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Chronic Neuroimmune Diseases
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Last updated January 1, 2014

Studies assessing structural and functional neuroimaging, autonomic activity and neuroendocrine abnormalities all point to neuropathology in chronic fatigue syndrome (CFS) patients. While the nature and the extent of neuropathologic involvement in CFS is still unclear, neurocognitive studies make up a very large body of CFS research.

This is an important area for clinicians to familiarize themselves with, as cognitive problems have been cited as one of the most disruptive and functionally disabling symptoms of CFS, with up to 85% of patients reporting impairments in attention, concentration and memory abilities.¹

This article provides an overview of neurocognitive findings in CFS patients and the possible underlying structural changes in the brain.

Cognitive problems observed
Neuropsychological testing confirms cognitive abnormalities, although the data is not consistent as to their nature and testing abnormalities may be subtle in contrast to patients' descriptions of day-to-day problems.

Several formal neuropsychological studies report impairments in attention, verbal memory, visual memory, reaction time and complex auditory information processing.^2-5 However, others have not found memory or attentional deficits.^6-7

Despite methodology limitations, research with CFS patients is fairly consistent in showing that neuropsychological impairments are primarily in the area of complex information processing. Whether the complaints of difficulties in learning and memory result from slowed information processing efficiency, verbal processing difficulties or susceptibility to interference are important questions that were addressed in a recent addressed in a recent study. Patients were found to be susceptible to brief distraction, which resulted in impaired immediate and delayed recall.⁸

Another important question for neuropsychological research in CFS is the relationship between self-reported fatigue, perceived cognitive impairment, and objective neuropsychological performance. Some research findings have demonstrated that fatigue brought about by mental challenges did not universally impair performance.

A study at the NIH-funded New Jersey Cooperative Research Center found that after exhaustive treadmill exercise, CFS patients demonstrated impaired cognitive processing compared to healthy controls, suggesting that physical fatigue may be a crucial variable in explaining impaired cognition.⁹ Several other studies have arrived at similar conclusions. It is important to note that the impaired cognition experienced by many CFS patients may not necessarily be explained by an underlying psychiatric condition. In at least one study, CFS patients without psychiatric comorbidity were impaired relative to controls and patients without CFS with concurrent psychiatric disease on tests of memory, attention and information processing.¹⁰

Neuroimaging study findings
It has been postulated that some of the symptoms of CFS, such as impaired cognition, may result from brain abnormalities. Several studies have reported significantly more abnormalities on MRI among CFS subjects relative to controls.

Overall, MRI studies are generally consistent in demonstrating T2 signal hyperintensities in the subcortical white matter, often in the frontal lobes. One study found that CFS patients without depression had a significantly larger number of small, punctate subcortical white matter hyperintensities compared to CFS patients with depression or sedentary controls.¹¹

Another approach to neuroimaging is assessing cerebral blood flow via single-photon emission computed tomography (SPECT). Most SPECT studies have shown significantly decreased blood flow. This technique has demonstrated changes in some patients' brains that were not apparent on MRI.

In one study, decreases in regional cerebral blood flow throughout the brain have been reported on SPECT in a CFS group relative to healthy controls, and abnormalities were observed in 80% of the CFS patients. CFS patients could be distinguished from controls with unipolar depression based on the pattern of SPECT abnormalities.¹²

In addition, significant brain stem hypoperfusion on SPECT was found in patients with CFS relative to controls and depressed patients.¹³

At least one research group reported a positive correlation between frontal blood flow (on SPECT) and cognitive impairment. They hypothesized that the blood flow abnormalities may play a pathophysiological role in cognitive impairment and physical activity limitations in CFS patients.¹⁴

There have been few published reports of positron emission tomography (PET) scans in CFS patients. One research group reported hypometabolism on PET in the brain stem of 18 CFS patients, which was not found in six depression patients or six healthy controls.¹⁵

How does CFS differ from depression?
CFS symptoms rely on subjective report, which fuels the controversy over an organic versus emotional etiology of the illness. Some practitioners confuse clinical depression, which may also cause difficulty in cognitive processing, with CFS.

High diagnosis rates of depression in CFS patients may result from overlapping symptomatology, reaction to disability imposed by fatigue or viral/immune changes in the brain. However, as has already been pointed out, studies have shown that some of the brain abnormalities found in CFS may be differentiated from patients who are psychiatrically depressed. However, this research is in its infancy, and more studies are needed. In addition, one recent study showed that the pattern of depressive symptoms in CFS patients is dissimilar to that observed in clinically depressed patients and more closely resembles the pattern observed in patients with multiple sclerosis (MS).¹⁶

Implications for treatment
Much of the data on brain abnormalities in CFS is still too preliminary to use in practice. Although the MRI and SPECT findings of the brain in CFS patients are intriguing, more carefully designed and controlled studies still need to be undertaken.

However, physicians and other health care professionals could still make use of the information that neuroimaging provides. Some patients with apparent CFS and brain lesions on MRI may actually have mild presentation of other neurologic illnesses, such as MS.

Clinicians should also keep in mind that patients' diminished neurocognitive processing can be addressed through rehabilitation.

Clinicians should also take patients' impaired cognition into account during office visits. Patients may need assistance in completing complex tasks, such as filling out medical forms.

They may also have difficulty expressing themselves verbally and understanding questions during exams. One way to help patients is to make questions very specific and to state them one at a time, rather than as an uninterrupted series, since slowed processing speed is a major problemin patients with CFS.

Sidebar: COGNITIVE IMPAIRMENTS RELATED TO CFS

• Attention
• Concentration
• Verbal memory
• Visual memory
• Reaction time
• Complex auditory information processing
• Difficulty learning
• Susceptibility to interference

Image: POSSIBLE BRAIN ABNORMALITIES*

• Punctate white lesions in forebrain
• Blood flow abnormalities
• Hypoperfusion
• Diminished brain stem metabolism

*Note: These abnormalities have not been documented in all studies.

References:

1. Grafman J. In: Struas SE, ed. Chronic Fatigue Syndrome. NY: Marcel Deckker, 1994: 263-84.

2. DeLuca, J et al. J Neurol Neurosurg Psych. 1995; 58:38-43.

3. Riccio M et al. Brit J Clin Psych. 1992; 31: 111-120.

4. Grafman J et al. J Neurol Neurosurg Psych. 1993: 56: 684-9.

5. Scheffers MK et al. Neurol. 1992; 42: 1667-75.

6. Johnson SK et al. Clin Infect Dis. 1994; 18: S84-S85.

7. Krupp LB et al. Arch Neurol. 1994; 51: 705-10.

8. Johnson SK et al. Cog Neuropsych. 1998; 3:269-85.

9. LaManca Jet al. Am J Med. 1998; 105: 59S-655.

10. LeLuca J et al. J Neurol Neurosurg Psych. 1997; 62: 151-55.

11.. Natelson BH et al. J Neurol Sci. 1993; 120: 213-7.

12. Ichise M et al. Nuclear Med Commun. 1992; 13: 767-72.

13. Costa DC et al. Quarterly J Med. 1995; 88: 767-73.

14. Fischler B et al. Neuropsychobiol. 1996; 34: 175-83.

15. Tirelli U et al. Am J Med. 1998; 105: 54S-58S.

16. Johnson SK et al. J Affect Dis. 1996; 39: 21-30.

Dr DeLuca is Director of Neuroscience Research, Kessler Medical Rehabilitation and Education Corporation, and Professor of Physical Medicine, Rehabilitation and Neurosciences, University of Medicine and Dentistry of New Jersey (UMDNJ)-New Jersey Medical School.

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