Case reports
Patient 1 was well until a viral gastrointestinal illness at age 12. Thereafter she reported progressive fatigue along with unrefreshing sleep, post-exertional malaise (PEM), problems with short-term memory and attention, headache, myalgias, arthralgias, sore throat, and tender glands, thus satisfying the clinical criteria for ME/CFS. In addition, she had daily lightheadedness and frequent anxiety. At age 15, her supine heart rate was 86 beats per minute (bpm), rising 64 bpm to a peak of 150 bpm after 3 min of standing, associated with increased fatigue, headache, lightheadedness, and dyspnea, consistent with POTS. The physical examination at 15 years revealed a head-forward posture, as well as abnormal responses bilaterally on the upper limb neurodynamic test with a median nerve bias (a measure of neural tension) [25]. Her physical therapist (SH) noted tenderness and increased resting tone in the mid-cervical muscles on the right side. The Beighton score was 0.
She was unable to attend her last 2.5 years of high school due to the severity of her symptoms. She was minimally responsive to medications directed at POTS and anxiety. The neurological examination was initially normal, but when repeated at age 19 due to emergence of tinnitus, she had developed a positive right Hoffman sign. Her mother had undergone surgical decompressions at ages 34 and 43 years for congenital cervical spinal stenosis. Patient 1′s cervical spine MRI showed a congenitally narrow cervical spinal canal, with spondylotic stenosis and an AP diameter of 6 mm at C6–7 (Fig. 1).
At age 21, she underwent cervical disc replacement at C6–7. She reported some improvement in neck discomfort, tachycardia, and cognitive fogginess in the first week after surgery. Two months after surgery, repeat physical therapy evaluation showed a normal upper limb neurodynamic test with a median nerve bias, and resolution of the neck muscle tightness. She began part-time employment. Exercise tolerance increased gradually, and her lightheadedness, tachycardia, and anxiety decreased significantly in frequency and intensity. By 6 months post-operatively, she was able to work 12-h shifts as a horse wrangler, which involved saddling and feeding horses, leading trail rides, and cleaning barn stalls. One year after surgery she began full-time university studies as well as up to 20 h of work each week. At 5 years of follow-up, she has no further ME/CFS symptoms, and has continued to enjoy full activity with no restrictions.
Patient 2 had been generally healthy and active, employed full-time until age 29 when she initially developed profound fatigue, unrefreshing sleep, PEM, difficulties with short-term memory and concentration, headaches, myalgias, and arthralgias, thus meeting clinical criteria for ME/CFS. Neurological symptoms included burning in the legs with standing, numbness in the limbs, electric shock sensations in the arms, difficulty swallowing, and clumsy gait. She developed anxiety and depression as well. The patient had several features of hereditary connective tissue disorders, including a pectus excavatum repair at age 12 years and leg varicosities treated with vein ligation and stripping at age 28, but did not have generalized joint hypermobility (Beighton score was 2). Her sister had scoliosis and Chiari I malformation.
At age 30, deep tendon reflexes (DTRs) were rated 2–3+. Electroencephalogram, electromyogram, and nerve conduction velocity studies were normal. An MRI of the brain and complete spine revealed degenerative disc desiccation extending from C3 through C7, rated as mild. The consulting neurologist felt it was very unlikely that the disc protrusions were contributing to her symptoms. At age 31, a 70-degree head-up tilt table test showed a 61 bpm increase in HR from 65 bpm supine to a peak of 126 bpm at 10 min, with reproduction of her typical orthostatic symptoms, but without orthostatic hypotension, thus consistent with POTS. Medications directed at her POTS were ineffective.
By age 35, she had daily profound fatigue, generalized weakness, lightheadedness, and presyncopal episodes. She was unable to work, and required a wheelchair for trips outside the home. Any trips out of the house precipitated up to 2 weeks of exacerbation of symptoms. The presence of generalized 3+ hyper-reflexia prompted a repeat MRI of the cervical spine that showed a 9 mm cervical canal at C5–6 and a 7 mm cervical canal diameter at C6–7 (Fig. 2). Her spine surgeon identified an absent gag reflex, diminished strength in triceps and wrist flexors, and 4+ DTRs at the ankles. The Hoffman sign was negative.
At age 35, she underwent a hybrid anterior cervical disc fusion and disc replacement. She noted a general sense of improvement in the first week after surgery. She was able to walk a 1/2 mile several days in a row and no longer needed a wheelchair for doctor visits. Activity tolerance increased. The burning in both upper and lower limbs with standing resolved at 6 months, and she was symptom free during 5 min of standing. By 8 months after surgery she was able to walk for 35 min a day with less relapse of symptoms afterwards, and could remain upright and active for most of the day. At 20 months, she could exercise on an elliptical machine and recumbent bicycle, perform daily house-keeping chores, run multiple errands in a day, and paint the interior rooms of her parents’ house. She was able to successfully discontinue 3 of the 4 antidepressant/anti-anxiety medications.
Patient 3 was previously healthy, working full-time until age 31, when she developed profound fatigue upon return from an overseas trip. A tilt test was performed to investigate orthostatic intolerance as the possible etiology of her symptoms, during which she became syncopal and unresponsive at 25 min into the test, with a junctional bradycardia and an undetectable blood pressure, consistent with neurally mediated syncope. Her blood pressure and HR normalized with return to supine position. She stopped working after 4 months due to persistent fatigue. She also reported unrefreshing sleep, post-exertional malaise, difficulty with concentration, headache, arthralgias and myalgias, nausea, lightheadedness, tremulousness, visual disturbances, and excessive thirst. After 6 months of symptoms, she met the clinical criteria for ME/CFS. She reported decreased fine motor coordination. Anxiety and depression emerged as the other symptoms progressed.
After 2 years of symptoms, a 10-min standing test demonstrated a HR change of 34 bpm consistent with POTS. Her physical exam was notable for joint hypermobility (Beighton score 5). On upper limb neurodynamic testing with a median nerve bias, elbow extension was limited by 46 and 22° on the left and right, respectively. Neurological findings included brisk DTRs in the 2–3+ range with spread of the patellar reflex, a fine resting tremor, and a positive Hoffman sign bilaterally. Treatments for her orthostatic intolerance were ineffective or poorly tolerated. Progression of symptoms led to an inability to work, drive, or walk more than short distances. She required wheelchair use for most trips outside the house.
Her cervical spine MRI at age 35 showed spondylosis at C5–6, with a canal diameter of 8.5 mm (Fig. 3). Her spine surgeon noted right wrist weakness and some loss of sensation in the median nerve distribution. She elected to undergo anterior C5–6 disc replacement surgery. Tremor, headache, and right shoulder and neck discomfort all resolved in the first week after surgery, at which time she informally noted a lower resting HR and an increase in activity tolerance. She was able to build strength and endurance through gradual increases in exercise, and tolerated 45 min of symptom-free standing. By 3 months post-operatively she was able to complete 5 downhill ski runs. At 7 months post-operatively she was able to engage in regular vigorous physical exercise without provoking increased malaise. She tolerated a reduction in her venlafaxine dose. One year after surgery she reported minimal physical limitations. Cognition improved and she was able to resume reading complex literature.
Figure 4 illustrates the improvements in the heart rate changes during standing tests, as well as the Karnofsky and SF-36 scores for the 3 patients.