The following articles are presented as support for the
possible use of ionic minerals as a dietary supplement and nutritional supplement for
natural therapy. You will find more on fibromyalgia
here. You can also purchase this diet supplement disease treatment package below.
ALPHA-DELTA SLEEP IN PATIENTS WITH A CHIEF COMPLAINT OF CHRONIC FATIGUE
Magazine: Southern Medical Journal, April, 1994
ABSTRACT: Our prospective, standardized cohort study was designed to
assess the presence of alpha wave intrusions during non-rapid eye movement sleep
(alpha-delta sleep) and its relationship to fibromyalgia, major
depression, and chronic fatigue syndrome (CFS) in patients with a chief complaint of
chronic fatigue. The study group comprised 30 consecutive patients seen at a university
hospital referral clinic for evaluation of chronic fatigue. All patients had nocturnal
polysomnography, dolorimetric tender point assessment for fibromyalgia,
a comprehensive history, physical, and laboratory evaluation, and a structured psychiatric
interview. Alpha-delta sleep was identified in 8 of the 30 patients (26%), major
depression in 20 (67%), CFS in 15 (50%), and fibromyalgia in 4
(13%). Ten of the 30 patients (33%) had a primary sleep disorder (sleep apnea, periodic
limb movements, or narcolepsy). Alpha-delta sleep was not significantly correlated with fibromyalgia,
CFS, major depression, or primary sleep disorders, but was significantly more common among
patients who had chronic fatigue without major depression. We conclude that primary sleep
disorders are relatively common among patients with chronic fatigue and must be diligently
sought and treated. Alpha-delta sleep is not a marker of fibromyalgia
or CFS, but may contribute to the illness of nondepressed patients with these conditions.
ALPHA-DELTA SLEEP was first described in 1973 as an unexpected finding
during studies of sleep in patients with various psychiatric disorders. The anomaly
observed was an atypical electroencephalographic (EEG) pattern recorded during non-rapid
eye movement (non-REM) sleep. The EEG appearance contained the expected delta waves
(amplitude greater than 75 microvolts, frequency 0.5 to 2.0 cycles per second), intruded
upon by prominent alpha activity (frequency 7 to 10 cycles per second). In normal
individuals, alpha activity is characteristic of drowsy wakefulness, and delta activity
indicates restorative non-REM sleep. The only clinical similarity among the patients with
alpha-delta sleep was "a general feeling of chronic, somatic malaise and
fatigue".(r1)
In a landmark study published in 1975, alpha delta sleep was noted to
occur in a majority (70%) of patients with fibromyalgia, a common
rheumatologic condition characterized by muscle pain, dysphoria, and fatigue, and among
healthy subjects deprived of non-REM sleep.(r2) In the latter group, the alpha-delta sleep
was correlated with objective evidence of increased muscle tenderness and the appearance
of depression and irritability. Additional studies indicated that the experimental
production of non-REM sleep deprivation induced alpha-delta sleep and muscle achiness and
stiffness, overwhelming physical tiredness, heaviness, and sluggishness.(r3) Because mood
disorders are often diagnosable in patients with fibromyalgial,(r4) the presence of
alpha-delta sleep was assessed in patients with fibromyalgia and
depressed patients of similar age and sex distribution.(r5) Alpha-delta sleep was present
in 60% of patients with fibromyalgia and 42% of patients with
major depression.
Alpha-delta sleep was also invoked as a mechanism for symptom production
in patients with chronic fatigue syndrome (CFS), an entity characterized by disabling
fatigue, myalgias, arthralgias, sleep disturbance, neuropsychologic abnormalities, fever,
pharyngitis, and cervical adenopathy.(r6) CFS has been shown to overlap substantially with
major depression(r7-r11) and to share many features of the syndrome of fibromyalgia.(r12)
In the only study available to date, 14 patients with CFS were compared with 12 healthy
controls. Prominent alpha intrusions during non-REM sleep were observed in all
patients.(r13)
If consistently found, alpha-delta sleep could emerge as an important
feature and perhaps as a biologic marker of many states characterized by chronic fatigue.
Based on this premise, we undertook a prospective study to determine the frequency of
alpha-delta sleep among patients with a chief complaint of chronic fatigue and to clarify
the relationship of alpha-delta sleep with CFS fibromyalgia, and
major depression as diagnosed in our study's patient population.
METHODS
This prospective study was conducted in the Chronic Fatigue Clinic of the
University of Connecticut Health Center, Farmington. The 30 consecutive patients in the
study were 18 years of age or older (mean age 41 years, SD 7.9 years), had experienced
persistent tiredness for at least 6 months, and had not been hospitalized during the 3
months before evaluation. All patients were non-Hispanic whites, and 21 (70%) were female.
All patients agreed to the following study protocol: (1) a one-night sleep study; (2) a
rheumatologic evaluation including dolorimetric testing for fibromyalgia;
(3) a comprehensive laboratory evaluation including a general health panel, virologic and
bacteriologic testing, and assessment of cellular and humoral immunity; (4) a complete
history and physical examination; and (5) a psychiatric evaluation using a highly
structured interview schedule. For patients with irresistible daytime somnolence,
additional laboratory investigations included diurnal multiple sleep latency testing.
Sleep Studies
One-night sleep studies were done by accredited clinical
polysomnographers. The recording montage included the EEG leads C[sub3]/A[sub2] and
C[sub4]/A[sub1], electro-oculogram, and submental and anterior tibialis electromyograms.
Nasal and oral airflow, respiratory effort (by inductance plethysmography), and arterial
oxygen saturation were also continuously and simultaneously recorded. The sleep recordings
were scored in 30-second epochs according to standard criteria.(r14) Alpha-delta sleep was
diagnosed in the presence of prominent alpha frequency activity occurring tonically during
non-rapid eye movement sleep (Figure). Arousals and awakenings were recorded and were
designated as associated with limb movements or with apnea. Sleep apnea was diagnosed in
patients whose oral-nasal airflow ceased for longer than 10 seconds at least five times
per hour of sleep.(r15) For those patients having multiple sleep latency testing,
narcolepsy was diagnosed if two or more sleep onset REM periods with a mean latency of
less than 5 minutes occurred during five 20-minute nap opportunities spaced about 2 hours
apart.(r15)
Examination for Fibromyalgia
This portion of the study was done according to the American College of
Rheumatology criteria. for the diagnosis of fibromyalgia.(r16)
Patients were tested for 18 tender points by applying pressure with the index, third, and
fourth fingers of the examiner's hand at the following nine bilateral surface sites: (1)
the suboccipital muscle insertions, (2) the anterior aspects of the intertransverse spaces
at C5-7, (3) the midpoint of the upper border of the trapezius, (4) the supraspinatus, at
its origins above the scapular spine near the medial border, (5) the second costodhondral
junctions, (6) 2 cm distal to the epicondyles, (7) in the upper outer quadrants of the
buttocks, (8) posterior to the trodhanteric prominence, and (9) the knee, at the medial
fat pad proximal to the joint line. Patients with 11 or more significantly tender points,
generalized myalgias, and no other rheumatologic disease were classified as having fibromyalgia.
Laboratory Investigations
Comprehensive laboratory testing was done to identify medical disorders
known to be associated with chronic fatigue. Data collected on all patients included
complete blood cell count with differential white blood cell count, erythrocyte
sedimentation rate, plasma glucose, creatinine, sodium, potassium, chloride, bicarbonate,
calcium, phosphorus, magnesium, alanine aminotransferase, total protein, alkaline
phosphatase, total bilirubin, iron, thyroid-stimulating hormone, thyroxine
radioimmunoassay, triiodothyronine resin-uptake, cortisol, rheumatoid factor, antinuclear
antibody, complement (CH[sub50]) levels, antithyroid microsomal antibody,
antithyroglobulin antibody, total immunoglobulin (IgG) and IgG subclass levels, T4 and T8
surface marker cell counts, Lyme disease IgM and IgG antibodies by ELISA and Western
immunoblot, and urinalysis.
History and Physical Examination
The history-taking was semistructured and included explicit questions
about the time of onset of fatigue, the degree of disability produced by the fatigue
syndrome, and the presence and timing of the 11 CFS symptom criteria (feverishness, sore
throat, tender or swollen cervical or axillary lymph nodes, myalgias, arthralgias,
generalized headache, muscle weakness, postexercise fatigue, sleep disturbance,
neuropsychologic abnormalities, and sudden onset). The physical-sign criteria of CFS
(fever, nonexudative pharyngitis, and cervical or axillary lymphadenopathy) were assessed
both by thorough review of previous medical evaluations and as part of the complete
physical examination. The diagnosis of CFS was made in patients with (1) disabling fatigue
(50% reduction in activity as compared with the premorbid activity level) of at least 6
months' duration and (2) at least eight of the symptom criteria or at least six symptom
criteria and two physical-sign criteria.(r16)
Psychiatric Interviews
Psychiatric diagnoses were based on the results of the Diagnostic
Interview Schedule (DIS) of the National Institute of Mental Health, Version III-A, a
highly structured diagnostic instrument.(r17) The questions 16-100 and 210-213 of this
instrument were used to obtain diagnostic assessments for somatization disorder, panic
disorder, generalized anxiety disorder, major depression, and dysthymia in current,
previous 6 months, and lifetime time frames according to standard diagnostic criteria for
mental disorders.(r18)
Data Analysis
The study population was divided according to the presence of alpha
intrusions during non-REM sleep. The statistical significance of differences was assessed
by the chi-square test for proportions and the two-tailed t test for ordinal variables.
RESULTS
Medical and Psychiatric Diagnoses
Medical and/or psychiatric conditions were diagnosed in 26 patients (87%)
(Table 1). The most common diagnosis was that of major depression, active at the time of
the examination in 20 patients (67%). Fibromyalgia was present in
four (13%). All four patients with fibromyalgia were women, and
all also met diagnostic criteria for both CFS and major depression, current at the time of
examination. Two patients had medical conditions other than primary sleep disorders and fibromyalgia;
Sjogren's syndrome and anemia were diagnosed in one patient and chronic Lyme disease in
the other.
Fifteen (50%) of the 30 patients met the recently proposed research
criteria for the diagnosis of CFS. The difference in the proportion of patients with
active psychiatric disorders, sleep disorders, and alpha-delta sleep was statistically
similar among the 15 patients with CFS and the 15 other patients with chronic fatigue
(Table 2). Patients with CFS and the others with chronic fatigue also showed similar sleep
architecture and sleep continuity (Table 3).
Sleep Disorders
Eleven sleep disorders (5 cases of periodic limb movements with frequent
awakenings, 3 cases of sleep apnea with oxygen desaturation, 1 case of both sleep apnea
and periodic limb movements, and 1 case of narcolepsy) were found in 10 patients (33%).
The age and sex distribution of the patients with sleep disorders were not statistically
different from those of patients with normal sleep. Eight of the 10 patients with sleep
disorders had a total of 12 psychiatric diagnoses likely to contribute to their chronic
fatigue (7 cases of depression, 3 of panic disorder, and 2 of somatization disorder).
Alpha-Delta Sleep
Alpha-delta sleep was recorded in 8 of the 30 patients with chronic
fatigue (27%). Alpha-delta sleep was present in 4 of the 10 patients with sleep disorders:
2 patients had periodic limb movements and 1 each had sleep apnea and narcolepsy. None of
the 4 cases of fibromyalgia showed evidence of alpha-delta sleep.
Major depression was diagnosed in 3 of the 8 patients (37%) with alpha-delta sleep and in
17 of the 22 patients (77%) without this atypical sleep EEG pattern (Table 4). Patients
with alpha-delta sleep and the other patients with chronic fatigue had similar
architecture and continuity (Table 5).
DISCUSSION
This prospective study of sleep characteristics of patients with a chief
complaint of chronic-fatigue has identified a relatively large number of treatable sleep
disorders contributing to chronic fatigue and has demonstrated that alpha-delta sleep did
not correlate with the presence of major depression, fibromyalgia,
or CFS in this population The findings raise a number of clinically relevant issues with
regard to the relationship between chronic fatigue and disordered sleep.
The first issue is the correlation between EEG sleep patterns and the
presence of a depressive disorder. Mood disorders are commonly diagnosed among patients
with chronic fatigue, the predominant diagnosis being that of major depression, either
with recurrent episodes or as a prolonged single episode.(r18-r19)Electroencephalographic
sleep research studies have identified REM sleep abnormalities as biologic markers for
primary depression.(r20-r23) Our findings offer indirect support to this thesis, because
we have identified a non-REM sleep event (ie, alpha intrusions during stage 4 of sleep) in
a larger proportion of patients without a depressive disorder.
The second issue is the association between alpha-delta sleep and
fibromyalgia. Alpha-delta sleep was not present on the polysomnograms of the patients with
fibromyalgia diagnosed among our clinical sample. The discrepancy between our results and
those of others(r2, r5) may be due to the small number of cases; because only 4 of the 30
patients with chronic fatigue had fibromyalgia, the possibility of a type I error cannot
be excluded. The fact that our patients had a chief complaint of chronic fatigue, whereas
"fibrositis" patients studied by other researchers reported muscle pain as their
most bothersome symptom(r2) may also be a confounding factor.
The third issue is the association between alpha-delta sleep and chronic
fatigue syndrome. In contrast to data contained in the only other study devoted to this
problem,(r13) this atypical EEG pattern did not appear to characterize patients with CFS.
However, the majority of our patients with CFS had nonpsychotic major depression, a
psychiatric disorder that is no longer considered exclusionary for the case definition of
CFS(r6) and one that, at least in our study, did not seem to be associated with
alpha-delta sleep.
Last but not least, the fourth issue raised by our study is the
identification of well-characterized sleep disorders as the most common physical disorders
diagnosable among patients with chronic fatigue. Six of the 10 patients with sleep
disorders reported significant daytime somnolence, but the specificity of this symptom
appeared to be low, given the fact that most of the patients we have seen with chronic
fatigue have disturbed sleep.(r24) Nevertheless, we believe the evaluation of patients
with chronic fatigue should include a thorough inventory of sleep-related symptoms and an
effort to distinguish fatigue and weakness from daytime somnolence.
Although the design of our prospective diagnostic study did not plan for a
therapeutic component, treatment was offered to patients with alpha-delta sleep and sleep
disorders, and substantial improvement was noted in some patients. For example, a
33-year-old machinist had a 7-year history of disabling fatigue and symptoms of
feverishness, muscle weakness, and difficulty with concentration. The patient had no
detectable medical or psychiatric disorder, and did not fulfill criteria for CFS.
Alpha-delta sleep was recorded by nocturnal polysomnography. All symptoms improved
considerably 1 month after initiation of treatment with a moderate dose of a
serotonin-reuptake inhibitor. He had shown no improvement on successive therapeutic
attempts with trazodone, amitriptyline, desipramine, bupropion, and alprazolam. Another
case is that of a 39-year-old woman who had a previous diagnosis of CFS and who complained
of excessive daytime sleepiness and difficulty with concentration. She was found to have
obstructive sleep apnea, which was eliminated by treatment with nasal continuous positive
airway pressure (CPAP). After several months of nasal CPAP therapy, she reported that she
no longer had fatigue or other symptoms. A third example is a 44-year-old woman who had
become so fatigued that she was barely able to carry out her household chores. She had
impaired concentration, poor memory, and muscle pain, and she required frequent naps
during the day because of fragmented sleep. In the sleep laboratory she was found to have
periodic limb movements with frequent awakenings. After the initiation of treatment with
low doses of clonazepam, she had no further symptoms of chronic fatigue or excessive
daytime somnolence.
The results of our study should be interpreted with caution, because the
sample size was relatively small and the results were not controlled by data obtained
simultaneously from patients with major depression and fibromyalgia, but without chronic
fatigue. Although a "first-night effect"(r25) was observed in only five of the
30 patients we studied, our data would have been stronger if confirmed by a second or
third night evaluation in the sleep laboratory. Nevertheless, we believe it is reasonable
to conclude that one-night EEG sleep studies, the current standard for the evaluation of
sleep disorders, may contribute to the understanding of the pathophysiology of chronic
fatigue by identifying two subgroups of patients. The first subgroup would include the
individuals in whom a well-characterized and treatable sleep disorder could be wholly or
partly responsible for the chronic fatigue state. Given the substantial proportion of
treatable sleep disorders identified in this prospective study, clinicians may want to
lower their threshold for using diagnostic sleep laboratories within the framework of a
cost/benefit decision that will acknowledge the financial burden of such a referral. The
second group would comprise patients with alpha-delta sleep, an atypical EEG pattern that
seems to be prevalent among nondepressed chronic fatigue patients who do not have chronic
fatigue syndrome or fibromyalgia. Continued research is clearly needed to understand the
mechanisms of this nonrestorative sleep, to clarify the nature of its relationship with
syndromes dominated by symptoms of fatigue and muscle pain, and to evaluate pharmacologic
agents that could prevent the alpha intrusion anomaly.
TABLE 1.
Diagnostic Categories in Chronic Fatigue |
|
No. |
% |
| Patients with attributable diagnoses |
26 |
87 |
| Psychiatric disorders |
24 |
80 |
| Chronic fatigue syndrome |
15 |
50 |
| Sleep disorders |
10 |
33 |
| Fibromyalgia |
4 |
13 |
| Other physical disorders |
2 |
7 |
| Patients without attributable diagnoses |
4 |
13 |
TABLE 2.
Diagnostic Findings in Patients With Chronic Fatigue Syndrome (CFS) and Other Chronic
Fatigue |
|
CFS (n=15) |
Other (n=15) |
|
No. |
% |
No. |
% |
| Fibromylagia |
4 |
27 |
0 |
0 |
| Alpha-delta sleep |
2 |
13 |
6 |
40 |
| Sleep disorders |
6 |
40 |
8 |
53 |
| Periodic limb movements |
5 |
33 |
1 |
7 |
| Obstructive sleep apnea |
1 |
7 |
3 |
20 |
| Narcolepsy |
0 |
0 |
1 |
7 |
| Psychiatric disorders |
12 |
80 |
12 |
80 |
| Major depression |
11 |
73 |
9 |
60 |
| Panic disorder |
4 |
26 |
3 |
20 |
| Somatization disorder |
3 |
20 |
2 |
13 |
| Generalized anxiety |
0 |
0 |
2 |
13 |
Some patients had more than one psychiatric diagnosis or sleep disorder.
TABLE 3.
Sleep Continuity and Architecture in Chronic Faitgue Syndrome (CFS) and Other Chronic
Fatigue |
|
CFS (n=15) |
Other (n=15) |
|
Mean |
SD |
Mean |
SD |
| Sleep continuity (minutes) |
|
|
|
|
| Sleep latency |
37 |
31 |
30 |
25 |
| REM latency |
116 |
53 |
106 |
50 |
| Total sleep time |
337 |
86 |
323 |
96 |
| Sleep architecture (%) |
|
|
|
|
| Stage 1 |
6 |
4 |
10 |
14 |
| Stage 2 |
56 |
10 |
53 |
11 |
| Stage 3 |
7 |
8 |
5 |
2 |
| Stage 4 |
11 |
7 |
14 |
9 |
| REM sleep |
19 |
7 |
17 |
8 |
TABLE 4.
Clinical Findings of Patients With Chronic Fatigue and Alpha-Delta Sleep |
|
Patients with Alpha-Delta Sleep
(n=8) |
Other Patients with Chronic Fatigue
(n=22) |
| Age (mean and SD) |
44.1 |
(10.2) |
39.9 |
(6.6) |
| Female sex |
6 |
(75%) |
15 |
(68%) |
| Psychiatric disorders |
5 |
(62%) |
19 |
(86%) |
| Major depression |
3 |
(37%) |
17 |
(77%)[*] |
| Somatization disorder |
3 |
(37%) |
2 |
(9%) |
| Panic disorder |
2 |
(25%) |
5 |
(22%) |
| Sleep disorders |
4 |
(50%) |
6 |
(27%) |
| Nocturnal myoclonus |
2 |
(25%) |
4 |
(18%) |
| Sleep apnea |
1 |
(12%) |
3 |
(13%) |
| Narcolepsy |
1 |
(12%) |
0 |
(0%) |
| Chronic fatigue syndrome |
2 |
(25%) |
13 |
(59%) |
[*] P <.05.
TABLE 5.
Electroencephalographic Sleep Measurements in Alpha-Delta Sleep |
|
Patients with Alpha-Delta Sleep
(n=8) |
Other Patients with Chronic Fatigue
(n=22) |
|
Mean |
SD |
Mean |
SD |
| Sleep continuity (minutes) |
|
|
|
|
| Sleep latency |
37 |
30 |
30 |
27 |
| REM latency |
101 |
33 |
115 |
80 |
| Total sleep time |
312 |
107 |
337 |
84 |
| Sleep architecture (%) |
|
|
|
|
| Stage 1 |
6 |
5 |
9 |
12 |
| Stage 2 |
49 |
7 |
56 |
11 |
| Stage 3 |
7 |
3 |
7 |
2 |
| Stage 4 |
4 |
19 |
10 |
7 |
| REM sleep |
19 |
9 |
18 |
7 |
GRAPHS: Electroencephalographic deep recordings of 42-year-old woman with
chronic fatigue. Clinical evaluation showed evidence of somatization disorder. Panel
A-alpha sleep. Panel B-delta sleep. Panel C-alpha intrusion during delta sleep.
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From the Departments of Medicine and Psychiatry, University of Connecticut
School of Medicine, Farmington, the Sleep Disorders Laboratory, Mount Sinai Hospital,
Hartford, and the New Haven Sleep Disorders Center and Yale School of Medicine, New Haven.
Dr. Matthews was the recipient of the George Morris Piersol Teaching and
Research Scholarship of the American College of Physicians (1989 to 1992). Dr. Abeles is
supported in part by the University of Connecticut-National Institutes of Health
Multipurpose Arthritis Center Grant No. 20621.
Reprint requests to Peter Manu, MD, Medical Director, Hillside Hospital,
Long Island Jewish Medical Center, 75-59 263rd St, Glen Oaks, NY 11004.
~~~~~~~~
PETER MANU, MD, THOMAS J. LANE, MD, DALE A. MATTHEWS, MD, RICHARD J.
CASTRIOTTA, MD, ROBERT K. WATSON, PhD, and MICHA ABELES, MD, Farmington, Connecticut
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