Degenerative Disease of the Spine

Degenerative disease of the spine includes changes to both the intervertebral discs and the vertebrae (“spondylosis”) that in general become more common with age. The lifelong mechanical stress sustained by the highly mobile cervical spine and the somewhat less mobile, weight-bearing lumbar spine accounts for the preponderance of degeneration in these two regions. Spinal degeneration may be entirely asymptomatic or may cause back or neck pain, referred pain, radiculopathy, or myelopathy. Degenerative spinal disease is commonly found on imaging of asymptomatic older adults.

The intervertebral discs change in composition and structure with age. From the second decade onward, disc degeneration and its consequent clinical manifestations become more frequent. Concomitant degeneration of the bony elements of the spine also occurs, including “lipping” of the superior and inferior margins of the vertebral bodies, the formation of osteophytes, osteoarthritic changes of the facet joints (subluxation, osteophytosis, and cartilaginous changes), narrowing of the intervertebral disc spaces, hypertrophy of the ligamentum flavum, instability of adjacent vertebrae with spondylolisthesis (anteroposterior slippage of one vertebra on an adjacent one), and narrowing of the lateral recess and intervertebral foramina.

Encroachment of bone or disc may compromise the spinal roots or the spinal cord, resulting in radiculopathy or myelopathy, respectively. Inflammatory mechanisms resulting from exposure of the normally immunologically sequestrated nucleus pulposus, in addition to simple mechanical compression, contribute to the development of radicular symptoms and signs. Although plain radiography of the spine may occasionally identify a vertebral fracture or other focal bony pathologic process, it is not an adequate screening investigation for patients with neurologic compromise. Spinal computed tomography (CT) provides detailed views of the bony components of the spine and, when paired with myelography, may demonstrate encroachment onto the thecal space. Spinal magnetic resonance imaging (MRI) is the modality of choice for demonstrating disc and other soft tissue anatomy; MRI can clearly show compression of the roots and spinal cord and does not expose the patient to ionizing radiation.

Electromyography (EMG) provides additional, complementary information that helps to distinguish radiculopathy from more peripheral pathology, localize involvement to individual nerve roots, and suggest whether the underlying pathophysiology relates to axonal or demyelinating injury.

Cervical Spondylosis and Disc Disease

In addition to disc degeneration and vertebral spondylosis, the contribution of a congenitally narrow spinal canal, buckling of the ligamentum flavum with neck extension, formation of compressive spondylotic “bars,” and ischemic factors have all been proposed as mechanisms leading to neural injury ( Figs. 22-1 and 22-2 ).

Cervical spondylosis. Sagittal T2-weighted magnetic resonance imaging (MRI) of the cervical spine. Multilevel spondylotic disease with spinal stenosis and signal changes in the spinal cord are indicative of myelopathic injury.

Cervical disc disease. Sagittal T2-weighted MRI of the cervical spine. A herniated cervical disc is seen to compress the thecal sac at the C6–C7 level.

Several aspects of the anatomy of this region are important to appreciate: eight pairs of cervical nerve roots are arranged such that a root exits above its respective vertebra after leaving its segmental origin in the spinal cord. A lateral disc herniation at the C5–C6 level, for example, will tend to compromise the C6 root. This is the most common level of cervical radicular involvement, followed in order by a herniation at C6–C7 (C7 root) and at C4–C5 (C5 root).

The clinical manifestations of cervical spondylosis can include midline pain over the spine, limited range of movement, referred pain to the ipsilateral neck and arm (often made worse with coughing, straining, or particular positions of the head), and radiculomyelopathy. An acute root injury may occasionally result from rapid movement of the neck with sudden disc herniation or manifest with a less-abrupt onset more often due to progressive foraminal stenosis secondary to spondylosis. Pain tends to be a prominent early symptom, and is often sharp, radiating to a particular dermatome in association with numbness and paresthesias; weakness occurs when motor roots are involved. Corresponding motor, sensory, and reflex changes are found on examination. Single-level disease is seen in 15 to 40 percent of patients, and multilevel disease occurs in 60 to 80 percent.

Cervical myelopathy tends to be a chronic, progressive process, but it may occasionally be abrupt in onset and catastrophic in severity. There are few data to indicate how often cervical spondylotic radiculopathy is eventually associated with myelopathy. Compression of the spinal cord is often heralded by difficulty in walking and may be followed by sensory loss in the lower limbs and the development of urinary frequency and nocturia. Lhermitte sign may be present. “Numb, clumsy hands” is an unusual symptom complex resulting from upper cord compression.

The natural history of cervical radiculomyelopathy is poorly documented. Good recovery of function frequently follows root injury, especially with a purely demyelinating radiculopathy, from which full recovery within weeks may be expected. Even after partial axonal injury, considerable reinnervation occurs in time. The course of untreated cervical myelopathy varies considerably. Slowly progressive worsening is common, but the myelopathy may remain static for years, improve with conservative measures, or progress rapidly.

Treatment of radiculopathy varies widely, and there is no universally agreed standard of care. Surgery is frequently performed for a variety of indications, despite a lack of large-scale controlled trials comparing surgical and nonsurgical outcomes. A 2010 systematic review found only a single acceptable randomized study of surgery compared with conservative measures. In view of the generally favorable prognosis for recovery of radiculopathy, it is reasonable to embark first on a trial of conservative treatment (limited rest, soft collar, analgesics, anti-inflammatory medications, muscle relaxants) in all patients except those with documented axonal radiculopathy accompanied by progressive muscle weakness. The utility of oral corticosteroids and cervical traction is based only on anecdotal evidence and these treatment modalities are probably best avoided. The role of local corticosteroid injection is not clearly established; temporary symptomatic relief is often achieved, but it probably has little influence on the ultimate outcome and is not free of complications. The most commonly performed surgery is anterior cervical discectomy and fusion. The role of disc replacement is as yet unclear. In general, surgery is indicated when clinical and electrodiagnostic findings are congruent with radiologic abnormalities, and either a progressive motor deficit or unremitting pain persists despite an adequate trial of conservative therapy. Established myelopathy is usually regarded as a firm indication for discectomy and decompressive laminectomy, with or without fusion; clinical improvement or arrest of progression usually follows, but some 15 to 20 percent of patients continue to deteriorate despite surgery.

Lumbar Disc Disease

Around 80 percent of the adult population will have a functionally significant episode of low back pain over a lifetime; a subset of this group will have discogenic disease. Middle-aged men are most frequently affected. Disc herniation is seen less often in the elderly, probably as a consequence of a less mobile lifestyle and the gradual replacement of the disc material with fibrocartilage. Lumbar spine disease ( Fig. 22-3 ) is frequently an asymptomatic finding on imaging, but it may produce a range of symptoms including low backache, locally referred pain, radiating radicular pain (“sciatica”), a radicular neurologic deficit, or some combination of these symptoms. The clinical onset may be spontaneous or associated with an episode of mechanical stress. A flexed posture or a transient increase in the pressure gradient across the dura (e.g., by coughing or sneezing) may exacerbate symptoms.

Degenerative disease of the lumbar spine with spinal stenosis. Sagittal ( A ) and axial ( B ) T2-weighted MRI of the lumbar spine. Multilevel discogenic disease is apparent in the lumbar spine on the sagittal view. Disc material is seen compressing the anterior aspect of the thecal sac on the axial image.

The site of disc pathology may be marked by local tenderness to palpation or percussion over the spinous processes. The patient may adopt a fixed posture, often tilted away from the affected side, and resist movement. Lumbosacral root or sciatic nerve involvement is suggested when passive hip flexion with the leg extended at the knee reproduces the patient’s usual back or leg pain. When radiculopathy is present, the pattern of neurologic deficit will allow identification of the affected root.

Most lumbar disc pathology involves the L4–L5 and L5–S1 interspaces. Disc abnormalities at L1–L2, L2–L3, and L3–L4 are rare, accounting for less than 5 percent of patients. Lumbar disc protrusions are most often posterolateral and affect either descending or exiting nerve roots; they typically cannot result in myelopathy because the spinal cord ends above the L1–L2 interspace. The roots are posterolaterally located at the intervertebral foramen and pass through this aperture in a superior position; therefore a disc protruding at the same level will tend to pass underneath the root exiting at the same interspace, often compressing the root of the segment immediately below. An L4–L5 disc, for example, will usually compromise the L5 root and leave the L4 root unaffected. There are exceptions to this rule—clinical assessment should always allow that a nerve root can be compromised at any point in its intraspinal course.

A large central disc may produce bilateral radicular signs or occasionally result in acute cauda equina syndrome characterized by flaccid paralysis, lower-limb areflexia, or urinary and fecal incontinence. Acute cauda equina syndrome is a surgical emergency and, even when managed promptly, carries a poor prognosis for neurologic recovery. Chronic lumbar canal stenosis may lead to neurogenic claudication (see later).

The differential diagnosis for these symptoms is wide. For patients who present with acute (duration of less than 3 months) low back pain, the emphasis of the initial assessment is on exclusion of serious underlying pathology. Neoplastic, infectious, and traumatic causes are important to identify and require specific treatment. Otherwise, conservative measures (limited bed rest, regular graded exercise, analgesic and anti-inflammatory treatment, physical therapy, and the use of local corticosteroid injections in selected patients) without further investigation represent the most appropriate initial management. When there is no improvement, further investigation is indicated.

The natural history of uncomplicated lumbar disc disease is usually one of eventual disc resorption with improvement of symptoms. Despite this generally good prognosis, lumbar disc surgery represents the most common elective surgical procedure involving the nervous system. The traditional approach is resection of the intervertebral disk and fusion of the vertebrae above and below. Other approaches include intervertebral disk replacement and intradiscal electrotherapy , but their role is yet to be established. Surgery is indicated when a motor deficit (by clinical examination or EMG) is worsening despite conservative management. There is much debate regarding the efficacy of surgery for other patients, and few prospective data are available to help predict which patients are likely to be successfully treated.

Lumbar Spinal Stenosis and Neurogenic Claudication

Stenosis of the lumbar spinal canal is frequently asymptomatic and found incidentally on imaging studies. Boden and colleagues found that 21 percent of asymptomatic adults older than 60 years had lumbar spinal stenosis on MRI. Such narrowing may, however, be associated with symptoms including low back pain and neurogenic claudication of the cauda equina, which classically is described as discomfort and aching pain in the lower back, buttocks, and legs that is precipitated by walking and relieved by sitting. Patients may experience numbness, paresthesias, or a sense of weakness in the legs, usually bilaterally and asymmetrically. Up to 11 percent of patients present with bladder and sexual dysfunction. Sitting for some time will usually relieve symptoms sufficiently to allow further walking. Relief of symptoms with flexion of the spine is the reason that it is often easier to walk up an incline than on a level surface. Neurogenic claudication is usually of gradual onset and, once established, results in symptoms that may become disabling, but tends not to be associated with progressive neurologic deficits.

The pathogenesis is incompletely understood. Venous pooling with exercise in the stenotic canal may lead to intermittent ischemic neurapraxia of the cauda equina with transient conduction failure and clinical and electrophysiologic changes. The anatomic substrate is most commonly that of progressive, chronic, degenerative lumbar spine disease on a background of a congenitally narrow lumbar spinal canal. Extension of the spine decreases, and flexion increases, the caliber of the spinal canal. Diagnosis requires recognition of the highly characteristic history together with radiologic evidence of lumbar spinal stenosis. Electrodiagnostic studies may show prolongation of minimum F-wave and H-reflex latencies, but are mainly useful to document associated radiculopathy. Vascular claudication may be confused with neurogenic claudication but typically causes burning pain in the calves when walking and is usually accompanied by evidence of circulatory insufficiency in the legs. A variety of other neurologic conditions may occasionally produce pseudoclaudication: these include multiple sclerosis and spinal cord arteriovenous malformation.

Many patients with lumbar spinal stenosis find that they can remain mobile within the specific constraints of their symptoms. Surgery aims to relieve symptoms and improve function. Of patients initially opting for conservative therapy, about 30 percent will eventually elect to have surgery. Surgery likely benefits some patients, but the literature provides few controlled data comparing it with conservative treatment. Decompressive laminectomy at one or several levels is typically performed with discectomy or simple foraminotomy, with or without fusion. Surgery is warranted if neurogenic claudication is progressive, significantly limits activities of daily living, or becomes intolerable. Fusion is more frequently employed when there is associated spondylolisthesis. Interspinous decompression with placement of a device between the spinous processes, preventing narrowing of the canal with extension, is a technique that is sometimes employed. Medical treatment of lumbar spinal stenosis may include limited bed rest, anti-inflammatory and analgesic medication, and physical therapy. Murakami and co-workers found that lipoprostaglandin E ₁ increased cauda equina blood flow and relieved symptoms in a small series.

Osteoporosis

Osteoporosis is a disorder characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and consequent increase in fracture risk. It is the most common bone disease; approximately 52 million Americans have osteoporosis or osteopenia. One half of Caucasian women and around 20 percent of Caucasian men will experience an osteoporotic fracture. Any neurologic disorder that impairs strength or balance leading to decreased mobility and an increased risk of falls is a risk factor for osteoporosis ( Table 22-1 ). Patients with spinal cord injury are particularly prone to severe osteoporosis and nontraumatic fractures. Neurologic patients share common risk factors with elderly patients for osteoporosis, such as disuse and lack of exercise, being homebound, vitamin D deficiency, and poor diet. There is growing interest in “neuroskeletal research” of the central nervous system (CNS) regulation of bone remodeling. Leptin is a peptide secreted by adipocytes that regulates appetite and energy metabolism by binding to a hypothalamic leptin receptor. Its effect on bone formation is through induction of the sympathetic nervous system. Osteoblasts in the bone marrow reside next to sympathetic neurons and express β ₂ -adrenergic receptors; catecholamines increase osteoblast proliferation and differentiation (bone formation) and increase bone resorption, with a resulting decrease in bone mass. There also is evidence of a circadian variation for bone remodeling.

The spine is the most frequent osteoporotic fracture site, accounting for approximately 650,000 clinically detected fractures annually. In the United States, 25 percent of women older than 70 and 50 percent of women older than 80 have evidence of vertebral fractures. Low thoracic and high lumbar vertebral fractures are the most common. There is a 10-fold increased risk of a second vertebral fracture in these patients. About 25 percent of vertebral fractures occur from falls, but the majority are triggered by trivial activity such as bending, lifting a light object, or getting out of bed.

Most vertebral fractures are painless and only around 30 percent come to medical attention. Less than 10 percent result in hospital admission. Symptomatic patients usually present with acute low back pain that is often localized to the site of the fracture, but can be diffuse and nonlocalizing. Radiating pain into the lower extremities is uncommon and usually does not correspond to a specific lumbar root pattern. Straining and local percussion typically increase the pain. The patient may not be able to bear weight initially, and symptoms often improve when lying down. There are typically no neurologic symptoms or signs.

Plain radiographs of the spine are the study of choice to document the presence of vertebral fracture. The most widely accepted radiologic definition of vertebral compression-fracture is a decrease of 15 to 25 percent in the anterior, central, or posterior height of a vertebral body compared with adjacent normal vertebrae or a population reference. The diagnosis can be confirmed by bone scan or CT when radiographs are equivocal.

The optimal treatment of acute osteoporotic vertebral fractures without neurologic compromise is uncertain. Prolonged bed rest may accelerate the underlying osteoporosis, so analgesics, local heat alternating with cold application, and mobilization with physical therapy and hydrotherapy are recommended. Rigid external support can prevent failed union of severe vertebral fractures when used in the first 6 months. Narcotics are occasionally required for pain, and calcitonin may provide relief in the acute phase. With persistent pain, an intercostal nerve block or epidural corticosteroid injection may be helpful. Vertebroplasty is a technique involving injecting polymethylmethacrylate into a fractured vertebral body; compared to conservative treatment, it shows greater pain relief, functional recovery, and health-related quality of life. Asymptomatic cement leaks are a potential side effect, and uncommon severe adverse events include radiculopathy due to cement leakage and osteomyelitis. Vertebral body stenting with an expandable metallic implant is another minimally invasive technique that may help preserve vertebral body height and prevent spinal deformity with a lower cement leakage rate.

Preventive treatments for osteoporosis play an increasing role in reducing the number of vertebral fractures in postmenopausal women and the elderly. Detailed recommendations for evidence-based osteoporosis prevention including exercise (weight bearing and muscle strengthening), calcium and vitamin D supplementation, bisphosphonates, hormone replacement, selective estrogen-receptor modulators, desosumab, and teriparatide are summarized elsewhere.

The association between vertebral fractures and chronic back pain is unclear. In patients with osteoporosis and vertebral fractures, the presence and severity of back pain correlate with the number of collapsed thoracic vertebrae and the degree of kyphosis. Neurologic complications are uncommon and include myelopathy, cauda equina syndrome, and lumbosacral radiculopathy. Spinal CT or MRI reveals violation of the posterior cortex of the vertebral bodies (burst fracture) with retropulsion of bone into the spinal canal. The most common location is the thoracolumbar junction. Lower-extremity symptoms may develop from 10 days to 1.5 years after the onset of acute spine pain, owing to extension of vertebral fracture. The etiology is thought to be late collapse of the vertebral body due to disruption of the microcirculation and aseptic necrosis. Severe kyphosis may be a risk factor for progression of vertebral fracture and neurologic compromise.

The best operative approach for those with neurologic deficits is not known. Goals include improvement of the deficit, correction of the deformity, and stabilization of the spine. Clinical results are mixed, ranging from marked improvement to worsening of function with significant postoperative mortality. The approach used is often guided by presence of intervertebral instability and the degree of kyphosis. Postoperative bracing potentially can reduce the rate of instrumentation failure. A small group of patients treated conservatively also has been found to experience significant recovery over months.

Occasionally, patients with vertebral fracture have purely radicular symptoms, with pain radiating into the lower extremity that worsens with change in position or on standing. There may be dermatomal sensory loss and weakness in muscles referable to that root. A study of seven patients with radiculopathy following osteoporotic vertebral fracture who were not operative candidates showed substantial or complete resolution of symptoms following vertebroplasty.

Osteomalacia

Osteomalacia is a metabolic bone disorder characterized by defective mineralization, which results in the accumulation of unmineralized matrix or osteoid in the skeleton. Normal bone mineralization requires adequate circulating levels of vitamin D metabolites, a normal supply of minerals, and optimal osteoblast function. The most common cause of osteomalacia is vitamin D deficiency. Other causes are listed in Table 22-2 . Reduced cutaneous production of vitamin D is a concern in the elderly who are institutionalized or housebound, and in postmenopausal women. Increased time indoors, sunscreen, and the use of ultraviolet-protective glass and clothing contribute to hypovitaminosis D. Dark-skinned individuals require 4 to 5 times more sun exposure than light-skinned people. Dietary sources of vitamin D are limited (wild oily fish, egg yolk, cod-liver oil, and fortified food). Malabsorption results in decreased absorption of vitamin D, increased catabolism of vitamin D metabolites, and malabsorption of calcium or phosphate. Malabsorption from gastric bypass surgery for morbid obesity is emerging as a leading cause of vitamin D deficiency in the United States.

The prevalence of low 25(OH)D levels (<20 ng/ml) is 36 percent in healthy young adults aged 18 to 29 years, 42 percent in black women aged 15 to 49 years, 41 percent in outpatients aged 49 to 83 years, and up to 57 percent in general medicine inpatients in the United States. A study of nonelderly, ambulatory primary-care patients with persistent, nonspecific musculoskeletal pain refractory to standard pharmaceutical agents demonstrated hypovitaminosis D in 93 percent. Current recommendations in North America are that all adults supplement with vitamin D3 600 IU/day and that those in at-risk groups or older than 70 years should take 800 IU/day.

The classic clinical features of osteomalacia include musculoskeletal pain, skeletal deformity, muscle weakness, and symptomatic hypocalcemia. The early symptoms are vague. Bone pain is invariably present, symmetric, and especially prominent in the spine, ribs, pelvis, and lower extremities. The pain is worse with muscle strain, weight bearing, or pressure, but persists with rest. Minimal pressure with the thumb or forefinger on the sternum, ribs, pelvic girdle, or anterior tibia can reproduce the pain on physical examination; it is postulated that collagen-rich osteoid deposited on the periosteal surface of the skeleton may become swollen, putting outward pressure on the periosteal covering that is innervated with nociceptors. These patients are often misdiagnosed as having fibromyalgia, chronic fatigue syndrome, or myositis and treated inappropriately with nonsteroidal anti-inflammatory drugs (NSAIDs).

Proximal myopathy is common, occurring in 73 to 97 percent of patients, and weakness is the presenting complaint in 30 percent. The limb-girdle muscles are the most affected and result in a waddling gait, Gower sign, or inability to walk. The proximal upper extremities and neck flexors are occasionally involved; distal weakness is rare, and bulbar and sphincter muscles are spared. Weakness is accompanied by myalgias and muscle atrophy, although the atrophy is often out of proportion to the degree of weakness. There is no known direct effect of vitamin D on muscle, but an animal model of osteomalacia relates the degree of weakness to hypophosphatemia. Deep tendon reflexes are often brisk and the combination of weakness, atrophy, and hyperreflexia can be mistaken for amyotrophic lateral sclerosis. Vitamin D deficiency may contribute to age-related muscle weakness and falls; a meta-analysis of randomized controlled trials of vitamin D supplementation for elderly ambulatory and institutionalized individuals showed a greater than 20 percent reduction in risk of falls. Other studies exploring vitamin D levels and fall risk also support the role of osteomalacia-associated myopathy in elderly patients.

Osteomalacia in childhood results in rickets with short stature, bowing of the legs, and widening of the metaphyses, which leads to a “rickety rosary” appearance in the ribs. Premature closure of the sagittal cranial sutures may result in craniotabes, and hydrocephalus may occur in severe cases.

Vitamin D modulates the immune system by decreasing the proliferation of proinflammatory T lymphocytes and regulating the production of cytokines. There is an association between high vitamin D levels and a reduced risk of developing multiple sclerosis, but the impact of vitamin D levels on the severity and progression of multiple sclerosis remains unclear. Supplementation in this population with 1000 IU/day is recommended to reach immune-modulating serum levels of vitamin D (30 ng/ml or 75 nmol/L).

Radiologic features of osteomalacia include cortical thinning of bone, cortical striations in the metacarpals and phalanges, and osteopenia. The most characteristic feature is the presence of Looser zones, which are lucent bands adjacent to the periosteum that may represent unhealed stress fractures and most commonly occur in the ribs, pubic rami, and outer borders of the scapulae. Biochemical abnormalities may be minimal and vary with the cause of osteomalacia. A classic triad is hypocalcemia, hypophosphatemia, and increased serum alkaline phosphatase. Serum 25(OH)D is the major circulating metabolite of vitamin D and reflects input from cutaneous synthesis and dietary intake. A minimum level of 20 ng/ml (50 nmol/L) is necessary to satisfy the body’s vitamin D requirement, but a level of 30 to 50 ng/ml (75 to 125 nmol/L) is preferred. Despite clinical evidence of myopathy, the serum creatine kinase level is typically normal. Parathyroid hormone levels may be elevated. Hypocalcemia is usually present in osteomalacia associated with renal failure, but the serum phosphate is normal or high because of reduced urinary excretion.

EMG may be normal in patients with weakness but in around 65 to 85 percent of patients shows small, short-duration, polyphasic motor unit action potentials in proximal muscles, without abnormal spontaneous activity. The findings on muscle biopsy are nonspecific and most often are of type II atrophy.

Treatment of osteomalacia includes ultraviolet irradiation (UV-B wavelength of 290 to 315 nm) and vitamin D replacement. An oral dose of 50,000 IU/week of vitamin D2 for 8 weeks, with monitoring of 25(OH)D and parathyroid hormone levels, should occur in those with vitamin D deficiency. In some cases, a second once-weekly 8-week course of 50,000 IU of vitamin D2 may be necessary to boost 25(OH)D levels into the desired range of more than 30 to 50 ng/ml (75 to 125 nmol/L). For patients prone to developing vitamin D deficiency, after correction of any deficiency, the administration of 50,000 IU every 2 weeks will maintain a vitamin D-sufficient state. An alternative to vitamin D2 is vitamin D3 1000 IU/ day. Calcium and magnesium supplements are also recommended concurrently. Complications of treatment are uncommon, but include hypercalcemia, renal dysfunction, and increased long bone and hip fractures as pain improves before bone mass and strength are restored. The bone pain, symptoms of hypocalcemia, and proximal weakness often resolve completely over weeks to months with treatment, but deformities persist despite remodeling of the bone.

Hypophosphatemic osteomalacia has different neurologic complications than other causes of osteomalacia. The most common form is an X-linked syndrome with hypophosphatemia, osteomalacia, short stature, and the eventual development of new bone at various body sites associated with mutations in the PHEX gene. The proximal myopathy seen with other forms of osteomalacia does not occur. Rarely, myelopathy develops as a result of intra- spinal new bone formation. The mid- and low thoracic spine is the predominant site of involvement, but the cervical spine may also be affected. The onset of symptoms is acute or insidious with paresis, sensory loss, and, less frequently, bladder symptoms. Symptoms can be intermittent and involve multiple levels of the spinal cord, mimicking multiple sclerosis. A rare autosomal dominant form is associated with a mutation of the fibroblast growth factor 23 gene ( FGF23 ). The clinical features are similar to the X-linked form but there is variable penetrance with variable age of onset and it may resolve later in life. An autosomal recessive form is defined by mutations in the dentin matrix protein 1 gene ( DMP1 ).

CT of the spine shows enlargement of the facet joints, thickening of the laminae, and ossification within the spinal canal, resulting in severe central stenosis. Surgery is difficult due to thickening of the bone and adherence of the dura to the ligamentum flavum but can result in improvement or resolution of deficit. Treatment includes an oral neutral phosphate along with 1,25-dihydroxyvitamin D (calcitriol). Excess vitamin D replacement can cause hypercalcemia leading to soft tissue calcification, and serum calcium levels should therefore be measured monthly. Diuretics such as amiloride or hydrochlorothiazide enhance calcium reabsorption and can reduce the risk of nephrocalcinosis.

Osteopetrosis

Osteopetrosis refers to a rare group of sclerosing bone disorders characterized by a generalized increase of skeletal bone mass due to a defect in osteoclastic bone resorption. At least 10 genes have been identified that result in a failure of osteoclast development or function ( Table 22-3 ). In osteopetrosis, the development of the marrow cavity is delayed or absent, and impaired bone modeling during longitudinal growth results in a broad cylindrical shape at the ends of the long bones. These bones become brittle, with an increased susceptibility to fracture. Radiographic features include diffuse sclerosis, bone modeling defects at the metaphyses of long bones, “bone in bone” appearance of the vertebrae and phalanges, as well as focal sclerosis of the skull base, pelvis, and vertebral endplates. The most serious complications of the osteopetroses affect the nervous system and hematopoietic system. Cranial nerves, blood vessels, and the spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina. The severity of osteopetrosis ranges from neonatal onset with life-threatening complications to asymptomatic.

Malignant osteopetrosis presents during infancy and is the most common form of childhood osteopetrosis. The course is severe, with only 30 percent surviving to the age of 6 years without treatment. Its incidence is approximately 1 in 300,000 births. Neurologic involvement occurs frequently and includes optic atrophy with blindness, nystagmus, strabismus, trigeminal neuropathies, facial paralysis, hearing loss (78%), dysarthria, hydrocephalus, intracranial hemorrhage, cognitive dysfunction, and tetanic convulsions. Hydrocephalus is due to obstruction of the venous outflow at the cranial foramina and to inadequate circulation of cerebrospinal fluid (CSF) as a consequence of thickening of the bones of the skull. Cranial nerve involvement relates to bony encroachment, and may necessitate decompression of the optic, facial, or vestibulocochlear nerves. Retinal degeneration has been described in some patients and is another cause of visual loss; the most frequent sign of early damage is a change in latency of the visual evoked potential.

Non-neurologic features include short stature, dental caries, and frequent fractures. The constricted bone marrow cavity cannot support adequate hematopoiesis, resulting in hepatosplenomegaly, thrombocytopenia, anemia, and infectious complications. Clinical symptoms respond to calcitriol, which enhances bone resorption; prednisone, which improves hematologic indices; and interferon-γ1b, which reduces the number of infections and increases bone resorption as well as the size of bone marrow spaces. Calcium and vitamin D supplementation can prevent tetanic seizures. Bone marrow failure is treated with transfusions of red blood cells and platelets. Allogenic hematopoietic cell transplantation is currently the only therapy capable of producing long-term benefit in children and only with mutations of the TGIRG1 gene. Early transplant (before 3 months) has been shown to limit neurosensory defects and impaired bone growth and results in reconstitution of normal hematopoiesis and neutrophil function. Significant risks include a high frequency of graft rejection, veno-occlusive disease, and severe pulmonary hypertension.

Neuropathic autosomal-recessive osteopetrosis is a rare form with nontetanic seizures, developmental delay, hypotonia, retinal atrophy, and sensorineural deafness. There is primary neurodegeneration, and brain MRI abnormalities include delayed myelination, diffuse progressive cortical and subcortical atrophy, and bilateral atrial subependydmal heterotopias.

Intermediate autosomal-recessive and autosomal-dominant osteopetroses have a less severe course and do not have neurologic complications with the uncommon exception of visual and hearing loss due to cranial nerve compression.

Carbonic anhydrase II deficiency (marble brain disease) is an autosomal-recessive disorder resulting in osteopetrosis, renal tubular acidosis, and cerebral calcification. It presents in late infancy or early childhood with developmental delay, cognitive abnormalities, short stature, failure to thrive, a large cranial vault, weakness, cranial nerve compression, and a history of multiple fractures. Patients may have apathy, global hypotonia, or muscle weakness that may be explained by acidosis and diminished blood levels of potassium from renal tubular acidosis. Rarely, episodic hypokalemic weakness occurs. More than one half of all patients develop optic atrophy associated with reduced optic canal size on imaging. Other cranial nerve deficits such as facial palsy and deafness are described in earlier, but not more recent, series.

Metabolic abnormalities include a metabolic acidosis with a persistently positive urinary anion gap without renal failure. Anemia and splenomegaly may be present. Plain radiographs show increased density in the long bones, vertebral bodies, pelvis, and skull. Cranial CT or MRI shows thickened skulls with small or absent paranasal sinuses. Symmetric brain calcifications are present involving the basal ganglia, thalamus, gray-white junction (with a frontal lobe predilection), or some combinations of these sites. The amount of calcification progresses over time but does not correlate with the degree of cognitive abnormalities in these patients. The diagnosis can be made through an erythrocyte assay or by molecular probes for carbonic anhydrase II. Prenatal diagnosis requires direct carbonic anhydrase II gene sequencing. Patients are treated for acidosis with bicarbonate and Na/K citrate. Although the impact of treatment on the natural progression of the bone and neurologic features is unclear, there may be some effect in delaying the development of hearing loss and extramedullary hematopoiesis.

Infantile neuroaxonal dystrophy is a rare autosomal recessive disorder with widespread accumulation of neuroaxonal spheroids in the cortex, basal ganglia, brainstem, and spinal cord, which has been reported in association with osteopetrosis. It presents during the first year of life with weakness, hypotonia, rigidity, pyramidal signs, diminished pain sensation, optic atrophy, and mental impairment, accompanied by hypocalcemia, hypomagnesemia, severe anemia, thrombocytopenia, hepatosplenomegaly, jaundice, and metabolic acidosis. Neuroimaging shows agenesis of the corpus callosum and ventriculomegaly. This form of osteopetrosis is fatal within the first year of life.

Paget Disease of Bone

Paget disease is a focal disorder of bone turnover in which there is excessive bone resorption coupled with abnormal new bone formation, resulting in architecturally disorganized and mechanically weak bone. It has a predilection for the axial skeleton and involves the cervical spine in 14 percent, thoracic spine in 45 percent, lumbar spine in 58 percent, and skull in 42 percent of cases. The prevalence (2.5%) increases with age, and the disorder is found primarily in Caucasians. There is an autosomal-dominant inheritance in up to 40 percent of patients. The etiology is incompletely understood but probably relates to a combination of genetic susceptibility and environmental factors, although the only disease-causing gene identified to date is sequestosome 1 ( SQSTM1 ), found in one-third of affected families and 9 percent of sporadic cases.

Most patients with Paget disease are asymptomatic. The most common presentation in symptomatic patients is local bone pain coupled with overlying skin warmth due to increased bone microvasculature. The pain is continuous and worse at rest and at night. There may be obvious deformity of the bones, and skeletal complications include osteoarthritis, fractures, and sarcomatous changes.

Plain radiographs may show lytic lesions early in the disease; as the disease progresses, a chaotic, crisscross pattern with thickened cortical and trabecular bone is seen, sometimes accompanied by pseudofractures. The most sensitive metabolic marker of Paget disease is total serum alkaline phosphatase, which is elevated in 95 percent of untreated patients.

Treatment depends on the location and activity of the disease. Asymptomatic patients usually do not require treatment, and pain is the only symptom for which there is proven benefit from treatment. Bisphosphonates (e.g., alendronate, ibandronate, pamidronate, risedronate, and zoledronic acid) produce a marked and prolonged inhibition of osteoclast function and are currently the first-line therapy. These agents reduce or normalize serum total alkaline phosphatase levels.

Neurologic involvement is rare and occurs as a result of the close anatomic relationship of bone with the brain, spinal cord, cauda equina, spinal roots, and cranial nerves. Compression from expanding bones or fracture is the most common cause of neurologic dysfunction. Less common causes include ossification of extradural structures, osteosarcoma, and epidural hematoma. Ischemia of the nervous system may occur occasionally due to compression of vascular structures or a vascular steal phenomenon; measurement of skeletal blood flow demonstrates that the affected bone receives up to 18 percent of cardiac output compared with 5 percent in normal bone.

Other neurologic complications of cranial disease include headache, epilepsy, dementia, brainstem and cerebellar dysfunction, and cranial neuropathies. Headache is severe, frequently occipital, and worsened by coughing, sneezing, or straining. Dementia may result from direct compression of the cerebral hemispheres or from hydrocephalus. Epilepsy may occur from direct compression of the cerebral cortex.

In advanced cranial disease, there is softening of the skull base that can result in an anatomic lowering of the skull onto the upper cervical vertebrae (i.e., basilar invagination), leading to obstructive hydrocephalus and compression of the cerebellum, lower cranial nerves, corticospinal tract, and upper cervical nerves. The severity ranges from asymptomatic to tonsillar herniation and death. The typical presentation is that of slowly progressive ataxia, vertigo, tinnitus, dysphagia, dysarthria, and occipital headache. Vertebrobasilar insufficiency as well as obstructed venous return may lead to cerebrovascular compromise. An unusual picture resembling amyotrophic lateral sclerosis sometimes occurs in association with cervical cord involvement.

Any of the cranial nerves may be affected with Paget disease, but the olfactory and auditory nerves are involved most commonly. Hearing loss is common, occurring in 37 percent of patients. It may be neuronal, conductive, or of mixed type. The cochlea is the most common site of involvement. The optic nerve may be affected at the optic foramen by compression of the vasa nervorum; patients present with diminished vision or blindness, retinal hemorrhages, choroiditis, optic atrophy, papilledema, and angioid streaks. The nerves controlling eye movements are vulnerable as they pass through the superior orbital fissure, leading to diplopia and abnormal pupillary responses. Exophthalmos from direct impingement of the extraocular muscles themselves occurs rarely. Trigeminal nerve involvement can lead to facial numbness and trigeminal neuralgia. Involvement of the facial nerve may result in hemifacial spasm or facial paresis with a frequency of 8 percent.

Osteosarcoma of the skull occurs in less than 1 percent of patients with Paget disease. It usually presents as a partially fluctuant and locally painful skull mass with rapid neurologic deterioration in the setting of long-standing disease. The prognosis is poor despite radiation therapy and surgery. Epidural hematomas can cause acute compression of the spinal cord or brain and are related to the increased blood flow to bone and increased risk of pathologic fractures. The prognosis in these cases is also poor, owing to excessive bleeding during surgery.

The spine is the second most common site of involvement in Paget disease and, prior to effective treatment with bisphosphonates, resulted in symptoms of spinal stenosis in 26 percent of patients. Mechanisms of neurologic compromise include: (1) direct compression of the spinal cord, cauda equina, or nerve roots by enlarged vertebrae (most commonly) or expansion of facet joints; (2) pathologic fractures or subluxation; (3) ossification of extradural structures; (4) diversion of the local blood supply to highly vascular bones; and (5) pressure on vessels as they pass through the intervertebral foramina. Sarcomas or epidural hematomas are rare. The onset of continuous severe spinal pain and rapid neurologic deterioration should raise concern of osteosarcoma.

Back pain occurs in 11 to 43 percent of patients with involvement of the spine. Osteoarthritis is prevalent in this elderly population and can be difficult to distinguish from Paget disease as the cause of pain. Other changes in the spine include thickening of the pedicles and laminae, flattening of the vertebral bodies, and encroachment of the spinal canal by osteophytes. Involved vertebrae are increased in width and reduced in height. The most commonly involved levels are the upper and lower cervical, low thoracic, and midlumbar regions. Of those with involvement of the spine demonstrated on plain radiographs, two-thirds will have evidence of spinal stenosis by CT and half of those patients will have clinical evidence of myelopathy or a cauda equina syndrome. There is no association between the number of vertebrae involved and presence of symptoms.

Low back pain may respond to treatment with bisphosphonates. Pain that does not respond after 3 months should be treated with nonsteroidal anti-inflammatory agents. Improvement or reversal of symptoms of spinal stenosis has been demonstrated with mithramycin, etidronate, pamidronate, and clodronate. Prompt surgical decompression is appropriate for patients who do not respond to pharmacologic treatment. Preoperative assessment of bone vascularity by radionuclide bone blood flow can help direct perioperative medical therapy and prevent massive bleeding.

Extradural ossification of the ligamentum flavum and epidural fat can result in compression of the spinal cord or nerve roots and may require surgical decompression. Myelopathy and cauda equina syndrome can occur without evidence of compression on neuroimaging and respond dramatically to medical therapy, suggesting that ischemia due to a vascular steal phenomenon is responsible.

Serum alkaline phosphatase concentrations and urine hydroxyproline are usually increased in patients with neurologic complications, but alkaline phosphatase levels are normal in one-third of those with spinal stenosis. Plain radiographs and radionuclide scans should be obtained to localize disease activity and identify pathologic fractures. Cranial CT or MRI and CT myelography or MRI of the spine are necessary to demonstrate compression of neural structures and to exclude other causes of symptoms ( Fig. 22-4 ). Sarcomatous transformation is best assessed with MRI. Patients with neurologic complications should have serum alkaline phosphatase and urinary hydroxyproline level determinations every 6 months. Clinical monitoring of neurologic function in symptomatic patients and repeat radiographs of the skull and weight-bearing long bones are recommended every 6 to 12 months in those with osteolytic lesions.

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