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InternalMed_Harrison. The cause of low back pain occasionally remains unclear. Some patients have had multiple operations for disk disease but have persistent pain and disability. The original indications for surgery may have been questionable, with back pain only, no definite neurologic signs, or a minor disk bulge noted on CT or MRI. Scoring systems based on neurologic signs, psychological factors, physiologic studies, and imaging studies have been devised to minimize the likelihood of unsuccessful surgery. HEALTH CARE FOR POPuLATIONS OF BACK PAIN PATIENTS: A CLINICAL CARE SYSTEMS VIEW There are increasing pressures to contain health care costs, especially when expensive care is not based on sound evidence. Physicians, patients, the insurance industry, and government providers of health care will need to work together to ensure cost-effective care for patients with back pain.


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InternalMed_Harrison. Surveys in the United States indicate that patients with back pain have reported progressively worse functional limitations in recent years, despite rapid increases in spine imaging, opioid prescribing, injections, and spine surgery. This suggests that more selective use of diagnostic and treatment modalities may be appropriate.


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InternalMed_Harrison. Spine imaging often reveals abnormalities of dubious clinical relevance that may alarm clinicians and patients and prompt further testing and unnecessary therapy. Both randomized trials and observational studies have suggested a “cascade effect” of imaging, which may create a gateway to other unnecessary care. Based in part on such evidence, the American College of Physicians has made parsimonious spine imaging a high priority in its “Choosing Wisely” campaign, aimed at reducing unnecessary care. Successful efforts to reduce unnecessary imaging have included physician education by clinical leaders, computerized decision support to identify recent imaging tests and eliminate duplication, and requiring an approved indication to order an imaging test. Other strategies have included audit and feedback regarding individual practitioners’ rates of ordering and indications and facilitating rapid access to physical therapy for patients who do not need imaging. When imaging tests are reported,


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InternalMed_Harrison. feedback regarding individual practitioners’ rates of ordering and indications and facilitating rapid access to physical therapy for patients who do not need imaging. When imaging tests are reported, it may also be useful to routinely note that some degenerative findings are common in normal, pain-free individuals. In an observational study, this strategy was associated with lower rates of repeat imaging, opioid therapy, and referral for physical therapy.


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InternalMed_Harrison. Mounting evidence of morbidities from long-term opioid therapy (including overdose, dependency, addiction, falls, fractures, accident risk, and sexual dysfunction) has prompted efforts to reduce use for chronic pain, including back pain (Chap. 18). Safety may be improved with automated reminders for high doses, early refills, or overlapping opioid and benzodiazepine prescriptions. Greater access to alternative treatments for chronic pain, such as tailored exercise programs and cognitive-behavioral therapy, may also reduce opioid prescribing.


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InternalMed_Harrison. The high cost, wide geographic variations, and rapidly increasing rates of spinal fusion surgery have prompted scrutiny over appropriate indications. Some insurance carriers have begun to limit coverage for the most controversial indications, such as low back pain without radiculopathy. Finally, educating patients and the public about the risks of imaging and excessive therapy may be necessary. A successful media campaign in Australia provides a successful model for this approach. ALBP is defined as pain of <3 months in duration. Full recovery can be expected in more than 85% of adults with ALBP without leg pain. Most have purely “mechanical” symptoms (i.e., pain that is aggravated by motion and relieved by rest).


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InternalMed_Harrison. The initial assessment excludes serious causes of spine pathology that require urgent intervention including infection, cancer, or trauma. Risk factors for a serious cause of ALBP are shown in Table 22-1. Laboratory and imaging studies are unnecessary if risk factors are absent. CT, MRI, or plain spine films are rarely indicated in the first month of symptoms unless a spine fracture, tumor, or infection is suspected. The prognosis is generally excellent. Many patients do not seek medical care and improve on their own. Even among those seen in primary care, two-thirds report being substantially improved after 7 weeks. This spontaneous improvement can mislead clinicians and researchers about the efficacy of treatment interventions unless subjected to rigorous prospective trials. Many treatments commonly used in the past but now known to be ineffective, including bed rest, lumbar traction, and coccygectomy, have been largely abandoned.


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InternalMed_Harrison. Clinicians should reassure patients that improvement is very likely and instruct them in self-care. Education is an important part of treatment. Satisfaction and the likelihood of follow-up increase when patients are educated about prognosis, treatment methods, 119 activity modifications, and strategies to prevent future exacerbations. Patients who report that they did not receive an adequate explanation for their symptoms are likely to request further diagnostic tests. In general, bed rest should be avoided for relief of severe symptoms or kept to a day or two at most. Several randomized trials suggest that bed rest does not hasten the pace of recovery. In general, the best activity recommendation is for early resumption of normal physical activity, avoiding only strenuous manual labor. Possible advantages of early ambulation for ALBP include maintenance of cardiovascular conditioning, improved disk and cartilage nutrition, improved bone and muscle strength, and increased endorphin


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InternalMed_Harrison. Possible advantages of early ambulation for ALBP include maintenance of cardiovascular conditioning, improved disk and cartilage nutrition, improved bone and muscle strength, and increased endorphin levels. Specific back exercises or early vigorous exercise have not shown benefits for acute back pain, but may be useful for chronic pain. Use of heating pads or blankets is sometimes helpful.


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InternalMed_Harrison. Evidence-based guidelines recommend over-the-counter medicines such as acetaminophen and NSAIDs as first-line options for treatment of ALBP. In otherwise healthy patients, a trial of acetaminophen can be followed by NSAIDs for time-limited periods. In theory, the anti-inflammatory effects of NSAIDs might provide an advantage over acetaminophen to suppress inflammatory changes that accompany many causes of ALBP, but in practice, there is no clinical evidence to support the superiority of NSAIDs. The risk of renal and gastrointestinal toxicity with NSAIDs is increased in patients with preexisting medical comorbidities (e.g., renal insufficiency, cirrhosis, prior gastrointestinal hemorrhage, use of anticoagulants or steroids, heart failure). Skeletal muscle relaxants, such as cyclobenzaprine or methocarbamol, may be useful, but sedation is a common side effect. Limiting the use of muscle relaxants to nighttime only may be an option for patients with back pain that interferes with sleep.


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InternalMed_Harrison. There is no good evidence to support the use of opioid analgesics or tramadol as first-line therapy for ALBP. Their use is best reserved for patients who cannot tolerate acetaminophen or NSAIDs or for those with severe refractory pain. As with muscle relaxants, these drugs are often sedating, so it may be useful to prescribe them at nighttime only. Side effects of short-term opioid use include nausea, constipation, and pruritus; risks of long-term opioid use include hypersensitivity to pain, hypogonadism, and dependency. Falls, fractures, driving accidents, and fecal impaction are other risks. Clinical efficacy of opioids beyond 16 weeks of use is unproven. There is no evidence to support use of oral or injected glucocorticoids for ALBP without radiculopathy. Similarly, therapies for neuropathic pain, such as gabapentin or tricyclic antidepressants, are not indicated for ALBP.


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InternalMed_Harrison. Nonpharmacologic treatments for ALBP include spinal manipulation, exercise, physical therapy, massage, acupuncture, transcutaneous electrical nerve stimulation, and ultrasound. Spinal manipulation appears to be roughly equivalent to conventional medical treatments and may be a useful alternative for patients who wish to avoid or who cannot tolerate drug therapy. There is little evidence to support the use of physical therapy, massage, acupuncture, laser therapy, therapeutic ultrasound, corsets, or lumbar traction. Although important for chronic pain, back exercises for ALBP are generally not supported by clinical evidence. There is no convincing evidence regarding the value of ice or heat applications for ABLP; however, many patients report temporary symptomatic relief from ice or frozen gel packs, and heat may produce a short-term reduction in pain after the first week. Patients often report improved satisfaction with the care that they receive when they actively participate in the


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InternalMed_Harrison. gel packs, and heat may produce a short-term reduction in pain after the first week. Patients often report improved satisfaction with the care that they receive when they actively participate in the selection of symptomatic approaches that are tried.


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InternalMed_Harrison. CLBP is defined as pain lasting >12 weeks; it accounts for 50% of total back pain costs. Risk factors include obesity, female gender, older age, prior history of back pain, restricted spinal mobility, pain radiating into a leg, high levels of psychological distress, poor self-rated health, minimal physical activity, smoking, job dissatisfaction, and widespread pain. In general, the same treatments that are 120 recommended for ALBP can be useful for patients with CLBP. In this setting, however, the long-term benefit of opioid therapy or muscle relaxants is less clear. Evidence supports the use of exercise therapy, and this can be one of the mainstays of treatment for CLBP. Effective regimens have generally included a combination of gradually increasing aerobic exercise, strengthening exercises, and stretching exercises. Motivating patients is sometimes challenging, and in this setting, a program of supervised exercise can improve compliance. In general, activity tolerance is the


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InternalMed_Harrison. exercises, and stretching exercises. Motivating patients is sometimes challenging, and in this setting, a program of supervised exercise can improve compliance. In general, activity tolerance is the primary goal, while pain relief is secondary. Supervised intensive physical exercise or “work hardening” regimens have been effective in returning some patients to work, improving walking distance, and reducing pain. In addition, some forms of yoga have been evaluated in randomized trials and may be helpful for patients who are interested. A long-term benefit of spinal manipulation or massage for CLBP is unproven. Medications for CLBP may include acetaminophen, NSAIDs, and tricyclic antidepressants. Trials of tricyclics suggest benefit even for patients without evidence of depression. Trials do not support the efficacy of selective serotonin reuptake inhibitors (SSRIs) for CLBP. However, depression is common among patients with chronic pain and should be appropriately treated.


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InternalMed_Harrison. Trials do not support the efficacy of selective serotonin reuptake inhibitors (SSRIs) for CLBP. However, depression is common among patients with chronic pain and should be appropriately treated. Cognitive-behavioral therapy is based on evidence that psychological and social factors, as well as somatic pathology, are important in the genesis of chronic pain and disability. Cognitive-behavioral therapy includes efforts to identify and modify patients’ thinking about their pain and disability. A systematic review concluded that such treatments are more effective than a waiting list control group for short-term pain relief; however, long-term results remain unclear. Behavioral treatments may have effects similar in magnitude to exercise therapy. Back pain is the most frequent reason for seeking complementary and alternative treatments. The most common of these for back pain are spinal manipulation, acupuncture, and massage. The role of most complementary and alternative medicine


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InternalMed_Harrison. for seeking complementary and alternative treatments. The most common of these for back pain are spinal manipulation, acupuncture, and massage. The role of most complementary and alternative medicine approaches remains unclear. Biofeedback has not been studied rigorously. There is no convincing evidence that either spinal manipulation or transcutaneous electrical nerve stimulation (TENS) is effective in treating CLBP. Rigorous recent trials of acupuncture suggest that true acupuncture is not superior to sham acupuncture, but that both may offer an advantage over routine care. Whether this is due entirely to placebo effects provided even by sham acupuncture is uncertain. Some trials of massage therapy have been encouraging, but this has been less well studied than spinal manipulation or acupuncture. Various injections, including epidural glucocorticoid injections, facet joint injections, and trigger point injections, have been used for treating CLBP. However, in the absence of


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InternalMed_Harrison. or acupuncture. Various injections, including epidural glucocorticoid injections, facet joint injections, and trigger point injections, have been used for treating CLBP. However, in the absence of radiculopathy, there is no evidence that these approaches are effective. Injection studies are sometimes used diagnostically to help determine the anatomic source of back pain. The use of discography to provide evidence that a specific disk is the pain generator is not recommended. Pain relief following a glucocorticoid injection into a facet is commonly used as evidence that the facet joint is the pain source; however, the possibility that the response was a placebo effect or due to systemic absorption of the glucocorticoids is difficult to exclude. Another category of intervention for chronic back pain is electrothermal and radiofrequency therapy. Intradiskal therapy has been proposed using both types of energy to thermocoagulate and destroy nerves in the intervertebral disk, using


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InternalMed_Harrison. back pain is electrothermal and radiofrequency therapy. Intradiskal therapy has been proposed using both types of energy to thermocoagulate and destroy nerves in the intervertebral disk, using specially designed catheters or electrodes. Current evidence does not support the use of these intradiskal therapies. Radiofrequency denervation is sometimes used to destroy nerves that are thought to mediate pain, and this technique has been used for facet joint pain (with the target nerve being the medial branch of the primary dorsal ramus), for back pain thought to arise from the intervertebral disk (ramus communicans), and radicular back pain (dorsal root ganglia). A few small trials have produced conflicting results for facet joint and diskogenic pain. A trial in patients with chronic radicular pain found no difference between radiofrequency


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases denervation of the dorsal root ganglia and sham treatment. These interventional therapies have not been studied in sufficient detail to draw conclusions of their value for CLBP.


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InternalMed_Harrison. Surgical intervention for CLBP without radiculopathy has been evaluated in a small number of randomized trials, all conducted in Europe. Each of these studies included patients with back pain and a degenerative disk, but no sciatica. Three of the four trials concluded that lumbar fusion surgery was no more effective than highly structured, rigorous rehabilitation combined with cognitive-behavioral therapy. The fourth trial found an advantage of fusion surgery over haphazard “usual care,” which appeared to be less effective than the structured rehabilitation in other trials. Given conflicting evidence, indications for surgery for CLBP without radiculopathy have remained controversial. Both U.S. and British guidelines suggest considering referral for an opinion on spinal fusion for people who have completed an optimal nonsurgical treatment program (including combined physical and psychological treatment) and who have persistent severe back pain for which they would consider surgery.


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InternalMed_Harrison. Lumbar disk replacement with prosthetic disks is U.S. Food and Drug Administration approved for uncomplicated patients needing single-level surgery at the L3-S1 levels. The disks are generally designed as metal plates with a polyethylene cushion sandwiched in between. The trials that led to approval of these devices compared them to spine fusion and concluded that the artificial disks were “not inferior.” Serious complications are somewhat more likely with the artificial disk. This treatment remains controversial for CLBP. Intensive multidisciplinary rehabilitation programs may involve daily or frequent physical therapy, exercise, cognitive-behavioral therapy, a workplace evaluation, and other interventions. For patients who have not responded to other approaches, such programs appear to offer some benefit. Systematic reviews suggest that the evidence is limited and benefits are incremental.


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InternalMed_Harrison. Some observers have raised concern that CLBP may often be overtreated. For CLBP without radiculopathy, new British guidelines explicitly recommend against use of SSRIs, any type of injection, TENS, lumbar supports, traction, radiofrequency facet joint denervation, intradiskal electrothermal therapy, or intradiskal radiofrequency thermocoagulation. These treatments are also not recommended in guidelines from the American College of Physicians and the American Pain Society. On the other hand, exercise therapy and treatment of depression appear to be useful and underused.


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InternalMed_Harrison. A common cause of back pain with radiculopathy is a herniated disk with nerve root impingement, resulting in back pain with radiation down the leg. The term sciatica is used when the leg pain radiates posteriorly in a sciatic or L5/S1 distribution. The prognosis for acute low back and leg pain with radiculopathy due to disk herniation is generally favorable, with most patients showing substantial improvement over months. Serial imaging studies suggest spontaneous regression of the herniated portion of the disk in two-thirds of patients over 6 months. Nonetheless, there are several important treatment options to provide symptomatic relief while this natural healing process unfolds. Resumption of normal activity is recommended. Randomized trial evidence suggests that bed rest is ineffective for treating sciatica as well as back pain alone. Acetaminophen and NSAIDs are useful for pain relief, although severe pain may require short courses of opioid analgesics.


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InternalMed_Harrison. Epidural glucocorticoid injections have a role in providing temporary symptom relief for sciatica due to a herniated disk. However, there does not appear to be a benefit in terms of reducing subsequent surgical interventions. Diagnostic nerve root blocks have been advocated to determine if pain originates from a specific nerve root. However, improvement may result even when the nerve root is not responsible for the pain; this may occur as a placebo effect, from a pain-generating lesion located distally along the peripheral nerve, or from effects of systemic absorption. The utility of diagnostic nerve root blocks remains a subject of debate.


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InternalMed_Harrison. Surgical intervention is indicated for patients who have progressive motor weakness due to nerve root injury demonstrated on clinical examination or EMG. Urgent surgery is recommended for patients who have evidence of CES or spinal cord compression, generally suggested by bowel or bladder dysfunction, diminished sensation in a saddle distribution, a sensory level on the trunk, and bilateral leg weakness or spasticity.


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InternalMed_Harrison. Surgery is also an important option for patients who have disabling radicular pain despite optimal conservative treatment. Sciatica is perhaps the most common reason for recommending spine surgery. Because patients with a herniated disk and sciatica generally experience rapid improvement over a matter of weeks, most experts do not recommend considering surgery unless the patient has failed to respond to 6–8 weeks of maximum nonsurgical management. For patients who have not improved, randomized trials indicate that, compared to nonsurgical treatment, surgery results in more rapid pain relief. However, after the first year or two of follow-up, patients with sciatica appear to have much the same level of pain relief and functional improvement with or without surgery. Thus, both treatment approaches are reasonable, and patient preferences and needs (e.g., rapid return to employment) strongly influence decision making. Some patients will want the fastest possible relief and find surgical


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InternalMed_Harrison. are reasonable, and patient preferences and needs (e.g., rapid return to employment) strongly influence decision making. Some patients will want the fastest possible relief and find surgical risks acceptable. Others will be more risk-averse and more tolerant of symptoms and will choose watchful waiting if they understand that improvement is likely in the end.


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InternalMed_Harrison. The usual surgical procedure is a partial hemilaminectomy with excision of the prolapsed disk (diskectomy). Fusion of the involved lumbar segments should be considered only if significant spinal instability is present (i.e., degenerative spondylolisthesis). The costs associated with lumbar interbody fusion have increased dramatically in recent years. There are no large prospective, randomized trials comparing fusion to other types of surgical intervention. In one study, patients with persistent low back pain despite an initial diskectomy fared no better with spine fusion than with a conservative regimen of cognitive intervention and exercise. Artificial disks have been in use in Europe for the past decade; their utility remains controversial in the United States.


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InternalMed_Harrison. Neck pain, which usually arises from diseases of the cervical spine and soft tissues of the neck, is common. Neck pain arising from the cervical spine is typically precipitated by movement and may be accompanied by focal tenderness and limitation of motion. Many of the prior com-121 ments made regarding causes of low back pain also apply to disorders of the cervical spine. The text below will emphasize differences. Pain arising from the brachial plexus, shoulder, or peripheral nerves can be confused with cervical spine disease (Table 22-4), but the history and examination usually identify a more distal origin for the pain. Cervical spine trauma, disk disease, or spondylosis with intervertebral foraminal narrowing may be asymptomatic or painful and can produce a myelopathy, radiculopathy, or both. The same risk factors for serious causes of low back pain also apply to neck pain with the additional feature that neurologic signs of myelopathy (incontinence, sensory level, spastic legs)


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InternalMed_Harrison. or both. The same risk factors for serious causes of low back pain also apply to neck pain with the additional feature that neurologic signs of myelopathy (incontinence, sensory level, spastic legs) may also occur. Lhermitte’s sign, an electrical shock down the spine with neck flexion, suggests involvement of the cervical spinal cord.


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InternalMed_Harrison. Trauma to the cervical spine (fractures, subluxation) places the spinal cord at risk for compression. Motor vehicle accidents, violent crimes, or falls account for 87% of cervical spinal cord injuries (Chap. 456). Immediate immobilization of the neck is essential to minimize further spinal cord injury from movement of unstable cervical spine segments. The decision to obtain imaging should be based on the nature of the injury. The NEXUS low-risk criteria established that normally alert patients without palpation tenderness in the midline; intoxication; neurologic deficits; or painful distracting injuries were very unlikely to have sustained a clinically significant traumatic injury to the cervical spine. The Canadian C-spine rule recommends that imaging should be obtained following neck region trauma if the patient is >65 years old or has limb paresthesias or if there was a dangerous mechanism for the injury (e.g., bicycle collision with tree or parked car, fall from height >3 feet or


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InternalMed_Harrison. trauma if the patient is >65 years old or has limb paresthesias or if there was a dangerous mechanism for the injury (e.g., bicycle collision with tree or parked car, fall from height >3 feet or five stairs, diving accident). These guidelines are helpful but must be tailored to individual circumstances; for example, patients with advanced osteoporosis, glucocorticoid use, or cancer may warrant imaging after even mild trauma. A CT scan is the diagnostic procedure of choice for detection of acute fractures following severe trauma; plain x-rays can be used for lesser degrees of trauma. When traumatic injury to the vertebral arteries or cervical spinal cord is suspected, visualization by MRI with magnetic resonance angiography is preferred.


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InternalMed_Harrison. Whiplash injury is due to rapid flexion and extension of the neck, usually in automobile accidents. The exact mechanism of the injury is unclear. This diagnosis should not be applied to patients with fractures, disk herniation, head injury, focal neurologic findings, or altered consciousness. Up to 50% of persons reporting whiplash injury acutely have persistent neck pain 1 year later. Once personal C5 Biceps Lateral deltoid Rhomboidsa (elbow extends backward with hand on Lateral arm, medial scapula hip) Infraspinatusa (arm rotates externally with elbow flexed at the side)


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InternalMed_Harrison. Deltoida (arm raised laterally 30–45° from the side) C6 Biceps Thumb/index finger; Bicepsa (arm flexed at the elbow in supination) Lateral forearm, thumb/index fingers Dorsal hand/lateral forearm Pronator teres (forearm pronated) C7 Triceps Middle fingers Tricepsa (forearm extension, flexed at elbow) Posterior arm, dorsal forearm, dorsal hand Dorsal forearm Wrist/finger extensorsa C8 Finger Palmar surface of little finger Abductor pollicis brevis (abduction of thumb) Fourth and fifth fingers, medial hand and flexors forearm Medial hand and forearm First dorsal interosseous (abduction of index finger) Abductor digiti minimi (abduction of little finger) T1 Finger Axilla and medial arm Abductor pollicis brevis (abduction of thumb) Medial arm, axilla flexors First dorsal interosseous (abduction of index finger) Abductor digiti minimi (abduction of little finger) aThese muscles receive the majority of innervation from this root.


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InternalMed_Harrison. 122 compensation for pain and suffering was removed from the Australian health care system, the prognosis for recovery at 1 year from whiplash injury improved also. Imaging of the cervical spine is not cost-effective acutely but is useful to detect disk herniations when symptoms persist for >6 weeks following the injury. Severe initial symptoms have been associated with a poor long-term outcome.


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InternalMed_Harrison. Herniation of a lower cervical disk is a common cause of pain or tingling in the neck, shoulder, arm, or hand. Neck pain, stiffness, and a range of motion limited by pain are the usual manifestations. Herniated cervical disks are responsible for ~25% of cervical radiculopathies. Extension and lateral rotation of the neck narrow the ipsilateral intervertebral foramen and may reproduce radicular symptoms (Spurling’s sign). In young adults, acute nerve root compression from a ruptured cervical disk is often due to trauma. Cervical disk herniations are usually posterolateral near the lateral recess. Typical patterns of reflex, sensory, and motor changes that accompany cervical nerve root lesions are summarized in Table 22-4. Although the classic patterns are clinically helpful, there are numerous exceptions because there is overlap in sensory function between adjacent nerve roots, symptoms and signs may be evident in only part of the injured nerve root territory, and (3) the location of


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InternalMed_Harrison. exceptions because there is overlap in sensory function between adjacent nerve roots, symptoms and signs may be evident in only part of the injured nerve root territory, and (3) the location of pain is the most variable of the clinical features.


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InternalMed_Harrison. Osteoarthritis of the cervical spine may produce neck pain that radiates into the back of the head, shoulders, or arms, or may be the source of headaches in the posterior occipital region (supplied by the C2-C4 nerve roots). Osteophytes, disk protrusions, or hypertrophic facet or uncovertebral joints may alone or in combination compress one or several nerve roots at the intervertebral foramina; these causes together account for 75% of cervical radiculopathies. The roots most commonly affected are C7 and C6. Narrowing of the spinal canal by osteophytes, ossification of the posterior longitudinal ligament (OPLL), or a large central disk may compress the cervical spinal cord and produce signs of radiculopathy and myelopathy in combination (myeloradiculopathy). When little or no neck pain accompanies cervical cord involvement, other diagnoses to be considered include amyotrophic lateral sclerosis (Chap. 452), multiple sclerosis (Chap. 458), spinal cord tumors, or syringomyelia (Chap.


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InternalMed_Harrison. accompanies cervical cord involvement, other diagnoses to be considered include amyotrophic lateral sclerosis (Chap. 452), multiple sclerosis (Chap. 458), spinal cord tumors, or syringomyelia (Chap. 456). The possibility of cervical spondylosis should be considered even when the patient presents with symptoms or signs in the legs only. MRI is the study of choice to define anatomic abnormalities of soft tissues in the cervical region including the spinal cord, but plain CT is adequate to assess bony spurs, foraminal narrowing, lateral recess stenosis, or OPLL. EMG and nerve conduction studies can localize and assess the severity of nerve root injury.


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InternalMed_Harrison. Rheumatoid arthritis (RA) (Chap. 380) of the cervical facet joints produces neck pain, stiffness, and limitation of motion. Synovitis of the atlantoaxial joint (C1-C2; Fig. 22-2) may damage the transverse ligament of the atlas, producing forward displacement of the atlas on the axis (atlantoaxial subluxation). Radiologic evidence of atlantoaxial subluxation occurs in up to 30% of patients with RA. The degree of subluxation correlates with the severity of erosive disease. When subluxation is present, careful assessment is important to identify early signs of myelopathy. Occasional patients develop high spinal cord compression leading to quadriparesis, respiratory insufficiency, and death. Surgery should be considered when myelopathy or spinal instability is present. MRI is the imaging modality of choice. Ankylosing spondylitis can cause neck pain and less commonly atlantoaxial subluxation; surgery may be required to prevent spinal cord compression.


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InternalMed_Harrison. Acute herpes zoster can presents as acute posterior occipital or neck pain prior to the outbreak of vesicles. Neoplasms metastatic to the cervical spine, infections (osteomyelitis and epidural abscess), and metabolic bone diseases may be the cause of neck pain, as discussed above PART 2 Cardinal Manifestations and Presentation of Diseases among causes of low back pain. Neck pain may also be referred from the heart with coronary artery ischemia (cervical angina syndrome). The thoracic outlet contains the first rib, the subclavian artery and vein, the brachial plexus, the clavicle, and the lung apex. Injury to these structures may result in postural or movement-induced pain around the shoulder and supraclavicular region, classified as follows.


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InternalMed_Harrison. True neurogenic thoracic outlet syndrome (TOS) is an uncommon disorder resulting from compression of the lower trunk of the brachial plexus or ventral rami of the C8 or T1 nerve roots, caused most often by an anomalous band of tissue connecting an elongate transverse process at C7 with the first rib. Pain is mild or may be absent. Signs include weakness and wasting of intrinsic muscles of the hand and diminished sensation on the palmar aspect of the fifth digit. An anteroposterior cervical spine x-ray will show an elongate C7 transverse process (an anatomic marker for the anomalous cartilaginous band), and EMG and nerve conduction studies confirm the diagnosis. Treatment consists of surgical resection of the anomalous band. The weakness and wasting of intrinsic hand muscles typically does not improve, but surgery halts the insidious progression of weakness.


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InternalMed_Harrison. Arterial TOS results from compression of the subclavian artery by a cervical rib, resulting in poststenotic dilatation of the artery and in some cases secondary thrombus formation. Blood pressure is reduced in the affected limb, and signs of emboli may be present in the hand. Neurologic signs are absent. Ultrasound can confirm the diagnosis noninvasively. Treatment is with thrombolysis or anticoagulation (with or without embolectomy) and surgical excision of the cervical rib compressing the subclavian artery. Venous TOS is due to subclavian vein thrombosis resulting in swelling of the arm and pain. The vein may be compressed by a cervical rib or anomalous scalene muscle. Venography is the diagnostic test of choice.


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InternalMed_Harrison. Disputed TOS accounts for 95% of patients diagnosed with TOS; chronic arm and shoulder pain are prominent and of unclear cause. The lack of sensitive and specific findings on physical examination or specific markers for this condition results in diagnostic uncertainty. The role of surgery in disputed TOS is controversial. Multidisciplinary pain management is a conservative approach, although treatment is often unsuccessful.


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InternalMed_Harrison. Pain from injury to the brachial plexus or peripheral nerves of the arm can occasionally mimic referred pain of cervical spine origin including cervical radiculopathy. Neoplastic infiltration of the lower trunk of the brachial plexus may produce shoulder or supraclavicular pain radiating down the arm, numbness of the fourth and fifth fingers or medial forearm, and weakness of intrinsic hand muscles innervated by the ulnar and median nerves. Delayed radiation injury may produce similar findings, although pain is less often present and almost always less severe. A Pancoast tumor of the lung (Chap. 107) is another cause and should be considered, especially when a concurrent Horner’s syndrome is present. Suprascapular neuropathy may produce severe shoulder pain, weakness, and wasting of the supraspinatus and infraspinatus muscles. Acute brachial neuritis is often confused with radiculopathy; the acute onset of severe shoulder or scapular pain is followed typically over days by weakness of


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InternalMed_Harrison. and infraspinatus muscles. Acute brachial neuritis is often confused with radiculopathy; the acute onset of severe shoulder or scapular pain is followed typically over days by weakness of the proximal arm and shoulder girdle muscles innervated by the upper brachial plexus. The onset may be preceded by an infection, vaccination, or minor surgical procedure. The long thoracic nerve may be affected resulting in a winged scapula. Brachial neuritis may also present as an isolated paralysis of the diaphragm with or without involvement of other nerves of the upper limb. Recovery may take up to 3 years.


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InternalMed_Harrison. Occasional cases of carpal tunnel syndrome produce pain and paresthesias extending into the forearm, arm, and shoulder resembling a C5 or C6 root lesion. Lesions of the radial or ulnar nerve can mimic a radiculopathy at C7 or C8, respectively. EMG and nerve conduction studies can accurately localize lesions to the nerve roots, brachial plexus, or peripheral nerves. For further discussion of peripheral nerve disorders, see Chap. 459.


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InternalMed_Harrison. For further discussion of peripheral nerve disorders, see Chap. 459. Pain arising from the shoulder can on occasion mimic pain from the spine. If symptoms and signs of radiculopathy are absent, then the differential diagnosis includes mechanical shoulder pain (tendonitis, bursitis, rotator cuff tear, dislocation, adhesive capsulitis, or rotator cuff impingement under the acromion) and referred pain (subdiaphragmatic irritation, angina, Pancoast tumor). Mechanical pain is often worse at night, associated with local shoulder tenderness and aggravated by passive abduction, internal rotation, or extension of the arm. Pain from shoulder disease may radiate into the arm or hand, but focal neurologic signs (sensory, motor, or reflex changes) are absent.


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InternalMed_Harrison. The evidence regarding treatment for neck pain is less complete than that for low back pain, but the approach is remarkably similar in many respects. As with low back pain, spontaneous improvement is the norm for acute neck pain. The usual goals of therapy are to promote a rapid return to normal function and provide symptom relief while healing proceeds. The evidence in support of nonsurgical treatments for whiplash-associated disorders is generally of limited quality and neither supports nor refutes the common treatments used for symptom relief. Gentle mobilization of the cervical spine combined with exercise programs may be beneficial. Evidence is insufficient to recommend for or against the routine use of acupuncture, cervical traction, TENS, ultrasound, diathermy, or massage. Some patients obtain modest relief using a soft neck collar; there is little risk or cost.


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InternalMed_Harrison. For patients with neck pain unassociated with trauma, supervised exercise with or without mobilization appears to be effective. Exercises often include shoulder rolls and neck stretches. The evidence for the use of muscle relaxants, analgesics, and NSAIDs in acute and chronic neck pain is of lower quality and less consistent than for low back pain.


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InternalMed_Harrison. Low-level laser therapy directed at areas of tenderness, local acupuncture points, or a grid of predetermined points is a controversial approach to the treatment of neck pain. A 2009 meta-analysis suggested that this treatment may provide greater pain relief than sham fever Charles A. Dinarello, Reuven Porat Body temperature is controlled by the hypothalamus. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two kinds of signals: one from peripheral nerves that transmit information from warmth/cold receptors in the skin and the other 23 SECTion 2 from the temperature of the blood bathing the region. These two types of signals are integrated by the thermoregulatory center of the hypothalamus to maintain normal temperature. In a neutral temperature environment, the human metabolic rate produces more heat than is necessary to maintain the core body temperature in the range of 36.5–37.5°C (97.7–99.5°F).


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InternalMed_Harrison. therapy for both acute and chronic neck pain, but comparison to 123 other conservative and less expensive treatment measures is needed. Although some surgical studies have proposed a role for anterior diskectomy and fusion in patients with neck pain, these studies generally have not been rigorously conducted. A systematic review suggested that there was no valid clinical evidence to support either cervical fusion or cervical disk arthroplasty in patients with neck pain without radiculopathy. Similarly, there is no evidence to support radiofrequency neurotomy or cervical facet injections for neck pain without radiculopathy.


InternalMed_Harrison

InternalMed_Harrison. The natural history of neck pain with acute radiculopathy due to disk disease is favorable, and many patients will improve without specific therapy. Although there are no randomized trials of NSAIDs for neck pain, a course of NSAIDs, acetaminophen, or both, with or without muscle relaxants, is reasonable as initial therapy. Other nonsurgical treatments are commonly used, including opioid analgesics, oral glucocorticoids, cervical traction, and immobilization with a hard or soft cervical collar. However, there are no randomized trials that establish the effectiveness of these treatments. Soft cervical collars can be modestly helpful by limiting spontaneous and reflex neck movements that exacerbate pain.


InternalMed_Harrison

InternalMed_Harrison. As for lumbar radiculopathy, epidural glucocorticoids appear to provide short-term symptom relief in cervical radiculopathy, but rigorous studies addressing this question have not been conducted. If cervical radiculopathy is due to bony compression from cervical spondylosis with foraminal narrowing, periodic follow-up to assess for progression is indicated and consideration of surgical decompression is reasonable. Surgical treatment can produce rapid pain relief, although it is unclear whether long-term outcomes are improved over nonsurgical therapy. Indications for cervical disk surgery include a progressive radicular motor deficit, functionally limiting pain that fails to respond to conservative management, or spinal cord compression.


InternalMed_Harrison

InternalMed_Harrison. Surgical treatments include anterior cervical diskectomy alone, laminectomy with diskectomy, or diskectomy with fusion. The risk of subsequent radiculopathy or myelopathy at cervical segments adjacent to a fusion is ~3% per year and 26% per decade. Although this risk is sometimes portrayed as a late complication of surgery, it may also reflect the natural history of degenerative cervical disk disease.


InternalMed_Harrison

InternalMed_Harrison. A normal body temperature is ordinarily maintained despite environmental variations because the hypothalamic thermoregulatory center balances the excess heat production derived from metabolic activity in muscle and the liver with heat dissipation from the skin and lungs. According to studies of healthy individuals 18–40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F), with low levels at 6 a.m. and higher levels at 4–6 p.m. The maximal normal oral temperature is 37.2°C (98.9°F) at 6 a.m. and 37.7°C (99.9°F) at 4 p.m.; these values define the 99th percentile for healthy individuals. In light of these studies, an a.m. temperature of >37.2°C (>98.9°F) or a p.m. temperature of >37.7°C (>99.9°F) would define a fever. The normal daily temperature variation is typically 0.5°C (0.9°F). However, in some individuals recovering from a febrile illness, this daily variation can be as great as 1.0°C. During a febrile illness, the diurnal variation is usually maintained, but


InternalMed_Harrison

InternalMed_Harrison. (0.9°F). However, in some individuals recovering from a febrile illness, this daily variation can be as great as 1.0°C. During a febrile illness, the diurnal variation is usually maintained, but at higher, febrile levels. The daily temperature 124 variation appears to be fixed in early childhood; in contrast, elderly individuals can exhibit a reduced ability to develop fever, with only a modest fever even in severe infections. Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. The lower oral readings are probably attributable to mouth breathing, which is a factor in patients with respiratory infections and rapid breathing. Lower-esophageal temperatures closely reflect core temperature. Tympanic membrane thermometers measure radiant heat from the tympanic membrane and nearby ear canal and display that absolute value (unadjusted mode) or a value automatically calculated from the absolute reading on the basis of nomograms relating the radiant temperature measured


InternalMed_Harrison

InternalMed_Harrison. nearby ear canal and display that absolute value (unadjusted mode) or a value automatically calculated from the absolute reading on the basis of nomograms relating the radiant temperature measured to actual core temperatures obtained in clinical studies (adjusted mode). These measurements, although convenient, may be more variable than directly determined oral or rectal values. Studies in adults show that readings are lower with unadjusted-mode than with adjusted-mode tympanic membrane thermometers and that unadjusted-mode tympanic membrane values are 0.8°C (1.6°F) lower than rectal temperatures. In women who menstruate, the a.m. temperature is generally lower in the 2 weeks before ovulation; it then rises by ∼0.6°C (1°F) with ovulation and remains at that level until menses occur. Body temperature can be elevated in the postprandial state. Pregnancy and endocrinologic dysfunction also affect body temperature.


InternalMed_Harrison

InternalMed_Harrison. Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point (e.g., from 37°C to 39°C). This shift of the set point from “normothermic” to febrile levels very much resembles the resetting of the home thermostat to a higher level in order to raise the ambient temperature in a room. Once the hypothalamic set point is raised, neurons in the vasomotor center are activated and vasoconstriction commences. The individual first notices vasoconstriction in the hands and feet. Shunting of blood away from the periphery to the internal organs essentially decreases heat loss from the skin, and the person feels cold. For most fevers, body temperature increases by 1–2°C. Shivering, which increases heat production from the muscles, may begin at this time; however, shivering is not required if heat conservation mechanisms raise blood temperature sufficiently. Nonshivering heat production from the liver also


InternalMed_Harrison

InternalMed_Harrison. from the muscles, may begin at this time; however, shivering is not required if heat conservation mechanisms raise blood temperature sufficiently. Nonshivering heat production from the liver also contributes to increasing core temperature. Behavioral adjustments (e.g., putting on more clothing or bedding) help raise body temperature by decreasing heat loss.


InternalMed_Harrison

InternalMed_Harrison. The processes of heat conservation (vasoconstriction) and heat production (shivering and increased nonshivering thermogenesis) continue until the temperature of the blood bathing the hypothalamic neurons matches the new thermostat setting. Once that point is reached, the hypothalamus maintains the temperature at the febrile level by the same mechanisms of heat balance that function in the afebrile state. When the hypothalamic set point is again reset downward (in response to either a reduction in the concentration of pyrogens or the use of antipyretics), the processes of heat loss through vasodilation and sweating are initiated. Loss of heat by sweating and vasodilation continues until the blood temperature at the hypothalamic level matches the lower setting. Behavioral changes (e.g., removal of clothing) facilitate heat loss.


InternalMed_Harrison

InternalMed_Harrison. A fever of >41.5°C (>106.7°F) is called hyperpyrexia. This extraordinarily high fever can develop in patients with severe infections but most commonly occurs in patients with central nervous system (CNS) hemorrhages. In the preantibiotic era, fever due to a variety of infectious diseases rarely exceeded 106°F, and there has been speculation that this natural “thermal ceiling” is mediated by neuropeptides functioning as central antipyretics. In rare cases, the hypothalamic set point is elevated as a result of local trauma, hemorrhage, tumor, or intrinsic hypothalamic malfunction. The term hypothalamic fever is sometimes used to describe elevated temperature caused by abnormal hypothalamic function. However, most patients with hypothalamic damage have subnormal, not supra-normal, body temperatures. PART 2 Cardinal Manifestations and Presentation of Diseases


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Although most patients with elevated body temperature have fever, there are circumstances in which elevated temperature represents not fever but hyperthermia (heat stroke). Hyperthermia is characterized by an uncontrolled increase in body temperature that exceeds the body’s ability to lose heat. The setting of the hypothalamic thermoregulatory center is unchanged. In contrast to fever in infections, hyperthermia does not involve pyrogenic molecules. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperthermia can result in dangerously high internal temperatures. Excessive heat production can easily cause hyperthermia despite physiologic and behavioral control of body temperature. For example, work or exercise in hot environments can produce heat faster than peripheral mechanisms can lose it. For a detailed discussion of hyperthermia, see Chap. 479e.


InternalMed_Harrison

InternalMed_Harrison. It is important to distinguish between fever and hyperthermia since hyperthermia can be rapidly fatal and characteristically does not respond to antipyretics. In an emergency situation, however, making this distinction can be difficult. For example, in systemic sepsis, fever (hyperpyrexia) can be rapid in onset, and temperatures can exceed 40.5°C (104.9°F). Hyperthermia is often diagnosed on the basis of the events immediately preceding the elevation of core temperature— e.g., heat exposure or treatment with drugs that interfere with thermoregulation. In patients with heat stroke syndromes and in those taking drugs that block sweating, the skin is hot but dry, whereas in fever the skin can be cold as a consequence of vasoconstriction. Antipyretics do not reduce the elevated temperature in hyperthermia, whereas in fever—and even in hyperpyrexia—adequate doses of either aspirin or acetaminophen usually result in some decrease in body temperature.


InternalMed_Harrison

InternalMed_Harrison. The term pyrogen (Greek pyro, “fire”) is used to describe any substance that causes fever. Exogenous pyrogens are derived from outside the patient; most are microbial products, microbial toxins, or whole microorganisms (including viruses). The classic example of an exogenous pyrogen is the lipopolysaccharide (endotoxin) produced by all gram-negative bacteria. Pyrogenic products of gram-positive organisms include the enterotoxins of Staphylococcus aureus and the groups A and B streptococcal toxins, also called superantigens. One staphylococcal toxin of clinical importance is that associated with isolates of S. aureus from patients with toxic shock syndrome. These products of staphylococci and streptococci cause fever in experimental animals when injected intravenously at concentrations of 1–10 μg/kg. Endotoxin is a highly pyrogenic molecule in humans: when injected intravenously into volunteers, a dose of 2–3 ng/kg produces fever, leukocytosis, acute-phase proteins, and generalized


InternalMed_Harrison

InternalMed_Harrison. of 1–10 μg/kg. Endotoxin is a highly pyrogenic molecule in humans: when injected intravenously into volunteers, a dose of 2–3 ng/kg produces fever, leukocytosis, acute-phase proteins, and generalized symptoms of malaise.


InternalMed_Harrison

InternalMed_Harrison. Cytokines are small proteins (molecular mass, 10,000–20,000 Da) that regulate immune, inflammatory, and hematopoietic processes. For example, the elevated leukocytosis seen in several infections with an absolute neutrophilia is attributable to the cytokines interleukin (IL) 1 and IL-6. Some cytokines also cause fever; formerly referred to as endogenous pyrogens, they are now called pyrogenic cytokines. The pyrogenic cytokines include IL-1, IL-6, tumor necrosis factor (TNF), and ciliary neurotropic factor, a member of the IL-6 family. Interferons (IFNs), particularly IFN-α, also are pyrogenic cytokines; fever is a prominent side effect of IFN-α used in the treatment of hepatitis. Each pyrogenic cytokine is encoded by a separate gene, and each has been shown to cause fever in laboratory animals and in humans. When injected into humans at low doses (10–100 ng/kg), IL-1 and TNF produce fever; in contrast, for IL-6, a dose of 1–10 μg/kg is required for fever production.


InternalMed_Harrison

InternalMed_Harrison. A wide spectrum of bacterial and fungal products induce the synthesis and release of pyrogenic cytokines. However, fever can be a manifestation of disease in the absence of microbial infection. For example, inflammatory processes, trauma, tissue necrosis, and antigen-antibody complexes induce the production of IL-1, TNF, and/or IL-6; individually or in combination, these cytokines trigger the hypothalamus to raise the set point to febrile levels.


InternalMed_Harrison

InternalMed_Harrison. During fever, levels of prostaglandin E2 (PGE2) are elevated in hypothalamic tissue and the third cerebral ventricle. The concentrations of PGE2 are highest near the circumventricular vascular organs (organum vasculosum of lamina terminalis)—networks of enlarged capillaries surrounding the hypothalamic regulatory centers. Destruction of these organs reduces the ability of pyrogens to produce fever. Most studies in animals have failed to show, however, that pyrogenic cytokines pass from the circulation into the brain itself. Thus, it appears that both exogenous pyrogens and pyrogenic cytokines interact with the endothelium of these capillaries and that this interaction is the first step in initiating fever—i.e., in raising the set point to febrile levels.


InternalMed_Harrison

InternalMed_Harrison. The key events in the production of fever are illustrated in Fig. 23-1. Myeloid and endothelial cells are the primary cell types that produce pyrogenic cytokines. Pyrogenic cytokines such as IL-1, IL-6, and TNF are released from these cells and enter the systemic circulation. Although these circulating cytokines lead to fever by inducing the synthesis of PGE2, they also induce PGE2 in peripheral tissues. The increase in PGE2 in the periphery accounts for the nonspecific myalgias and arthralgias that often accompany fever. It is thought that some systemic PGE2 escapes destruction by the lung and gains access to the hypothalamus via the internal carotid. However, it is the elevation of PGE2 in the brain that starts the process of raising the hypothalamic set point for core temperature.


InternalMed_Harrison

InternalMed_Harrison. There are four receptors for PGE2, and each signals the cell in different ways. Of the four receptors, the third (EP-3) is essential for fever: when the gene for this receptor is deleted in mice, no fever follows the injection of IL-1 or endotoxin. Deletion of the other PGE2 receptor genes leaves the fever mechanism intact. Although PGE2 is essential for fever, it is not a neurotransmitter. Rather, the release of PGE2 from the brain side of the hypothalamic endothelium triggers the PGE2 receptor on glial cells, and this stimulation results in the rapid release of cyclic adenosine 5′-monophosphate (cAMP), which is a neurotransmitter. As shown in Fig. 23-1, the release of cAMP from glial cells activates neuronal endings from the thermoregulatory center that extend into the area. The elevation of cAMP is thought to account for changes in the hypothalamic set point either directly or indirectly (by inducing the release of neurotransmitters). Distinct receptors for microbial products are


InternalMed_Harrison

InternalMed_Harrison. of cAMP is thought to account for changes in the hypothalamic set point either directly or indirectly (by inducing the release of neurotransmitters). Distinct receptors for microbial products are located on the hypothalamic endothelium. These receptors are called Toll-like receptors and are similar in many ways to IL-1 receptors. IL-1 receptors and Toll-like receptors share the same signaltransducing mechanism. Thus, the direct activation of Toll-like receptors or IL-1 receptors results in PGE2 production and fever.


InternalMed_Harrison

InternalMed_Harrison. Infection, microbial toxins, mediators of inflammation, immune reactions Microbial toxins Fever Monocytes/macrophages, endothelial cells, others Heat conservation, heat production Hypothalamic endotheliumPyrogenic cytokines IL-1, IL-6, TNF, IFN Elevated thermoregulatory set point Circulation PGE2 Cyclic AMP FIguRE 23-1 Chronology of events required for the induction of fever. AMP, adenosine 5′-monophosphate; IFN, interferon; IL, interleukin; PGE2, prostaglandin E2; TNF, tumor necrosis factor.


InternalMed_Harrison

InternalMed_Harrison. FIguRE 23-1 Chronology of events required for the induction of fever. AMP, adenosine 5′-monophosphate; IFN, interferon; IL, interleukin; PGE2, prostaglandin E2; TNF, tumor necrosis factor. Cytokines produced in the brain may account for the hyperpyrexia of CNS hemorrhage, trauma, or infection. Viral infections of the CNS induce microglial and possibly neuronal production of IL-1, TNF, and IL-6. In experimental animals, the concentration of a cytokine required to cause fever is several orders of magnitude lower with direct injection into the brain substance or brain ventricles than with systemic injection. Therefore, cytokines produced in the CNS can raise the hypothalamic set point, bypassing the circumventricular organs. CNS cytokines likely account for the hyperpyrexia of CNS hemorrhage, trauma, or infection. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: The chronology of events preceding fever, including exposure to other infected individuals or to vectors of disease, should be ascertained. Electronic devices for measuring oral, tympanic membrane, or rectal temperatures are reliable, but the same site should be used consistently to monitor a febrile disease. Moreover, physicians should be aware that newborns, elderly patients, patients with chronic liver or renal failure, and patients taking glucocorticoids or being treated with an anticytokine may have active infection in the absence of fever due to a blunted febrile response. The workup should include a complete blood count; a differential count should be performed manually or with an instrument sensitive to the identification of juvenile or band forms, toxic granulations, and Döhle bodies, which are suggestive of bacterial infection. Neutropenia may be present with some viral infections.


InternalMed_Harrison

InternalMed_Harrison. Measurement of circulating cytokines in patients with fever is not helpful since levels of cytokines such as IL-1 and TNF in the circulation often are below the detection limit of the assay or do not coincide with fever. However, in patients with low-grade fevers or possible disease, the most valuable measurements are the C-reactive protein level and the erythrocyte sedimentation rate. These markers of inflammatory processes are particularly helpful in detecting occult disease. Measurement of circulating IL-6 is useful because IL-6 induces C-reactive protein. Acute-phase reactants are discussed in Chap. 325.


InternalMed_Harrison

InternalMed_Harrison. Patients receiving long-term treatment with anticytokine-based regimens are at a disadvantage because of lowered host defense against infection. Even when the results of tests for latent Mycobacterium tuberculosis infection are negative, active tuberculosis can develop in patients receiving anti-TNF therapy. With the increasing use of anticytokines to reduce the activity of IL-1, IL-6, IL-12, or TNF in patients with Crohn’s disease, rheumatoid arthritis, or psoriasis, the possibility that these therapies blunt the febrile response must be kept in mind. The blocking of cytokine activity has the distinct clinical drawback of lowering the level of host defenses against both routine bacterial and opportunistic infections. The opportunistic infections reported in patients treated with agents that neutralize TNF-α are similar to those reported in the HIV-1-infected population (e.g., a new infection with or reactivation of Mycobacterium tuberculosis, with dissemination).


InternalMed_Harrison

InternalMed_Harrison. In nearly all reported cases of infection associated with anticytokine therapy, fever is among the presenting signs. However, the extent to which the febrile response is blunted in these patients remains unknown. A similar situation is seen in patients receiving high-dose glucocorticoid therapy or anti-inflammatory agents such as ibuprofen. Therefore, low-grade fever is of considerable concern in patients receiving anticytokine therapies. The physician should conduct an early and rigorous diagnostic evaluation in these patients. PART 2 Cardinal Manifestations and Presentation of Diseases


InternalMed_Harrison

InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Most fevers are associated with self-limited infections, such as common viral diseases. The use of antipyretics is not contraindicated in these infections: no significant clinical evidence indicates either that antipyretics delay the resolution of viral or bacterial infections or that fever facilitates recovery from infection or acts as an adjuvant to the immune system. In short, treatment of fever and its symptoms with routine antipyretics does no harm and does not slow the resolution of common viral and bacterial infections.


InternalMed_Harrison

InternalMed_Harrison. However, in bacterial infections, the withholding of antipyretic therapy can be helpful in evaluating the effectiveness of a particular antibiotic, especially in the absence of positive cultures of the infecting organism, and the routine use of antipyretics can mask an inadequately treated bacterial infection. Withholding antipyretics in some cases may facilitate the diagnosis of an unusual febrile disease. Temperature-pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, and factitious fever. As stated earlier, in newborns, elderly patients, patients with chronic liver or kidney failure, and patients taking glucocorticoids, fever may not be present despite infection. Hypothermia can develop in patients with septic shock.


InternalMed_Harrison

InternalMed_Harrison. Some infections have characteristic patterns in which febrile episodes are separated by intervals of normal temperature. For example, Plasmodium vivax causes fever every third day, whereas fever occurs every fourth day with P. malariae. Another relapsing fever is related to Borrelia infection, with days of fever followed by a several-day afebrile period and then a relapse into additional days of fever. In the Pel-Ebstein pattern, fever lasting 3–10 days is followed by afebrile periods of 3–10 days; this pattern can be classic for Hodgkin’s disease and other lymphomas. In cyclic neutropenia, fevers occur every 21 days and accompany the neutropenia. There is no periodicity of fever in patients with familial Mediterranean fever. However, these patterns have limited or no diagnostic value compared with specific and rapid laboratory tests.


InternalMed_Harrison

InternalMed_Harrison. Recurrent fever is documented at some point in most autoimmune diseases and nearly all autoinflammatory diseases. Although fever can be a manifestation of autoimmune diseases, recurrent fevers are characteristic of autoinflammatory diseases (Table 23-1), including adult and juvenile Still’s disease, familial Mediterranean fever, and hyper-IgD syndrome. In addition to recurrent fevers, neutrophilia and serosal inflammation characterize autoinflammatory diseases. The fevers associated with these illnesses are dramatically reduced aPyogenic arthritis, pyoderma gangrenosum, and acne. by blocking of IL-1β activity. Anticytokines therefore reduce fever in autoimmune and autoinflammatory diseases. Although fevers in autoinflammatory diseases are mediated by IL-1β, patients also respond to antipyretics.


InternalMed_Harrison

InternalMed_Harrison. The reduction of fever by lowering of the elevated hypothalamic set point is a direct function of reduction of the PGE2 level in the thermoregulatory center. The synthesis of PGE2 depends on the constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic acid released from the cell membrane, and this release is the rate-limiting step in the synthesis of PGE2. Therefore, inhibitors of cyclooxygenase are potent antipyretics. The antipyretic potency of various drugs is directly correlated with the inhibition of brain cyclooxygenase. Acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and lacks noteworthy anti-inflammatory activity; in the brain, however, acetaminophen is oxidized by the p450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity. Moreover, in the brain, the inhibition of another enzyme, COX-3, by acetaminophen may account for the antipyretic effect of this agent. However, COX-3 is not found outside


InternalMed_Harrison

InternalMed_Harrison. cyclooxygenase activity. Moreover, in the brain, the inhibition of another enzyme, COX-3, by acetaminophen may account for the antipyretic effect of this agent. However, COX-3 is not found outside the CNS.


InternalMed_Harrison

InternalMed_Harrison. Oral aspirin and acetaminophen are equally effective in reducing fever in humans. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and specific inhibitors of COX-2 also are excellent antipyretics. Chronic, high-dose therapy with antipyretics such as aspirin or any NSAID does not reduce normal core body temperature. Thus, PGE2 appears to play no role in normal thermoregulation. As effective antipyretics, glucocorticoids act at two levels. First, similar to the cyclooxygenase inhibitors, glucocorticoids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2, which is needed to release arachidonic acid from the cell membrane. Second, glucocorticoids block the transcription of the mRNA for the pyrogenic cytokines. Limited experimental evidence indicates that ibuprofen and COX-2 inhibitors reduce IL-1induced IL-6 production and may contribute to the antipyretic activity of NSAIDs.


InternalMed_Harrison

InternalMed_Harrison. The objectives in treating fever are first to reduce the elevated hypothalamic set point and second to facilitate heat loss. Reducing fever with antipyretics also reduces systemic symptoms of headache, myalgias, and arthralgias. Oral aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and the gastrointestinal tract. Therefore, acetaminophen is preferred as an antipyretic. In children, acetaminophen or oral ibuprofen must be used because aspirin increases the risk of Reye’s syndrome. If the patient cannot take oral antipyretics, parenteral preparations of NSAIDs and rectal suppositories of various antipyretics can be used.


InternalMed_Harrison

InternalMed_Harrison. Treatment of fever in some patients is highly recommended. Fever increases the demand for oxygen (i.e., for every increase of 1°C over 37°C, there is a 13% increase in oxygen consumption) and can aggravate the condition of patients with preexisting impairment of cardiac, pulmonary, or CNS function. Children with a history of febrile or nonfebrile seizure should be aggressively treated to reduce fever. However, it is unclear what triggers the febrile seizure, and there is no correlation between absolute temperature elevation and onset of a febrile seizure in susceptible children. In hyperpyrexia, the use of cooling blankets facilitates the reduction of temperature; however, cooling blankets should not be used without oral antipyretics. In hyperpyretic patients with CNS disease or trauma (CNS bleeding), reducing core temperature mitigates the detrimental effects of high temperature on the brain. For a discussion of treatment for hyperthermia, see Chap. 479e.


InternalMed_Harrison

InternalMed_Harrison. For a discussion of treatment for hyperthermia, see Chap. 479e. Diseases with fever and rash may be classified by type of erup-127 fever and Rash tion: centrally distributed maculopapular, peripheral, confluent desquamative erythematous, vesiculobullous, urticaria-like, nodular, Elaine T. Kaye, Kenneth M. Kaye purpuric, ulcerated, or with eschars. Diseases are listed by these cat- The acutely ill patient with fever and rash may present a diagnostic challenge for physicians. However, the distinctive appearance of an eruption in concert with a clinical syndrome can facilitate a prompt diagnosis and the institution of life-saving therapy or critical infection-control interventions. Representative images of many of the rashes discussed in this chapter are included in Chap. 25e. APPROACH TO THE PATIENT:


InternalMed_Harrison

InternalMed_Harrison. APPROACH TO THE PATIENT: A thorough history of patients with fever and rash includes the following relevant information: immune status, medications taken within the previous month, specific travel history, immunization status, exposure to domestic pets and other animals, history of animal (including arthropod) bites, recent dietary exposures, existence of cardiac abnormalities, presence of prosthetic material, recent exposure to ill individuals, and exposure to sexually transmitted diseases. The history should also include the site of onset of the rash and its direction and rate of spread.


InternalMed_Harrison

InternalMed_Harrison. A thorough physical examination entails close attention to the rash, with an assessment and precise definition of its salient features. First, it is critical to determine what type of lesions make up the eruption. Macules are flat lesions defined by an area of changed color (i.e., a blanchable erythema). Papules are raised, solid lesions <5 mm in diameter; plaques are lesions >5 mm in diameter with a flat, plateau-like surface; and nodules are lesions >5 mm in diameter with a more rounded configuration. Wheals (urticaria, hives) are papules or plaques that are pale pink and may appear annular (ringlike) as they enlarge; classic (nonvasculitic) wheals are transient, lasting only 24 h in any defined area. Vesicles (<5 mm) and bullae (>5 mm) are circumscribed, elevated lesions containing fluid. Pustules are raised lesions containing purulent exudate; vesicular processes such as varicella or herpes simplex may evolve to pustules. Nonpalpable purpura is a flat lesion that is due to


InternalMed_Harrison

InternalMed_Harrison. fluid. Pustules are raised lesions containing purulent exudate; vesicular processes such as varicella or herpes simplex may evolve to pustules. Nonpalpable purpura is a flat lesion that is due to bleeding into the skin. If <3 mm in diameter, the purpuric lesions are termed petechiae; if >3 mm, they are termed ecchymoses. Palpable purpura is a raised lesion that is due to inflammation of the vessel wall (vasculitis) with subsequent hemorrhage. An ulcer is a defect in the skin extending at least into the upper layer of the dermis, and an eschar (tâche noire) is a necrotic lesion covered with a black crust.


InternalMed_Harrison

InternalMed_Harrison. Other pertinent features of rashes include their configuration (i.e., annular or target), the arrangement of their lesions, and their distribution (i.e., central or peripheral). For further discussion, see Chaps. 70, 72, and 147.


InternalMed_Harrison

InternalMed_Harrison. For further discussion, see Chaps. 70, 72, and 147. This chapter reviews rashes that reflect systemic disease, but it does not include localized skin eruptions (i.e., cellulitis, impetigo) that may also be associated with fever (Chap. 156). The chapter is not intended to be all-inclusive, but it covers the most important and most common diseases associated with fever and rash. Rashes are classified herein on the basis of lesion morphology and distribution. For practical purposes, this classification system is based on the most typical disease presentations. However, morphology may vary as rashes evolve, and the presentation of diseases with rashes is subject to many variations (Chap. 72). For instance, the classic petechial rash of Rocky Mountain spotted fever (Chap. 211) may initially consist of blanchable erythematous macules distributed peripherally; at times, however, the rash associated with this disease may not be predominantly acral, or no rash may develop at all.


InternalMed_Harrison

InternalMed_Harrison. egories in Table 24-1, and many are highlighted in the text. However, for a more detailed discussion of each disease associated with a rash, the reader is referred to the chapter dealing with that specific disease. (Reference chapters are cited in the text and listed in Table 24-1.)


InternalMed_Harrison

InternalMed_Harrison. (Reference chapters are cited in the text and listed in Table 24-1.) Centrally distributed rashes, in which lesions are primarily truncal, are the most common type of eruption. The rash of rubeola (measles) starts at the hairline 2–3 days into the illness and moves down the body, typically sparing the palms and soles (Chap. 229). It begins as discrete erythematous lesions, which become confluent as the rash spreads. Koplik’s spots (1to 2-mm white or bluish lesions with an erythematous halo on the buccal mucosa) are pathognomonic for measles and are generally seen during the first 2 days of symptoms. They should not be confused with Fordyce’s spots (ectopic sebaceous glands), which have no erythematous halos and are found in the mouth of healthy individuals. Koplik’s spots may briefly overlap with the measles exanthem.


InternalMed_Harrison

InternalMed_Harrison. Rubella (German measles) also spreads from the hairline downward; unlike that of measles, however, the rash of rubella tends to clear from originally affected areas as it migrates, and it may be pruritic (Chap. 230e). Forchheimer spots (palatal petechiae) may develop but are nonspecific because they also develop in infectious mononucleosis (Chap. 218) and scarlet fever (Chap. 173). Postauricular and suboccipital adenopathy and arthritis are common among adults with rubella. Exposure of pregnant women to ill individuals should be avoided, as rubella causes severe congenital abnormalities. Numerous strains of enteroviruses (Chap. 228), primarily echoviruses and coxsackieviruses, cause nonspecific syndromes of fever and eruptions that may mimic rubella or measles. Patients with infectious mononucleosis caused by Epstein-Barr virus (Chap. 218) or with primary HIV infection (Chap. 226) may exhibit pharyngitis, lymphadenopathy, and a nonspecific maculopapular exanthem.


InternalMed_Harrison

InternalMed_Harrison. 226) may exhibit pharyngitis, lymphadenopathy, and a nonspecific maculopapular exanthem. The rash of erythema infectiosum (fifth disease), which is caused by human parvovirus B19, primarily affects children 3–12 years old; it develops after fever has resolved as a bright blanchable erythema on the cheeks (“slapped cheeks”) with perioral pallor (Chap. 221). A more diffuse rash (often pruritic) appears the next day on the trunk and extremities and then rapidly develops into a lacy reticular eruption that may wax and wane (especially with temperature change) over 3 weeks. Adults with fifth disease often have arthritis, and fetal hydrops can develop in association with this condition in pregnant women.


InternalMed_Harrison

InternalMed_Harrison. Exanthem subitum (roseola) is caused by human herpesvirus 6 and is most common among children <3 years of age (Chap. 219). As in erythema infectiosum, the rash usually appears after fever has subsided. It consists of 2to 3-mm rose-pink macules and papules that coalesce only rarely, occur initially on the trunk and sometimes on the extremities (sparing the face), and fade within 2 days.


InternalMed_Harrison

InternalMed_Harrison. Although drug reactions have many manifestations, including urticaria, exanthematous drug-induced eruptions (Chap. 74) are most common and are often difficult to distinguish from viral exanthems. Eruptions elicited by drugs are usually more intensely erythematous and pruritic than viral exanthems, but this distinction is not reliable. A history of new medications and an absence of prostration may help to distinguish a drug-related rash from an eruption of another etiology. Rashes may persist for up to two weeks after administration of the offending agent is discontinued. Certain populations are more prone than others to drug rashes. Of HIV-infected patients, 50–60% develop a rash in response to sulfa drugs; 90% of patients with mononucleosis due to Epstein-Barr virus develop a rash when given ampicillin.


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InternalMed_Harrison. Rickettsial illnesses (Chap. 211) should be considered in the evaluation of individuals with centrally distributed maculopapular eruptions. The usual setting for epidemic typhus is a site of war or natural disaster in which people are exposed to body lice. Endemic typhus or leptospirosis (the latter caused by a spirochete) (Chap. 208) may be CHAPTER 24 Fever and Rash PART 2 Cardinal Manifestations and Presentation of Diseases Rash beginning on wrists and ankles and spreading centripetally; appears on palms and soles later in disease; lesion evolution from blanchable macules to petechiae Coincident primary chancre in 10% of cases; copper-colored, scaly papular eruption, diffuse but prominent on palms and soles; rash never vesicular in adults; condyloma latum, mucous patches, and alopecia in some cases Maculopapular eruption; prominent on upper extremities and face, but can also occur on trunk and lower extremities


InternalMed_Harrison

InternalMed_Harrison. Maculopapular eruption; prominent on upper extremities and face, but can also occur on trunk and lower extremities Tender vesicles, erosions in mouth; 0.25-cm papules on hands and feet with rim of erythema evolving into tender vesicles Target lesions (central erythema surrounded by area of clearing and another rim of erythema) up to 2 cm; symmetric on knees, elbows, palms, soles; spreads centripetally; papular, sometimes vesicular; when extensive and involving mucous membranes, termed EM major Maculopapular eruption over palms, soles, and extremities; tends to be more severe at joints; eruption sometimes becoming generalized; may be purpuric; may desquamate Subacute course: Osler’s nodes (tender pink nodules on finger or toe pads); petechiae on skin and mucosa; splinter hemorrhages. Acute course (e.g., Staphylococcus aureus): Janeway lesions (painless erythematous or hemorrhagic macules, usually on palms and soles) —


InternalMed_Harrison

InternalMed_Harrison. Tick vector; widespread but more common in southeastern and southwest-central U.S. Aedes aegypti and A. albopictus mosquito bites; primarily in Africa and Indian Ocean region infection; drug intake (i.e., sulfa, phenytoin, penicillin) Rat bite, ingestion of contaminated food Abnormal heart valve (e.g., viridans group streptococci), intravenous drug use Headache, myalgias, abdominal pain; mortality rates up to 40% if untreated Fever, constitutional symptoms Severe polyarticular, migratory arthralgias, especially involving small joints (e.g., hands, wrists, ankles) 50% of patients <20 years old; fever more common in most severe form, EM major, which can be confused with Stevens-Johnson syndrome (but EM major lacks prominent skin sloughing) 180, 181, 221 Chronic meningococcemia, disseminated gonococcal infection,a human parvovirus B19 infectione Infection, drugs, idiopathic causes Streptococcus, Staphylococcus, etc.


InternalMed_Harrison

InternalMed_Harrison. Chronic meningococcemia, disseminated gonococcal infection,a human parvovirus B19 infectione Infection, drugs, idiopathic causes Streptococcus, Staphylococcus, etc. PART 2 Cardinal Manifestations and Presentation of Diseases disease) Streptococcus (pyrogenic exotoxins A, B, C) shock syndrome Streptococcus (associated with pyrogenic exotoxin A and/or B or certain M types) Staphylococcal toxic S. aureus (toxic shock shock syndrome syndrome toxin 1, enterotoxins B and others) Diffuse blanchable erythema beginning on face and spreading to trunk and extremities; circumoral pallor; “sandpaper” texture to skin; accentuation of linear erythema in skin folds (Pastia’s lines); enanthem of white evolving into red “strawberry” tongue; desquamation in second week Rash similar to scarlet fever (scarlatiniform) or EM; fissuring of lips, strawberry tongue; conjunctivitis; edema of hands, feet; desquamation later in disease When present, rash often scarlatiniform


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InternalMed_Harrison. When present, rash often scarlatiniform Diffuse erythema involving palms; pronounced erythema of mucosal surfaces; conjunctivitis; desquamation 7–10 days into illness Most common among children 2–10 years old; usually follows group A streptococcal pharyngitis May occur in setting of severe group A streptococcal infections (e.g., necrotizing fasciitis, bacteremia, pneumonia) Colonization with toxin-producing S. aureus Fever, pharyngitis, headache Cervical adenopathy, pharyngitis, coronary artery vasculitis Multiorgan failure, hypo-tension; mortality rate 30% Fever >39°C (>102°F), hypotension, multiorgan dysfunction 72, 385 Staphylococcal S. aureus, phage scalded-skin syndrome group II Diffuse tender erythema, often with bullae and desquamation; Nikolsky’s sign Diffuse erythema (often scaling) interspersed with lesions of underlying condition


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InternalMed_Harrison. Diffuse tender erythema, often with bullae and desquamation; Nikolsky’s sign Diffuse erythema (often scaling) interspersed with lesions of underlying condition Maculopapular eruption (mimicking exanthematous drug rash), sometimes progressing to exfoliative erythroderma; profound edema, especially facial; pustules may occur Erythematous and purpuric macules, sometimes targetoid, or diffuse erythema progressing to bullae, with sloughing and necrosis of entire epidermis; Nikolsky’s sign; involves mucosal surfaces; TEN (>30% epidermal necrosis) is maximal form; SJS involves <10% of epidermis; SJS/TEN overlap involves 10–30% of epidermis Colonization with toxin-producing S. aureus; occurs in children <10 years old (termed Ritter’s disease in neonates) or adults with renal dysfunction Individuals genetically unable to detoxify arene oxides (anticonvulsants), patients with slow Nacetylating capacity (sulfonamides)


InternalMed_Harrison

InternalMed_Harrison. Individuals genetically unable to detoxify arene oxides (anticonvulsants), patients with slow Nacetylating capacity (sulfonamides) Uncommon among children; more common among patients with HIV infection, SLE, certain HLA types, or slow acetylators Irritability; nasal or con-172 junctival secretions Macules (2–3 mm) evolving into papules, then vesicles (sometimes umbilicated), on an erythematous base (“dewdrops on a rose petal”); pustules then forming and crusting; lesions appearing in crops; may involve scalp, mouth; intensely pruritic Pruritic erythematous follicular, papular, vesicular, or pustular lesions that may involve axillae, buttocks, abdomen, and especially areas occluded by bathing suits; can manifest as tender isolated nodules on palmar or plantar surfaces (the latter designated “Pseudomonas hot-foot syndrome”)


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InternalMed_Harrison. Red macules on tongue and palate evolving to papules and vesicles; skin macules evolving to papules, then vesicles, then pustules over 1 week, with subsequent lesion crusting; lesions initially appearing on face and spreading centrifugally from trunk to extremities; differs from varicella in that (1) skin lesions in any given area are at same stage of development and (2) there is a prominent distribution of lesions on face and extremities (including palms, soles) Erythema rapidly followed by hallmark painful grouped vesicles that may evolve into pustules that ulcerate, especially on mucosal surfaces; lesions at site of inoculation: commonly gingivostomatitis for HSV-1 and genital lesions for HSV-2; recurrent disease milder (e.g., herpes labialis does not involve oral mucosa) — Usually affects children; 10% of adults susceptible; most common in late winter and spring; incidence down by 90% in U.S. as a result of varicella vaccination Nonimmune individuals exposed to smallpox


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InternalMed_Harrison. Nonimmune individuals exposed to smallpox Malaise; generally mild disease in healthy children; more severe disease with complications in adults and immunocompromised children Earache, sore eyes and/ or throat; fever may be absent; generally self-limited Prodrome of fever, headache, backache, myalgias; vomiting in 50% of cases PART 2 Cardinal Manifestations and Presentation of Diseases Disseminated Vibrio V. vulnificus vulnificus infection Ecthyma gangrenosum P. aeruginosa, other gram-negative rods, fungi


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InternalMed_Harrison. PART 2 Cardinal Manifestations and Presentation of Diseases Disseminated Vibrio V. vulnificus vulnificus infection Ecthyma gangrenosum P. aeruginosa, other gram-negative rods, fungi Generalized vesicles that can evolve to pustules and ulcerations; individual lesions similar for VZV and HSV. Zoster cutaneous dissemination: >25 lesions extending outside involved dermatome. HSV: extensive, progressive mucocutaneous lesions that may occur in absence of dissemination, sometimes disseminate in eczematous skin (eczema herpeticum); HSV visceral dissemination may occur with only localized mucocutaneous disease; in disseminated neonatal disease, skin lesions diagnostically helpful when present, but rash absent in a substantial minority of cases Eschar found at site of mite bite; generalized rash involving face, trunk, extremities; may involve palms and soles; <100 papules and plaques (2–10 mm); tops of lesions developing vesicles that may evolve into pustules


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InternalMed_Harrison. Tiny sterile nonfollicular pustules on erythematous, edematous skin; begins on face and in body folds, then becomes generalized Indurated plaque evolving into hemorrhagic bulla or pustule that sloughs, resulting in eschar formation; erythematous halo; most common in axillary, groin, perianal regions Patients with immunosuppression, eczema; neonates Appears 2–21 days after start of drug therapy, depending on whether patient has been sensitized Patients with cirrhosis, diabetes, renal failure; exposure by ingestion of contaminated saltwater, seafood Usually affects neutropenic patients; occurs in up to 28% of individuals with Pseudomonas bacteremia Visceral organ involvement (e.g., liver, lungs) in some cases; neonatal disease particularly severe Headache, myalgias, regional adenopathy; mild disease Acute fever, pruritus, leukocytosis Clinical signs of sepsis 164, 216,


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InternalMed_Harrison. Headache, myalgias, regional adenopathy; mild disease Acute fever, pruritus, leukocytosis Clinical signs of sepsis 164, 216, Urticarial vasculitis Serum sickness, Erythematous, edematous “urticaria-like” Patients with serum sick-Fever variable; arthralgias/ 385f often due to infec-plaques, pruritic or burning; unlike urticaria: ness (including hepatitis arthritis tion (including typical lesion duration >24 h (up to 5 days) B), connective tissue hepatitis B viral, and lack of complete lesion blanching with disease enteroviral, parasitic), compression due to hemorrhage drugs; connective tissue disease Disseminated infection Fungal infections (e.g., candidiasis, histoplasmosis, cryptococcosis, sporotrichosis, coccidioidomycosis); mycobacteria


InternalMed_Harrison

InternalMed_Harrison. Disseminated infection Fungal infections (e.g., candidiasis, histoplasmosis, cryptococcosis, sporotrichosis, coccidioidomycosis); mycobacteria Erythema nodosum Infections (e.g., (septal panniculitis) streptococcal, fungal, mycobacterial, yersinial); drugs (e.g., sulfas, penicillins, oral contraceptives); sarcoidosis; idiopathic causes dermatosis) inflammatory bowel disease; pregnancy; malignancy (usually hematologic); drugs (G-CSF) Subcutaneous nodules (up to 3 cm); fluctuance, draining common with mycobacteria; necrotic nodules (extremities, periorbital or nasal regions) common with Aspergillus, Mucor Large, violaceous, nonulcerative, subcutaneous nodules; exquisitely tender; usually on lower legs but also on upper extremities


InternalMed_Harrison

InternalMed_Harrison. Large, violaceous, nonulcerative, subcutaneous nodules; exquisitely tender; usually on lower legs but also on upper extremities Tender red or blue edematous nodules giving impression of vesiculation; usually on face, neck, upper extremities; when on lower extremities, may mimic erythema nodosum Immunocompromised Features vary with —f hosts (i.e., bone marrow organism transplant recipients, patients undergoing chemotherapy, HIV-infected patients, alcoholics) More common among Arthralgias (50%); features —f girls and women 15–30 vary with associated years old condition


InternalMed_Harrison

InternalMed_Harrison. More common among Arthralgias (50%); features —f girls and women 15–30 vary with associated years old condition PART 2 Cardinal Manifestations and Presentation of Diseases aSee “Purpuric Eruptions.” bSee “Confluent Desquamative Erythemas.” cIn human granulocytotropic ehrlichiosis or anaplasmosis (caused by Anaplasma phagocytophila; most common in the upper midwestern and northeastern United States), rash is rare. dSee “Viral hemorrhagic fever” under “Purpuric Eruptions” for dengue hemorrhagic fever/dengue shock syndrome. eSee “Centrally Distributed Maculopapular Eruptions.” fSee etiology-specific chapters. gSee “Peripheral Eruptions.” hSee “Vesiculobullous or Pustular Eruptions.” Abbreviations: CNS, central nervous system; DIC, disseminated intravascular coagulation; G-CSF, granulocyte colony-stimulating factor; HLA, human leukocyte antigen.


InternalMed_Harrison

InternalMed_Harrison. Abbreviations: CNS, central nervous system; DIC, disseminated intravascular coagulation; G-CSF, granulocyte colony-stimulating factor; HLA, human leukocyte antigen. seen in urban environments where rodents proliferate. Outside the United States, other rickettsial diseases cause a spotted-fever syndrome and should be considered in residents of or travelers to endemic areas. Similarly, typhoid fever, a nonrickettsial disease caused by Salmonella typhi (Chap. 190), is usually acquired during travel outside the United States. Dengue fever, caused by a mosquito-transmitted flavivirus, occurs in tropical and subtropical regions of the world (Chap. 233).


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InternalMed_Harrison. Some centrally distributed maculopapular eruptions have distinctive features. Erythema migrans, the rash of Lyme disease (Chap. 210), typically manifests as single or multiple annular plaques. Untreated erythema migrans lesions usually fade within a month but may persist for more than a year. Southern tick-associated rash illness (STARI) (Chap. 210) has an erythema migrans–like rash but is less severe than Lyme disease and often occurs in regions where Lyme is not endemic. Erythema marginatum, the rash of acute rheumatic fever (Chap. 381), has a distinctive pattern of enlarging and shifting transient annular lesions.


InternalMed_Harrison

InternalMed_Harrison. Collagen vascular diseases may cause fever and rash. Patients with systemic lupus erythematosus (Chap. 378) typically develop a sharply defined, erythematous eruption in a butterfly distribution on the cheeks (malar rash) as well as many other skin manifestations. Still’s disease (Chap. 398) presents as an evanescent, salmon-colored rash on the trunk and proximal extremities that coincides with fever spikes.


InternalMed_Harrison

InternalMed_Harrison. These rashes are alike in that they are most prominent peripherally or begin in peripheral (acral) areas before spreading centripetally. Early diagnosis and therapy are critical in Rocky Mountain spotted fever (Chap. 211) because of its grave prognosis if untreated. Lesions evolve from macular to petechial, start on the wrists and ankles, spread centripetally, and appear on the palms and soles only later in the disease. The rash of secondary syphilis (Chap. 206), which may be generalized but is prominent on the palms and soles, should be considered in the differential diagnosis of pityriasis rosea, especially in sexually active patients. Chikungunya fever (Chap. 233), which is transmitted by mosquito bite in Africa and the Indian Ocean region, is associated with a maculopapular eruption and severe polyarticular small-joint arthralgias. Hand-foot-and-mouth disease (Chap. 228), most commonly caused by coxsackievirus A16, is distinguished by tender vesicles distributed peripherally and


InternalMed_Harrison

InternalMed_Harrison. and severe polyarticular small-joint arthralgias. Hand-foot-and-mouth disease (Chap. 228), most commonly caused by coxsackievirus A16, is distinguished by tender vesicles distributed peripherally and in the mouth; outbreaks commonly occur within families. The classic target lesions of erythema multiforme appear symmetrically on the elbows, knees, palms, soles, and face. In severe cases, these lesions spread diffusely and involve mucosal surfaces. Lesions may develop on the hands and feet in endocarditis (Chap. 155).


InternalMed_Harrison

InternalMed_Harrison. These eruptions consist of diffuse erythema frequently followed by desquamation. The eruptions caused by group A Streptococcus or Staphylococcus aureus are toxin-mediated. Scarlet fever (Chap. 173) usually follows pharyngitis; patients have a facial flush, a “strawberry” tongue, and accentuated petechiae in body folds (Pastia’s lines). Kawasaki disease (Chaps. 72 and 385) presents in the pediatric population as fissuring of the lips, a strawberry tongue, conjunctivitis, adenopathy, and sometimes cardiac abnormalities. Streptococcal toxic shock syndrome (Chap. 173) manifests with hypotension, multiorgan failure, and, often, a severe group A streptococcal infection (e.g., necrotizing fasciitis). Staphylococcal toxic shock syndrome (Chap.


InternalMed_Harrison

InternalMed_Harrison. 172) also presents with hypotension and multiorgan failure, but usually only S. aureus colonization—not a severe S. aureus infection—is documented. Staphylococcal scalded-skin syndrome (Chap. 172) is seen primarily in children and in immunocompromised adults. Generalized erythema is often evident during the prodrome of fever and malaise; profound tenderness of the skin is distinctive. In the exfoliative stage, the skin can be induced to form bullae with light lateral pressure (Nikolsky’s sign). In a mild form, a scarlatiniform eruption mimics scarlet fever, but the patient does not exhibit a strawberry tongue or circumoral pallor. In contrast to the staphylococcal scalded-skin syndrome, in which the cleavage plane is superficial in the epidermis, toxic epidermal necrolysis (Chap. 74), a maximal variant of Stevens-Johnson syndrome, involves sloughing of the entire epidermis, resulting in severe disease. Exfoliative erythroderma syndrome (Chaps. 72 and 74) is a serious reaction


InternalMed_Harrison

InternalMed_Harrison. 74), a maximal variant of Stevens-Johnson syndrome, involves sloughing of the entire epidermis, resulting in severe disease. Exfoliative erythroderma syndrome (Chaps. 72 and 74) is a serious reaction associated with systemic toxicity that is often due to eczema, psoriasis, a drug reaction, or mycosis fungoides. Drug rash with eosinophilia and systemic symptoms (DRESS), often due to antiepileptic and antibiotic agents (Chap. 74), initially appears similar to an exanthematous drug reaction but may progress to exfoliative erythroderma; it is accompanied by multi-organ failure and has an associated mortality rate of ~10%.


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InternalMed_Harrison. Varicella (Chap. 217) is highly contagious, often occurring in winter or spring. At any point in time, within a given region of the body, varicella lesions are in different stages of development. In immunocompromised hosts, varicella vesicles may lack the characteristic erythematous base or may appear hemorrhagic. Lesions of Pseudomonas “hot-tub” folliculitis (Chap. 189) are also pruritic and may appear similar to those of varicella. However, hot-tub folliculitis generally occurs in outbreaks after bathing in hot tubs or swimming pools, and lesions occur in regions occluded by bathing suits. Lesions of variola (smallpox) (Chap. 261e) also appear similar to those of varicella but are all at the same stage of development in a given region of the body. Variola lesions are most prominent on the face and extremities, while varicella lesions are most prominent on the trunk. Herpes simplex virus infection (Chap. 216) is characterized by hallmark grouped vesicles on an erythematous base.