 1998).
Interleukin-1 (IL-1) crosses the blood-brain barrier, with the highest rate of entry occurring in the hypothalamus (Dantzer et al. 1992). The hypothalamus has rich connections with the brainstem, frontal cortex, and limbic system. IL-1 and its receptors are found in many areas of the brain. IL-1 messenger RNA is found in abundance in the hippocampus (Dantzer et al. 1992), a critical structure for memory processes. IL-1P depresses the influx of calcium into hippocampus neurons, which may explain the preponderance of memory impairment in patients with IL-1-associated toxicity (Plata-Salaman and Ffrench-Mullen 1992). TNF is also neurotoxic, and is associated with demyelination in the brain (Ellison and Merchant 1991). TNF and IL-1 are synergisti-cally toxic (Waage and Espevik 1988) and are associated with the development of multiple sclerosis plaques and gliosis (Wollman et al. 1992). Patients with Alzheimer's disease have elevated levels of IL-6 (Huberman et al. 1995). We have found that patients who have severe neurotoxicity following administration of intraventricular IL-2, as treatment for leptomeningeal disease, also have increased IL-6 levels in the cerebrospinal fluid compared with pretreatment values (Sherman et al. 2002). In addition to their direct effects on brain function, these cytokines also provoke a stress hormone cascade that can affect mood and cognition, as well as having discrete effects on brain neurotransmitter systems (Meyers and Valentine 1995; Marsh et al. 1991). The cancer itself may also produce cytokines. Concentrations of IL-6 have been demonstrated to be higher on average in patients with large cell lymphoma and Hodgkin's disease than in normal controls. Patients with high levels are more likely to have poor performance status and B-symptoms than patients with lower levels (Preti et al. 1997; Seymour et al. 1997). IL-1, IL-6, and TNF-a appear to be elevated in patients with leukaemia and myelodysplastic syndrome (Sugiyama et al. 1996; Bruserud et al. 1995; Kurzrock et al. 1995).
Elevated cytokine levels are observed in other illnesses characterized by mental fatigue. For example, individuals who contract Q fever often develop a syndrome that persists after the illness remits, characterized by fatigue, pain, mood disturbance, and sleep disturbance (Pentilla et al. 1998). It is thought that this syndrome may be related to upregulation of certain proinflammatory cytokines, particularly IL-6. Increased IL-6 secretion has also been found in patients with CFS, although the IL-6 changes are not sufficient to explain the entire constellation of symptoms (Cannon et al. 1999), as well as in patients with chronic daytime sleepiness (Vgontzas et al. 1999). TNF is another cytokine that has been associated with CFS (Moss et al. 1999). These studies suggest that potential avenues for treatment may be in the development of cytokine blockers or anti-inflammatory agents.
Anaemia can also cause mental fatigue and cognitive deficits. For instance, cognitive deficits have been reported in well-dialysed patients with end-stage renal disease who are anaemic but do not have uraemia (Nissenson 1992). Cognitive deficits are also seen in patients who have anaemia due to iron deficiency (Lozoff 1988). The cognitive problems observed on neuropsychological testing include deficits in attention, perceptual-motor speed, memory, and verbal fluency (Temple et al. 1995; Brown et al. 1991; Marsh et al. 1991). Neurophysiological assessment of auditory evoked potentials also reveal increased latency of certain components (Brown et al. 1991; Marsh et al. 1991). These cognitive deficits and slowed evoked potentials often improve following reversal of anaemia with erythropoietin (Temple et al. 1995; Brown et al. 1991; Marsh et al. 1991; Nissenson 1989).
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