Harrison Neurology in Clinical Medicine Second Edition

SECTION III Diseases of the Central Nervous System382 usually respond to surgical decompression of the facial ear because of involvement of the tympanic branch of the nerve. Blepharospasm is an involuntary recurrent spasm of glossopharyngeal nerve. Spasms of pain may be initiated both eyelids that usually occurs in elderly persons as an by swallowing or coughing. There is no demonstrable isolated phenomenon or with varying degrees of spasm motor or sensory deficit; the glossopharyngeal nerve sup- of other facial muscles. Severe, persistent cases of ble- plies taste sensation to the posterior third of the tongue pharospasm can be treated by local injection of botu- and, together with the vagus nerve, sensation to the pos- linum toxin into the orbicularis oculi. Facial myokymia terior pharynx. Cardiac symptoms—bradycardia or asys- refers to a fine rippling activity of the facial muscles; it tole, hypotension, and fainting—have been reported. may be caused by multiple sclerosis or follow Guillain- Medical therapy is similar to that for trigeminal neuralgia, Barré syndrome (Chap. 41). and carbamazepine is generally the first choice. If drug Facial hemiatrophy occurs mainly in women and is therapy is unsuccessful, surgical procedures—including characterized by a disappearance of fat in the dermal microvascular decompression if vascular compression is and subcutaneous tissues on one side of the face. It usu- evident—or rhizotomy of glossopharyngeal and vagal ally begins in adolescence or early adult years and is fibers in the jugular bulb is frequently successful. slowly progressive. In its advanced form, the affected side of the face is gaunt, and the skin is thin, wrinkled, and Very rarely, herpes zoster involves the glossopharyn- brown. The facial hair may turn white and fall out, and geal nerve. Glossopharyngeal neuropathy in conjunction the sebaceous glands become atrophic. Bilateral involve- with vagus and accessory nerve palsies may also occur ment may occur. A limited form of systemic sclerosis with a tumor or aneurysm in the posterior fossa or in (scleroderma) may be the cause of some cases.Treatment the jugular foramen. Hoarseness due to vocal cord paral- is cosmetic, consisting of transplantation of skin and sub- ysis, some difficulty in swallowing, deviation of the soft cutaneous fat. palate to the intact side, anesthesia of the posterior wall of the pharynx, and weakness of the upper part of the OTHER CRANIAL NERVE DISORDERS trapezius and sternocleidomastoid muscles make up the jugular foramen syndrome (Table 29-2). GLOSSOPHARYNGEAL NEURALGIA DYSPHAGIA AND DYSPHONIA This form of neuralgia involves the ninth (glossopharyn- geal) and sometimes portions of the tenth (vagus) cranial When the intracranial portion of one vagus (tenth cra- nerves. It resembles trigeminal neuralgia in many respects nial) nerve is interrupted, the soft palate droops ipsilater- but is much less common.The pain is intense and parox- ally and does not rise in phonation. There is loss of the ysmal; it originates on one side of the throat, approxi- gag reflex on the affected side, as well as of the “curtain mately in the tonsillar fossa. In some cases the pain is movement” of the lateral wall of the pharynx, whereby localized in the ear or may radiate from the throat to the the faucial pillars move medially as the palate rises in say- ing “ah.” The voice is hoarse and slightly nasal, and the TABLE 29-2 CRANIAL NERVE SYNDROMES SITE CRANIAL NERVES USUAL CAUSE III, IV, first division V, VI Sphenoid fissure Invasive tumors of sphenoid bone; aneurysms (superior orbital) III, IV, first division V, VI, often with proptosis Infection, thrombosis, aneurysm, or fistula of Lateral wall of cavernous sinus cavernous sinus; invasive tumors from sinuses and sella turcica; benign granuloma responsive to Retrosphenoid space II, III, IV, V, VI glucocorticoids Apex of petrous bone V, VI Large tumors of middle cranial fossa Internal auditory meatus VII, VIII Petrositis; tumors of petrous bone Tumors of petrous bone (dermoids, etc.); infectious Pontocerebellar angle V, VII, VIII, and sometimes IX processes; acoustic neuroma Jugular foramen IX, X, XI Acoustic neuroma; meningioma Posterior laterocondylar space IX, X, XI, XII Tumors and aneurysms Tumors of parotid gland and carotid body and Posterior retroparotid space IX, X, XI, XII and Horner metastatic tumors syndrome Tumors of parotid gland, carotid body, lymph nodes; metastatic tumor; tuberculous adenitis

vocal cord lies immobile midway between abduction and TONGUE PARALYSIS 383 adduction. Loss of sensation at the external auditory meatus and the posterior pinna may also be present. The hypoglossal (twelfth cranial) nerve supplies the ipsi- lateral muscles of the tongue. The nucleus of the nerve The pharyngeal branches of both vagal nerves may be or its fibers of exit may be involved by intramedullary affected in diphtheria; the voice has a nasal quality, and lesions such as tumor, poliomyelitis, or most often motor regurgitation of liquids through the nose occurs during neuron disease. Lesions of the basal meninges and the the act of swallowing. occipital bones (platybasia, invagination of occipital condyles, Paget’s disease) may compress the nerve in its The vagus nerve may be involved at the meningeal extramedullary course or in the hypoglossal canal. Iso- level by neoplastic and infectious processes and within lated lesions of unknown cause can occur. Atrophy and the medulla by tumors, vascular lesions (e.g., the lateral fasciculation of the tongue develop weeks to months medullary syndrome), and motor neuron disease. This after interruption of the nerve. nerve may be involved by infection with herpes zoster virus. Polymyositis and dermatomyositis, which cause MULTIPLE CRANIAL NERVE PALSIES CHAPTER 29 Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders hoarseness and dysphagia by direct involvement of laryngeal and pharyngeal muscles, may be confused with Several cranial nerves may be affected by the same dis- diseases of the vagus nerves. Dysphagia is also a symp- ease process. In this situation, the main clinical problem tom in some patients with myotonic dystrophy. is to determine whether the lesion lies within the brain- stem or outside it. Lesions that lie on the surface of the The recurrent laryngeal nerves, especially the left, are brainstem are characterized by involvement of adjacent most often damaged as a result of intrathoracic disease. cranial nerves (often occurring in succession) and late Aneurysm of the aortic arch, an enlarged left atrium, and rather slight involvement of the long sensory and and tumors of the mediastinum and bronchi are much motor pathways and segmental structures lying within more frequent causes of an isolated vocal cord palsy the brainstem. The opposite is true of primary lesions than are intracranial disorders. However, a substantial within the brainstem.The extramedullary lesion is more number of cases of recurrent laryngeal palsy remain likely to cause bone erosion or enlargement of the fora- idiopathic. mens of exit of cranial nerves.The intramedullary lesion involving cranial nerves often produces a crossed sensory When confronted with a case of laryngeal palsy, the or motor paralysis (cranial nerve signs on one side of the physician must attempt to determine the site of the body and tract signs on the opposite side). lesion. If it is intramedullary, there are usually other signs, such as ipsilateral cerebellar dysfunction, loss of Involvement of multiple cranial nerves outside the pain and temperature sensation over the ipsilateral face brainstem is frequently the result of diabetes or trauma, and contralateral arm and leg, and an ipsilateral Horner localized infections such as herpes zoster, infectious and syndrome. If the lesion is extramedullary, the glos- noninfectious (especially carcinomatous) causes of menin- sopharyngeal and spinal accessory nerves are frequently gitis (Chaps. 35 and 36), granulomatous diseases such as involved (jugular foramen syndrome). If it is extracra- Wegener’s granulomatosis, Behçet’s disease, enlarging sac- nial in the posterior laterocondylar or retroparotid cular aneurysms, or tumors. Among the tumors, nasopha- space, there may be a combination of ninth, tenth, ryngeal cancers, lymphomas, neurofibromas, meningiomas, eleventh, and twelfth cranial nerve palsies and a chordomas, cholesteatomas, carcinomas, and sarcomas have Horner syndrome (Table 29-2). If there is no sensory all been observed to involve a succession of lower cranial loss over the palate and pharynx and no palatal weak- nerves. Owing to their anatomic relationships, the multi- ness or dysphagia, the lesion is below the origin of the ple cranial nerve palsies form a number of distinctive syn- pharyngeal branches, which leave the vagus nerve high dromes, listed in Table 29-2. Sarcoidosis is the cause of in the cervical region; the usual site of disease is then some cases of multiple cranial neuropathy, and chronic the mediastinum. glandular tuberculosis the cause of a few others. Platybasia, basilar invagination of the skull, and the adult Chiari mal- NECK WEAKNESS formation are additional causes. A purely motor disorder without atrophy always raises the question of myasthenia Isolated involvement of the accessory (eleventh cranial) gravis (Chap. 42). As noted above, Guillain-Barré syn- nerve can occur anywhere along its route, resulting in drome commonly affects the facial nerves bilaterally. In partial or complete paralysis of the sternocleidomastoid the Fisher variant of the Guillain-Barré syndrome, oculo- and trapezius muscles. More commonly, involvement motor paresis occurs with ataxia and areflexia in the limbs occurs in combination with deficits of the ninth and (Chap. 41). Wernicke encephalopathy can cause a severe tenth cranial nerves in the jugular foramen or after exit ophthalmoplegia combined with other brainstem signs. from the skull (Table 29-2). An idiopathic form of acces- sory neuropathy, akin to Bell’s palsy, has been described, and it may be recurrent in some cases. Most but not all patients recover.

384 Ant. cerebral a. In infectious cases, prompt administration of broad- Int. carotid a. spectrum antibiotics, drainage of any abscess cavities, and Optic identification of the offending organism are essential. chiasma Ant. clinoid process Anticoagulant therapy may benefit cases of primary Subarachnoid thrombosis. Repair or occlusion of the carotid artery may Hypophysis space be required for treatment of fistulas or aneurysms. The Tolosa-Hunt syndrome generally responds to glucocorti- Sphenoid Oculomotor (III) n. coids. A dramatic improvement in pain is usually evident sinus Trochlear (IV) n. within a few days; oral prednisone (60 mg daily) is usually continued for several weeks and then gradually tapered. Ophthalmic (VI) n. Maxillary (V2) n. An idiopathic form of multiple cranial nerve involve- Pia ment on one or both sides of the face is occasionally Arachnoid seen. The syndrome consists of a subacute onset of bor- Dura ing facial pain, followed by paralysis of motor cranial nerves. The clinical features overlap those of the Tolosa- SECTION III Diseases of the Central Nervous System Abducens (VI) n. Hunt syndrome and appear to be due to idiopathic inflammation of the dura mater, which may be visual- FIGURE 29-4 ized by MRI. The syndrome is frequently responsive to Anatomy of the cavernous sinus in coronal section, illus- glucocorticoids. trating the location of the cranial nerves in relation to the vas- cular sinus, internal carotid artery (which loops anteriorly to ACKNOWLEDGMENT the section), and surrounding structures. The authors acknowledge the contributions of Dr. Joseph B. The cavernous sinus syndrome (Fig. 29-4) is a distinctive Martin to this chapter in previous editions of Harrison’s Princi- and frequently life-threatening disorder. It often presents ples of Internal Medicine. as orbital or facial pain; orbital swelling and chemosis due to occlusion of the ophthalmic veins; fever; oculomotor FURTHER READINGS neuropathy affecting the third, fourth, and sixth cranial nerves; and trigeminal neuropathy affecting the ophthalmic ENGSTROM M et al: Prednisolone and valaciclovir in Bell’s palsy: a (V1) and occasionally the maxillary (V2) divisions of the randomised, double-blind, placebo-controlled, multicentre trial. trigeminal nerve. Cavernous sinus thrombosis, often sec- Lancet Neurol. 7:993, 2008 ondary to infection from orbital cellulitis (frequently Staphylococcus aureus), a cutaneous source on the face, or GILDEN DH: Clinical practice. Bell’s Palsy. N Engl J Med 351:13, sinusitis (especially with mucormycosis in diabetic patients), 2004 is the most frequent cause; other etiologies include aneurysm of the carotid artery, a carotid-cavernous fistula GRONSETH G et al: Practice parameter: the diagnostic evaluation and (orbital bruit may be present), meningioma, nasopharyngeal treatment of trigeminal neuralgia (an evidence-based review): carcinoma, other tumors, or an idiopathic granulomatous report of the Quality Standards Subcommittee of the American disorder (Tolosa-Hunt syndrome). The two cavernous Academy of Neurology and the European Federation of Neuro- sinuses directly communicate via intercavernous channels; logical Societies. Neurology 71:1183, 2008 thus, involvement on one side may extend to become bilateral. Early diagnosis is essential, especially when due PEARCE JMS: Glossopharyngeal neuralgia. Eur Neurol 55:49, 2006 to infection, and treatment depends on the underlying QUANT EC et al: The benefits of steroids versus steroids plus antivi- etiology. rals for treatment of Bell’s palsy: a meta-analysis. BMJ 339:b3354, 2009 SULLIVAN FM et al: Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med 357:1598, 2007 SWEENEY CJ, GILDEN DH: Ramsay Hunt syndrome. J Neurol Neu- rosurg Psychiatry 71:149, 2001

CHAPTER 30 DISEASES OF THE SPINAL CORD Stephen L. Hauser ■ Allan H. Ropper ■ Acute and Subacute Spinal Cord Diseases . . . . . . . . . . . . . . 388 Subacute Combined Degeneration Compressive Myelopathies . . . . . . . . . . . . . . . . . . . . . . . . . . 389 (Vitamin B12 Deficiency) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 Noncompressive Myelopathies . . . . . . . . . . . . . . . . . . . . . . . 392 Hypocupric Myelopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Tabes Dorsalis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 ■ Chronic Myelopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Familial Spastic Paraplegia . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Spondylitic Myelopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394 Adrenomyeloneuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397 Vascular Malformations of the Cord and Dura . . . . . . . . . . . . 394 Other Chronic Myelopathies . . . . . . . . . . . . . . . . . . . . . . . . . 397 Retrovirus-Associated Myelopathies . . . . . . . . . . . . . . . . . . . 395 Syringomyelia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 395 ■ Rehabilitation of Spinal Cord Disorders . . . . . . . . . . . . . . . . . 397 Chronic Myelopathy of Multiple Sclerosis . . . . . . . . . . . . . . . 396 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399 Diseases of the spinal cord are frequently devastating. neurons that innervate the upper and lower extremi- They produce quadriplegia, paraplegia, and sensory ties, respectively, are located. The white matter tracts deficits far beyond the damage they would inflict else- containing ascending sensory and descending motor where in the nervous system because the spinal cord pathways are located peripherally, whereas nerve cell contains, in a small cross-sectional area, almost the entire bodies are clustered in an inner region shaped like a motor output and sensory input of the trunk and limbs. four-leaf clover that surrounds the central canal Many spinal cord diseases are reversible if recognized (anatomically an extension of the fourth ventricle). and treated at an early stage (Table 30-1); thus, they are The membranes that cover the spinal cord—the pia, among the most critical of neurologic emergencies. The arachnoid, and dura—are continuous with those of efficient use of diagnostic procedures, guided by knowl- the brain. edge of the anatomy and the clinical features of spinal cord diseases, is required for a successful outcome. The spinal cord has 31 segments, each defined by an exiting ventral motor root and entering dorsal sensory Approach to the Patient: root. During embryologic development, growth of the SPINAL CORD DISEASE cord lags behind that of the vertebral column, and the mature spinal cord ends at approximately the first lum- SPINAL CORD ANATOMY RELEVANT TO bar vertebral body. The lower spinal nerves take an increasingly downward course to exit via intervertebral CLINICAL SIGNS The spinal cord is a thin, tubular foramina.The first seven pairs of cervical spinal nerves extension of the central nervous system contained exit above the same-numbered vertebral bodies, whereas within the bony spinal canal. It originates at the all the subsequent nerves exit below the same-num- medulla and continues caudally to the conus bered vertebral bodies because of the presence of eight medullaris at the lumbar level; its fibrous extension, the cervical spinal cord segments but only seven cervical filum terminale, terminates at the coccyx. The adult vertebrae.The relationship between spinal cord segments spinal cord is ~46 cm (18 in.) long, oval in shape, and and the corresponding vertebral bodies is shown in enlarged in the cervical and lumbar regions, where Table 30-2.These relationships assume particular impor- tance for localization of lesions that cause spinal cord 385

SECTION III Diseases of the Central Nervous System386 TABLE 30-1 Determining the Level of the Lesion The presence of a horizontally defined level below which TREATABLE SPINAL CORD DISORDERS sensory, motor, and autonomic function is impaired is a hallmark of spinal cord disease. This sensory level is Compressive sought by asking the patient to identify a pinprick or Epidural, intradural, or intramedullary neoplasm cold stimulus (e.g., a dry tuning fork after immersion Epidural abscess in cold water) applied to the proximal legs and lower Epidural hemorrhage trunk and sequentially moved up toward the neck on Cervical spondylosis each side. The sensory level indicates damage to the Herniated disc spinothalamic tract one to two segments above the Posttraumatic compression by fractured or displaced perceived level of a unilateral spinal cord lesion and at vertebra or hemorrhage the level of a bilateral lesion. That is the result of the ascent of second-order sensory fibers, which origi- Vascular nate in the dorsal horn, proceed to cross anterior to Arteriovenous malformation the central canal while ascending to join the opposite Antiphospholipid syndrome and other hypercoagulable spinothalamic tract. Lesions that transect the descend- states ing corticospinal and other motor tracts cause para- plegia or quadriplegia, with the evolution over time Inflammatory of increased muscle tone, heightened deep tendon Multiple sclerosis reflexes, and Babinski signs (the upper motor neuron Neuromyelitis optica syndrome). Such lesions also typically produce auto- Transverse myelitis nomic disturbances consisting of absent sweating Sarcoidosis below the implicated cord level and bladder, bowel, Vasculitis and sexual dysfunction. Infectious The uppermost level of a spinal cord lesion can Viral: VZV, HSV-1 and -2, CMV, HIV, HTLV-I, others also be localized by attention to the segmental signs Bacterial and mycobacterial: Borrelia, Listeria, syphilis, corresponding to disturbed motor or sensory inner- others vation by an individual cord segment. A band of Mycoplasma pneumoniae altered sensation (hyperalgesia or hyperpathia) at the Parasitic: schistosomiasis, toxoplasmosis upper end of the sensory disturbance, fasciculations or atrophy in muscles innervated by one or several Developmental segments, or a muted or absent deep tendon reflex Syringomyelia may be noted at this level.These signs also occur with Meningomyelocoele focal root or peripheral nerve disorders; thus, seg- Tethered cord syndrome mental signs are most useful when they occur together with signs of long tract damage. With severe Metabolic and acute transverse lesions, the limbs initially may be Vitamin B12 deficiency (subacute combined degeneration) flaccid rather than spastic.This state of “spinal shock” Copper deficiency lasts for several days, rarely for weeks, and should not be mistaken for extensive damage to many segments Note: VZV, varicella-zoster virus; HSV, herpes simplex virus; CMV, of the cord or for an acute polyneuropathy. cytomegalovirus; HTLV, human T cell lymphotropic virus. The main features of transverse damage at each compression.A T10 spinal cord sensory level, for exam- level of the spinal cord are summarized below. ple, indicates involvement of the cord adjacent to the seventh or eighth thoracic vertebral body (Figs. 12-2 Cervical Cord Upper cervical cord lesions pro- and 12-3). In addition, at every level the main ascend- duce quadriplegia and weakness of the diaphragm. ing and descending tracts are somatotopically organized Lesions at C4-C5 produce quadriplegia; at C5-C6, with a laminated distribution that reflects the origin or there is loss of power and reflexes in the biceps; at C7 destination of nerve fibers. weakness is found only in finger and wrist extensors and triceps; and at C8, finger and wrist flexion are TABLE 30-2 impaired. Horner’s syndrome (miosis, ptosis, and facial hypohidrosis) may accompany a cervical cord lesion SPINAL CORD LEVELS RELATIVE TO THE at any level. VERTEBRAL BODIES Thoracic Cord Lesions here are localized by the SPINAL CORD LEVEL CORRESPONDING VERTEBRAL BODY sensory level on the trunk and by the site of midline Upper cervical Same as cord level Lower cervical 1 level higher Upper thoracic 2 levels higher Lower thoracic 2 to 3 levels higher Lumbar T10-T12 Sacral T12-L1

back pain if it accompanies the syndrome. Useful impotence. The bulbocavernosus (S2-S4) and anal 387 markers for localization are the nipples (T4) and (S4-S5) reflexes are absent (Chap. 1). Muscle strength umbilicus (T10). Leg weakness and disturbances of is largely preserved. By contrast, lesions of the cauda bladder and bowel function accompany the paralysis. equina, the cluster of nerve roots derived from the Lesions at T9-T10 paralyze the lower—but not the lower cord, are characterized by low back and radicu- upper—abdominal muscles, resulting in upward lar pain, asymmetric leg weakness and sensory loss, movement of the umbilicus when the abdominal wall variable areflexia in the lower extremities, and relative contracts (Beevor’s sign). sparing of bowel and bladder function. Mass lesions in the lower spinal canal often produce a mixed clini- Lumbar Cord Lesions at the L2-L4 spinal cord cal picture in which elements of both cauda equina levels paralyze flexion and adduction of the thigh, and conus medullaris syndromes coexist. Cauda weaken leg extension at the knee, and abolish the equina syndromes are also discussed in Chap. 7. patellar reflex. Lesions at L5-S1 paralyze only move- ments of the foot and ankle, flexion at the knee, and Special Patterns of Spinal Cord Disease CHAPTER 30 Diseases of the Spinal Cord extension of the thigh, and abolish the ankle jerks (S1). The location of the major ascending and descending Sacral Cord/Conus Medullaris The conus pathways of the spinal cord are shown in Fig. 30-1. medullaris is the tapered caudal termination of the Most fiber tracts—including the posterior columns spinal cord, comprising the lower sacral and single and the spinocerebellar and pyramidal tracts—are sit- coccygeal segments. The conus syndrome is distinc- uated on the side of the body they innervate. How- tive, consisting of bilateral saddle anesthesia (S3-S5), ever, afferent fibers mediating pain and temperature prominent bladder and bowel dysfunction (urinary sensation ascend in the spinothalamic tract contralateral retention and incontinence with lax anal tone), and to the side they supply.The anatomic configurations of Posterior Columns (Joint Position, Vibration, Pressure) Dorsal root Fasciculus Fasciculus Anterior horn Dorsal cuneatus gracilis (motor neurons) spinocerebellar tract C TLS Ventral L/ Lateral Distal limb spinocerebellar S corticospinal movements tract (pyramidal tract) S L/ L Rubrospinal S T tract LT C C S PFD Lateral E reticulospinal Lateral tract spinothalamic Ventral tract SL T C (uncrossed) Vestibulospinal corticospinal tract Pain, tract Axial and temperature Distal limb Ventral proximal movements reticulospinal limb Ventral Ventral (minor role) tract movements root spinothalamic Tectospinal tract tract Pressure, touch (minor role) FIGURE 30-1 spinothalamic tracts (blue) ascend contralateral to the side of Transverse section through the spinal cord, composite the body that is innervated. C, cervical; T, thoracic; L, lumbar; representation, illustrating the principal ascending (left) S, sacral; P, proximal; D, distal; F, flexors, E, extensors. and descending (right) pathways. The lateral and ventral

SECTION III Diseases of the Central Nervous System388 these tracts produce characteristic syndromes that leg fibers in the corticospinal tract. Intramedullary provide clues to the underlying disease process. lesions tend to produce poorly localized burning pain rather than radicular pain and spare sensation in the Brown-Sequard Hemicord Syndrome This perineal and sacral areas (“sacral sparing”), reflecting consists of ipsilateral weakness (corticospinal tract) the laminated configuration of the spinothalamic and loss of joint position and vibratory sense (poste- tract with sacral fibers outermost; corticospinal tract rior column), with contralateral loss of pain and tem- signs appear later. Regarding extramedullary lesions, a perature sense (spinothalamic tract) one or two levels further distinction is made between extradural and below the lesion. Segmental signs, such as radicular intradural masses, as the former are generally malig- pain, muscle atrophy, or loss of a deep tendon reflex, nant and the latter benign (neurofibroma being a are unilateral. This classical pattern is rare, and partial common cause). Consequently, a long duration of forms are more commonly encountered. symptoms favors an intradural origin. Central Cord Syndrome The central cord syn- ACUTE AND SUBACUTE SPINAL CORD drome results from damage to the gray matter nerve DISEASES cells and crossing spinothalamic tracts near the central canal. In the cervical cord, the central cord syndrome The initial symptoms of disease that evolve over days or produces arm weakness out of proportion to leg weak- weeks are focal neck or back pain, followed by various ness and a “dissociated” sensory loss, signifying a loss of combinations of paresthesias, sensory loss, motor weak- pain and temperature sense in a cape distribution over ness, and sphincter disturbance evolving over hours to the shoulders, lower neck, and upper trunk in contrast several days. There may be only mild sensory symptoms to preservation of light touch, joint position, and vibra- or a devastating functional transection of the cord. Par- tion sense in these regions. Trauma, syringomyelia, tial lesions selectively involve the posterior columns or tumors, and anterior spinal artery ischemia (including anterior spinothalamic tracts or are limited to one side from aortic dissection) are the main causes. of the cord. Paresthesias or numbness typically begins in the feet and ascends symmetrically or asymmetrically. Anterior Spinal Artery Syndrome Infarction These symptoms initially simulate Guillain-Barré syn- of the cord is generally the result of occlusion or drome, but involvement of the trunk with a sharply diminished flow in this artery. The result is extensive demarcated spinal cord level indicates the myelopathic bilateral tissue destruction that spares the posterior nature of the process. In severe and abrupt cases, areflexia columns. All spinal cord functions—motor, sensory, reflecting spinal shock may be present, but hyperreflexia and autonomic—are lost below the level of the supervenes over days or weeks; persistent areflexic paral- lesion, with the striking exception of retained vibra- ysis with a sensory level indicates necrosis over multiple tion and position sensation. segments of the spinal cord. Foramen Magnum Syndrome Lesions in this Approach to the Patient: area interrupt decussating pyramidal tract fibers des- COMPRESSIVE AND NONCOMPRESSIVE tined for the legs, which cross caudal to those of the MYELOPATHY arms, resulting in weakness of the legs (crural paresis). Compressive lesions near the foramen magnum may DISTINGUISHING COMPRESSIVE FROM produce weakness of the ipsilateral shoulder and arm followed by weakness of the ipsilateral leg, then the NONCOMPRESSIVE MYELOPATHY The first contralateral leg, and finally the contralateral arm, an priority is to exclude a treatable compression of the “around the clock” pattern that may begin in any of cord by a mass.The common causes are tumor, epidural the four limbs. There is typically suboccipital pain abscess or hematoma, herniated disc, or vertebral spreading to the neck and shoulders. pathology. Epidural compression due to malignancy or abscess often causes warning signs of neck or back Intramedullary and Extramedullary Syn- pain, bladder disturbances, and sensory symptoms that precede the development of paralysis. Spinal subluxa- dromes It is useful to differentiate intramedullary tion, hemorrhage, and noncompressive etiologies such processes, arising within the substance of the cord, as infarction are more likely to produce myelopathy from extramedullary ones that compress the spinal cord without antecedent symptoms. MRI with gadolinium or its vascular supply. The differentiating features are only relative and serve as clinical guides. With extramedullary lesions, radicular pain is often promi- nent, and there is early sacral sensory loss (lateral spinothalamic tract) and spastic weakness in the legs (corticospinal tract) due to the superficial location of

infusion, centered on the clinically suspected level, is 389 the initial diagnostic procedure; in some cases it is appropriate to image the entire spine (cervical through sacral regions) to search for additional clinically silent lesions. Once compressive lesions have been excluded, noncompressive causes of acute myelopathy that are intrinsic to the cord are considered, primarily vascular, inflammatory, and infectious etiologies. COMPRESSIVE MYELOPATHIES AB CHAPTER 30 Diseases of the Spinal Cord FIGURE 30-2 Neoplastic Spinal Cord Compression Epidural spinal cord compression due to breast carci- noma. Sagittal T1-weighted (A) and T2-weighted (B) MRI In adults, most neoplasms are epidural in origin, result- scans through the cervicothoracic junction reveal an infil- ing from metastases to the adjacent spinal bones. The trated and collapsed second thoracic vertebral body with propensity of solid tumors to metastasize to the vertebral posterior displacement and compression of the upper tho- column probably reflects the high proportion of bone racic spinal cord. The low-intensity bone marrow signal in marrow located in the axial skeleton. Almost any malig- A signifies replacement by tumor. nant tumor can metastasize to the spinal column, with breast, lung, prostate, kidney, lymphoma, and plasma cell tumor, they may cross the disk space to involve the adja- dyscrasia being particularly frequent. The thoracic cord cent vertebral body. is most commonly involved; exceptions are metastases from prostate and ovarian cancer, which occur dispro- If spinal cord compression is suspected, imaging should portionately in the sacral and lumbar vertebrae, probably be obtained promptly. If there are radicular symptoms but resulting from spread through Batson’s plexus, a network no evidence of myelopathy, it is usually safe, if necessary, of veins along the anterior epidural space. Retroperi- to defer imaging for 24–48 h. With back or neck pain toneal neoplasms (especially lymphomas or sarcomas) only, imaging studies may be obtained within a few days. enter the spinal canal through the intervertebral foram- Up to 40% of patients who present with cord compres- ina; they produce radicular pain and other signs of root sion at one level are found to have asymptomatic epidural involvement prior to cord compression. disease elsewhere; thus, the length of the spine should be imaged when epidural malignancy is in question. Pain is usually the initial symptom; it may be aching and localized or sharp and radiating in quality. This Treatment: spinal ache typically worsens with movement, coughing, NEOPLASTIC SPINAL CORD or sneezing and characteristically awakens patients at COMPRESSION night. A recent onset of persistent back pain, particularly Management of cord compression includes glucocorti- if in the thoracic spine (which is uncommonly involved coids to reduce cord edema, local radiotherapy (initiated by spondylosis), should prompt consideration of verte- as early as possible) to the symptomatic lesion, and bral metastasis. Rarely, pain is mild or absent. Plain radi- specific therapy for the underlying tumor type. Gluco- ographs of the spine and radionuclide bone scans have corticoids (dexamethasone, up to 40 mg daily) can be only a limited role in diagnosis because they do not administered before the imaging study if the clinical identify 15–20% of metastatic vertebral lesions and fail suspicion is strong and continued at a lower dose until to detect paravertebral masses that reach the epidural radiotherapy (generally 3000 cGy administered in 15 space through the intervertebral foramina. MRI pro- daily fractions) is completed. Radiotherapy appears to vides excellent anatomic resolution of the extent of be as effective as surgery, even for most classically spinal tumors (Fig. 30-2) and is able to distinguish radioresistant metastases. Biopsy of the epidural mass is between malignant lesions and other masses—epidural abscess, tuberculoma, or epidural hemorrhage, among others—that present in a similar fashion. Vertebral metastases are usually hypointense relative to a normal bone marrow signal on T1-weighted MRI scans; after the administration of gadolinium, contrast enhancement may deceptively “normalize” the appearance of the tumor by increasing its intensity to that of normal bone marrow. Infections of the spinal column (osteomyelitis and related disorders) are distinctive in that, unlike

SECTION III Diseases of the Central Nervous System390 unnecessary in patients with known preexisting cancer the foramen magnum, although they can arise from the meninges anywhere along the spinal canal. Neurofibro- but is indicated if a history of underlying cancer is lack- mas are benign tumors of the nerve sheath that typically ing. Surgery, either decompression by laminectomy or arise near the posterior root; when multiple, neurofibro- vertebral body resection, should be considered when matosis is the likely etiology. Symptoms usually begin signs of cord compression worsen despite radiotherapy, with radicular sensory symptoms followed by an asym- when the maximum tolerated dose of radiotherapy has metric, progressive spinal cord syndrome. Therapy is by been delivered previously to the site, or when a verte- surgical resection. bral compression fracture or spinal instability contributes to cord compression. A good response to radiotherapy Primary intramedullary tumors of the spinal cord are can be expected in individuals who are ambulatory at uncommon.They present as central cord or hemicord syn- presentation; new weakness is prevented, and some dromes, often in the cervical region; there may be poorly recovery of motor function occurs in approximately half localized burning pain in the extremities and sparing of of treated patients. Fixed motor deficits (paraplegia or sacral sensation. In adults, these lesions are ependymomas, quadriplegia), once established for >12 h, do not usually hemangioblastomas, or low-grade astrocytomas (Fig. 30-4). improve, and beyond 48 h the prognosis for substantial Complete resection of an intramedullary ependymoma is motor recovery is poor. often possible with microsurgical techniques. Debulking of an intramedullary astrocytoma can also be helpful, as these In contrast to tumors of the epidural space, most are often slowly growing lesions; the value of adjunctive intradural mass lesions are slow-growing and benign. radiotherapy and chemotherapy is uncertain. Secondary Meningiomas and neurofibromas account for most of (metastatic) intramedullary tumors are also common, espe- these, with occasional cases caused by chordoma, cially in patients with advanced metastatic disease (Chap. 32). lipoma, dermoid, or sarcoma. Meningiomas (Fig. 30-3) are often located posterior to the thoracic cord or near Spinal Epidural Abscess Spinal epidural abscess presents as a clinical triad of mid- line dorsal pain, fever, and progressive limb weakness. Prompt recognition of this distinctive process will in most cases prevent permanent sequelae. Aching pain is almost always present, either over the spine or in a radicular FIGURE 30-3 FIGURE 30-4 MRI of a thoracic meningioma. Coronal T1-weighted post- MRI of an intramedullary astrocytoma. Sagittal T1-weighted contrast image through the thoracic spinal cord demonstrates post-contrast image through the cervical spine demonstrates intense and uniform enhancement of a well-circumscribed expansion of the upper cervical spine by a mass lesion ema- extramedullary mass (arrows) which displaces the spinal cord nating from within the spinal cord at the cervicomedullary to the left. junction. Irregular peripheral enhancement occurs within the mass (arrows).

pattern. The duration of pain prior to presentation is question of associated meningitis, a feature that is found 391CHAPTER 30 Diseases of the Spinal Cord generally Յ2 weeks but may on occasion be several in <25% of cases. The level of the puncture should be months or longer. Fever is usual, accompanied by ele- planned to minimize the risk of meningitis due to passage vated white blood cell count and sedimentation rate. As of the needle through infected tissue or herniation due to the abscess expands, further spinal cord damage results decompression below an area of obstruction to the flow from venous congestion and thrombosis. Once weakness of cerebrospinal fluid (CSF). A high cervical tap is often and other signs of myelopathy appear, progression may the safest approach. CSF abnormalities in subdural abscess be rapid. A more chronic sterile granulomatous form of consist of pleocytosis with a preponderance of polymor- abscess is also known, usually after treatment of an acute phonuclear cells, an elevated protein level, and a reduced epidural infection. glucose level, but the responsible organism is not cultured unless there is associated meningitis. Blood cultures are Risk factors include an impaired immune status (dia- positive in <25% of cases. betes mellitus, renal failure, alcoholism, malignancy), intravenous drug abuse, and infections of the skin or Treatment: other tissues. Two-thirds of epidural infections result SPINAL EPIDURAL ABSCESS from hematogenous spread of bacteria from the skin (furunculosis), soft tissue (pharyngeal or dental abscesses), Treatment is by decompressive laminectomy with or deep viscera (bacterial endocarditis). The remainder debridement combined with long-term antibiotic treat- arise from direct extension of a local infection to the ment. Surgical evacuation prevents development of subdural space; examples of local predisposing condi- paralysis and may improve or reverse paralysis in evolu- tions are vertebral osteomyelitis, decubitus ulcers, lumbar tion, but it is unlikely to improve deficits of more than puncture, epidural anesthesia, or spinal surgery. Most cases several days duration. Antibiotics should be started are due to Staphylococcus aureus; gram-negative bacilli, empirically before surgery and then modified on the Streptococcus, anaerobes, and fungi can also cause epidural basis of culture results; medication is continued for at abscesses.Tuberculosis from an adjacent vertebral source, least 4 weeks. If surgery is contraindicated or if there is a Pott’s disease, remains an important cause in the under- fixed paraplegia or quadriplegia that is unlikely to developed world. improve following surgery, long-term administration of systemic and oral antibiotics can be used; in such cases, MRI scans (Fig. 30-5) localize the abscess and exclude the choice of antibiotics may be guided by results of other causes of myelopathy. Lumbar puncture is only blood cultures. However, paralysis may develop or required if encephalopathy or other clinical signs raise the progress during antibiotic therapy; thus, initial surgical management remains the treatment of choice unless the abscess is limited in size and causes few or no neu- rologic signs. AB Spinal Epidural Hematoma FIGURE 30-5 Hemorrhage into the epidural (or subdural) space causes MRI of a spinal epidural abscess due to tuberculosis. acute focal or radicular pain followed by variable signs of A. Sagittal T2-weighted free spin-echo MR sequence. a spinal cord or conus medullaris disorder. Therapeutic A hypointense mass replaces the posterior elements of C3 anticoagulation, trauma, tumor, or blood dyscrasia are and extends epidurally to compress the spinal cord (arrows). predisposing conditions. Rare cases complicate lumbar B. Sagittal T1-weighted image after contrast administration puncture or epidural anesthesia, sometimes in association reveals a diffuse enhancement of the epidural process with use of low-molecular-weight heparin. MRI and (arrows) with extension into the epidural space. CT confirm the clinical suspicion and can delineate the extent of the bleeding. Treatment consists of prompt reversal of any underlying clotting disorder and surgical decompression. Surgery may be followed by substantial recovery, especially in patients with some preservation of motor function preoperatively. Because of the risk of hemorrhage, lumbar puncture should be avoided when- ever possible in patients with severe thrombocytopenia or other coagulopathies.

SECTION III Diseases of the Central Nervous System392 Hematomyelia TABLE 30-3 Hemorrhage into the substance of the spinal cord is a EVALUATION OF ACUTE TRANSVERSE MYELOPATHY rare result of trauma, intraparenchymal vascular malfor- mation (see later), vasculitis due to polyarteritis nodosa 1. MRI of spinal cord with and without contrast (exclude or systemic lupus erythematosus (SLE), bleeding disor- compressive causes). ders, or a spinal cord neoplasm. Hematomyelia presents as an acute painful transverse myelopathy. With large 2. CSF studies: Cell count, protein, glucose, IgG lesions, extension into the subarachnoid space may index/synthesis rate, oligoclonal bands, VDRL; Gram’s occur, resulting in subarachnoid hemorrhage (Chap. 22). stain, acid-fast bacilli, and India ink stains; PCR for Diagnosis is by MRI or CT. Therapy is supportive, and VZV, HSV-2, HSV-1, EBV, CMV, HHV-6, enteroviruses, surgical intervention is generally not useful. An excep- HIV; antibody for HTLV-I, B. burgdorferi, M. pneumo- tion is hematomyelia due to an underlying vascular mal- niae, and Chlamydia pneumoniae; viral, bacterial, formation, for which selective spinal angiography may mycobacterial, and fungal cultures. be indicated, followed by surgery to evacuate the clot and remove the underlying vascular lesion. 3. Blood studies for infection: HIV; RPR; IgG and IgM enterovirus antibody; IgM mumps, measles, rubella, NONCOMPRESSIVE MYELOPATHIES group B arbovirus, Brucella melitensis, Chlamydia psittaci, Bartonella henselae, schistosomal antibody; The most frequent causes of noncompressive acute cultures for B. melitensis. Also consider nasal/pharyn- transverse myelopathy (ATM) are spinal cord infarction; geal/anal cultures for enteroviruses; stool O&P for systemic inflammatory disorders, including SLE and sar- Schistosoma ova. coidosis; demyelinating diseases, including multiple scle- rosis (MS) and neuromyelitis optica; postinfectious or 4. Immune-mediated disorders: ESR; ANA; ENA; dsDNA; idiopathic transverse myelitis, which is presumed to be rheumatoid factor; anti-SSA; anti-SSB, complement an immune condition related to acute disseminated levels; antiphospholipid and anticardiolipin antibodies; encephalomyelitis (Chap. 34); and infectious (primarily p-ANCA; antimicrosomal and antithyroglobulin antibod- viral) causes. After spinal cord compression is excluded, ies; if Sjögren syndrome suspected, Schirmer test, sali- the evaluation generally requires a lumbar puncture and vary gland scintography, and salivary/lacrimal gland a search for underlying systemic disease (Table 30-3). biopsy. Spinal Cord Infarction 5. Sarcoidosis: Serum angiotensin-converting enzyme; serum Ca; 24-h urine Ca; chest x-ray; chest CT; total The cord is supplied by three arteries that course verti- body gallium scan; lymph node biopsy. cally over its surface: a single anterior spinal artery and paired posterior spinal arteries. In addition to the verte- 6. Demyelinating disease: Brain MRI scan, evoked poten- bral arteries, the anterior spinal artery is fed by radicular tials, CSF oligoclonal bands, neuromyelitis optica anti- vessels that arise at C6, at an upper thoracic level, and, body (aquaporin-4). most consistently, at T11-L2 (artery of Adamkiewicz). At each segment, paired penetrating vessels branch from the 7. Vascular causes: CT myelogram; spinal angiogram. anterior spinal artery to supply the anterior two-thirds of the spinal cord; the posterior spinal arteries, which Note: VDRL, Venereal Disease Research Laboratory; PCR, polymerase often become less distinct below the midthoracic level, chain reaction; VZV, varicella-zoster virus; HHV, human herpes virus; supply the posterior columns. RPR, rapid plasma reagin (test); O&P, ova and parasites; ESR, ery- throcyte sedimentation rate; ANA, antinuclear antibodies; ENA, Spinal cord ischemia can occur at any level; however, epithelial neutrophil-activating peptide. the presence of the artery of Adamkiewicz creates a watershed of marginal blood flow in the upper thoracic sparing vibration and position sense, and loss of sphinc- segments. With systemic hypotension, cord infarction ter control (“anterior cord syndrome”). Onset may be occurs at the level of greatest ischemic risk, usually T3- sudden and dramatic but more typically is progressive T4, and also at boundary zones between the anterior over minutes or a few hours, quite unlike stroke in the and posterior spinal artery territories. The latter may cerebral hemispheres. Sharp midline or radiating back result in a rapidly progressive syndrome over hours of pain localized to the area of ischemia is frequent. Are- weakness and spasticity with little sensory change. flexia due to spinal shock is often present initially; with time, hyperreflexia and spasticity appear. Less common is Acute infarction in the territory of the anterior spinal infarction in the territory of the posterior spinal arteries, artery produces paraplegia or quadriplegia, dissociated resulting in loss of posterior column function. sensory loss affecting pain and temperature sense but Spinal cord infarction results from aortic atheroscle- rosis, dissecting aortic aneurysm (manifest as chest or back pain with diminished pulses in legs), vertebral artery occlusion or dissection in the neck, or profound hypotension from any cause. Cardiogenic emboli, vas- culitis related to collagen vascular disease [particularly SLE and the antiphospholipid antibody syndrome (see later in this chapter)], and surgical interruption of aortic aneurysms are other causative conditions. Occasional cases

develop from embolism of nucleus pulposus material into mediastinal lymphadenopathy, serum angiotensin- 393 CHAPTER 30 Diseases of the Spinal Cord spinal vessels, usually from local spine trauma. In a sub- converting enzyme [(ACE); positive in only one-quarter stantial number of cases no cause can be found, and of cases], serum calcium, and a gallium scan may assist in thromboembolism in arterial feeders is suspected. The the diagnosis.The usefulness of spinal fluid ACE is uncer- MRI may fail to demonstrate limited infarctions of the tain. Initial treatment is with oral glucocorticoids; cord, especially in the first day, but as often it is abnor- immunosuppressant drugs are used for resistant cases. mal at the affected level. Demyelinating Myelopathies In cord infarction due to presumed thromboem- Multiple sclerosis (MS) (Chap. 34) may present with bolism, acute anticoagulation is probably not indicated, myelitis, particularly in individuals of Asian or African with the exception of the unusual transient ischemic ancestry. In whites, MS rarely causes a complete trans- attack or incomplete infarction with a stuttering or pro- verse myelopathy (i.e., acute bilateral signs), but it is gressive course. The antiphospholipid antibody syn- among the most common causes of a partial syndrome. drome is treated with anticoagulation. Drainage of spinal Neuromyelitis optica (NMO) is a demyelinating syn- fluid has reportedly been successful in some cases of drome consisting of a severe myelopathy associated with cord infarction but has not been studied systematically. optic neuritis; the optic neuritis is often bilateral and may precede or follow myelitis by weeks or months Inflammatory and Immune Myelopathies (Chap. 34). A specific serum antibody test is available. (Myelitis) NMO is also associated with SLE and antiphospholipid antibodies (see earlier) as well as with other connective This broad category includes MS and postinfectious tissue diseases. myelitis, both of which are demyelinating in nature (see later), as well as connective tissue disease. In approximately MRI findings in MS-associated myelitis typically con- one-quarter of cases of myelitis, no underlying cause can sist of mild swelling and edema of the cord and diffuse or be identified. Some will later manifest additional symp- multifocal areas of abnormal signal on T2-weighted toms of a systemic immune-mediated disease such as SLE sequences. Contrast enhancement, indicating disruption or, more often, MS. Recurrent episodes of myelitis are usually in the blood-brain barrier associated with inflammation, due to an immune-mediated disease such as a demyeli- is present in many acute cases. A brain MRI is most nating disease, SLE, or sarcoid; or to infection with herpes helpful in gauging the likelihood that a case of myelitis simplex virus (HSV) type 2 (see later). represents an initial attack of MS.A normal scan indicates that the risk of evolution to MS is low, ~10–15% over Systemic Inflammatory Disorders 5 years; in contrast, the finding of multiple periventricular Myelitis occurs in a small number of patients with SLE, T2-bright lesions indicates a much higher risk, >50% over many cases of which are associated with antiphospho- 5 years and >90% by 14 years.The CSF may be normal, lipid antibodies. The CSF is usually normal or shows a but more often there is a mild pleocytosis, occasionally mild lymphocytic pleocytosis; oligoclonal bands are a up to several hundred mononuclear cells per microliter, variable finding. Responses to glucocorticoids and/or with normal or mildly elevated CSF protein levels; oligo- cyclophosphamide have been reported, but there is no clonal bands are variable, but when bands are present, a systematic evidence of their benefit. Other immune- diagnosis of MS is more likely.These bands are generally mediated myelitides include cases associated with Sjögren’s absent in neuromyelitis optica. syndrome, mixed connective tissue disease, Behçet’s syn- drome, and vasculitis with perinuclear antineutrophilic There are no adequate trials of therapy for MS- cytoplasmic (p-ANCA) antibodies. associated transverse myelitis. Intravenous methylpred- nisolone (500 mg qd for 3 days) followed by oral Another important consideration in this group is sar- prednisone (1 mg/kg per day for several weeks, then coid myelopathy, in which an edematous swelling of the gradual taper) has been used as initial treatment. A spinal cord may mimic tumor; there is almost always course of plasma exchange is indicated for severe cases if gadolinium enhancement of the lesion and of the adja- glucocorticoids are ineffective. Preliminary data suggest cent surface of the cord. The CSF profile consists of that treatment with anti-CD20 (anti-B cell) monoclonal variable lymphocytic pleocytosis; oligoclonal bands are antibody may protect against relapses in patients with present in one-third of cases. The diagnosis is particu- NMO. larly difficult when systemic manifestations of sarcoid are minor or absent (nearly 50% of cases) or when other Postinfectious Myelitis classic neurologic manifestations of the disease—such Many cases of myelitis, termed postinfectious or postvaccinal, as cranial neuropathy, hypothalamic involvement, or follow an infection or vaccination. Numerous organisms meningeal enhancement visualized by MRI—are lacking. have been implicated, including Epstein-Barr virus A slit-lamp examination of the eye to search for uveitis, (EBV), cytomegalovirus (CMV), mycoplasma, influenza, chest x-ray and CT to assess pulmonary involvement and measles, varicella, rubeola, and mumps. As in the related

SECTION III Diseases of the Central Nervous System394 disorder acute disseminated encephalomyelitis (Chap. 34), radicular arm pain, most often in a C5 or C6 distribu- postinfectious myelitis often begins as the patient appears tion. Compression of the cervical cord, which occurs in to be recovering from an acute febrile infection, or in the fewer than one-third of cases, produces a slowly progres- subsequent days or weeks, but an infectious agent cannot sive spastic paraparesis, at times asymmetric and often be isolated from the nervous system or spinal fluid. The accompanied by paresthesias in the feet and hands.Vibra- presumption is that the myelitis represents an autoim- tory sense is diminished in the legs, there is a Romberg mune disorder triggered by infection and is not due to sign, and occasionally there is a sensory level for vibra- direct infection of the spinal cord. Treatment is usually tion on the upper thorax. In some cases, coughing or with glucocorticoids or, in fulminant cases, plasma exchange. straining produces leg weakness or radiating arm or There are no trials by which to adequately judge these shoulder pain. Dermatomal sensory loss in the arms, therapies. atrophy of intrinsic hand muscles, increased deep-tendon reflexes in the legs, and extensor plantar responses are Acute Infectious Myelitis common. Urinary urgency or incontinence occurs in Many viruses have been associated with an acute advanced cases, but there are many alternative causes of myelitis that is infectious in nature rather than postinfec- these problems in older individuals. A tendon reflex in tious. Nonetheless, the two processes are often difficult the arms is often diminished at some level; the biceps is to distinguish. Herpes zoster is the best characterized most often affected (C5-C6). In individual cases, radicu- viral myelitis, but HSV types 1 and 2, EBV, CMV, and lar, myelopathic, or combined signs may predominate. rabies virus are other well-described causes. HSV-2 (and The diagnosis should be considered in cases of progres- less commonly HSV-1) produces a distinctive syndrome sive cervical myelopathy, paresthesias of the feet and of recurrent sacral myelitis in association with outbreaks hands, or wasting of the hands. of genital herpes mimicking MS. Poliomyelitis is the prototypic viral myelitis, but it is more or less restricted Diagnosis is made by MRI or myelography. Extrinsic to the gray matter of the cord. Chronic viral myelitic cord compression and deformation is appreciated on axial infections, such as that due to HIV, are discussed below. MRI views, and T2-weighted sequences may reveal areas of high signal intensity within the cord adjacent to Bacterial and mycobacterial myelitis (most are essen- the site of compression. A cervical collar may be helpful tially abscesses) are far less common than viral causes. in milder cases, but definitive therapy consists of surgical Almost any pathogenic species may be responsible, decompression. Posterior laminectomy or an anterior including Listeria monocytogenes, Borrelia burgdorferi (Lyme approach with resection of the protruded disc and bony disease), and Treponema pallidum (syphilis). Mycoplasma material may be required. Cervical spondylosis and pneumoniae may be a cause of myelitis, but its status is related degenerative diseases of the spine are discussed in uncertain since many cases are more properly classified Chap. 7. as postinfectious. VASCULAR MALFORMATIONS OF THE Schistosomiasis is an important cause of parasitic CORD AND DURA myelitis in endemic areas.The process is intensely inflam- matory and granulomatous, caused by a local response to Although uncommon, vascular malformations of the cord tissue-digesting enzymes from the ova of the parasite. and overlying dura are treatable causes of progressive Toxoplasmosis can occasionally cause a focal myelopathy, myelopathy. True arteriovenous malformations (AVMs) and this diagnosis should be considered, particularly in are located posteriorly along the surface of the cord or patients with AIDS, Chap. 37). within the dura, where they are more properly classified as fistulas. Most are at or below the midthoracic level.The In cases of suspected viral myelitis, it may be appro- typical presentation is a middle-aged man with a progres- priate to begin specific therapy pending laboratory con- sive myelopathy that worsens slowly or intermittently and firmation. Herpes zoster, HSV, and EBV myelitis are may have periods of apparent remission resembling MS. treated with intravenous acyclovir (10 mg/kg q8h) or Acute deterioration due to hemorrhage into the spinal oral valacyclovir (2 gm tid) for 10–14 days; CMV with cord or subarachnoid space may also occur but is rare. A ganciclovir (5 mg/kg IV bid) plus foscarnet (60 mg/kg saltatory progression is most common and is the result of IV tid), or cidofovir (5 mg/kg per week for 2 weeks). local ischemia and edema from venous congestion. Most patients have incomplete sensory, motor, and bladder dis- CHRONIC MYELOPATHIES turbances. The motor disorder may predominate and produce a mixture of upper and restricted lower motor SPONDYLITIC MYELOPATHY neuron signs, simulating amyotrophic lateral sclerosis (ALS). Pain over the dorsal spine, dysesthesias, or radicular Spondylitic myelopathy is one of the most common pain may be present. Other symptoms suggestive of AVM causes of gait difficulty in the elderly. Neck and shoulder include intermittent claudication, symptoms that change pain with stiffness are early symptoms; impingement of bone and soft tissue overgrowth on nerve roots results in

with posture, exertion such as singing, menses, or fever. with variable sensory and bladder disturbance. Approxi- 395 CHAPTER 30 Diseases of the Spinal Cord A rare AVM process presents as a progressive thoracic mately half of patients have mild back or leg pain. The myelopathy with paraparesis developing over weeks or neurologic signs may be asymmetric, often lacking a several months, characterized pathologically by abnormally well-defined sensory level; the only sign in the arms thick, hyalinized vessels within the cord (Foix-Alajouanine may be hyperreflexia after several years of illness. The syndrome). onset is insidious, and the illness is slowly progressive at a variable rate; most patients are unable to walk within Spinal bruits are infrequent but should be sought at 10 years of onset. This presentation may resemble pri- rest and after exercise in suspected cases. High-resolution mary progressive MS or a thoracic AVM. Diagnosis is MRI with contrast administration detects many but not made by demonstration of HTLV-I–specific antibody in all AVMs (Fig. 30-6). A small number not detected by serum by enzyme-linked immunosorbent assay (ELISA), MRI may be visualized by CT myelography as enlarged confirmed by radioimmunoprecipitation or western blot vessels along the surface of the cord. Definitive diagnosis analysis. There is no effective treatment, but sympto- requires selective spinal angiography, which defines the matic therapy for spasticity and bladder symptoms may feeding vessels and the extent of the malformation. be helpful. Endovascular embolization of the major feeding vessels may stabilize a progressive neurologic deficit or allow A progressive myelopathy may also result from HIV for gradual recovery. infection (Chap. 37). It is characterized by vacuolar degeneration of the posterior and lateral tracts, resem- RETROVIRUS-ASSOCIATED MYELOPATHIES bling subacute combined degeneration (see later). The myelopathy associated with the human T cell lym- photropic virus type I (HTLV-I), formerly called tropical SYRINGOMYELIA spastic paraparesis, is a slowly progressive spastic syndrome Syringomyelia is a developmental cavitary expansion of AB the cervical cord that is prone to enlarge and produce FIGURE 30-6 progressive myelopathy. Symptoms begin insidiously in Arteriovenous malformation. Sagittal MR scans of the tho- adolescence or early adulthood, progress irregularly, and racic spinal cord: T2 fast spin-echo technique (A) and T1 may undergo spontaneous arrest for several years. Many post-contrast image (B). On the T2-weighted image (left), young patients acquire a cervical-thoracic scoliosis. More abnormally high signal intensity is noted in the central aspect than one-half of all cases are associated with Chiari type of the spinal cord (arrowheads). Numerous punctate flow 1 malformations in which the cerebellar tonsils protrude voids indent the dorsal and ventral spinal cord (arrow). These through the foramen magnum and into the cervical represent the abnormally dilated venous plexus supplied by spinal canal. The pathophysiology of syrinx expansion is a dural arteriovenous fistula. After contrast administration controversial, but some interference with the normal (B), multiple, serpentine, enhancing veins (arrows) on the flow of CSF seems likely, perhaps by the Chiari malfor- ventral and dorsal aspect of the thoracic spinal cord are visu- mation. Acquired cavitations of the cord in areas of alized, diagnostic of arteriovenous malformation. This patient necrosis are also termed syrinx cavities; these follow was a 54-year-old man with a 4-year history of progressive trauma, myelitis, necrotic spinal cord tumors, and chronic paraparesis. arachnoiditis due to tuberculosis and other etiologies. The classic presentation is a central cord syndrome consisting of a dissociated sensory loss and areflexic weakness in the upper limbs. The sensory deficit is rec- ognizable by loss of pain and temperature sensation with sparing of touch and vibration in a distribution that is “suspended” over the nape of the neck, shoulders, and upper arms (cape distribution) or in the hands. Most cases begin asymmetrically with unilateral sensory loss in the hands that leads to injuries and burns that are not appreciated by the patient. Muscle wasting in the lower neck, shoulders, arms, and hands with asymmetric or absent reflexes in the arms reflects expansion of the cav- ity into the gray matter of the cord. As the cavity enlarges and further compresses the long tracts, spasticity and weakness of the legs, bladder and bowel dysfunc- tion, and a Horner’s syndrome appear. Some patients develop facial numbness and sensory loss from damage to the descending tract of the trigeminal nerve (C2 level

396 of a number of methods, but the added benefit of this procedure is uncertain, and morbidity is common. With Chiari malformations, shunting of hydrocephalus should generally precede any attempt to correct the syrinx. Surgery may stabilize the neurologic deficit, and some patients improve. Syringomyelia secondary to trauma or infection is treated with a decompression and drainage procedure in which a small shunt is inserted between the syrinx cavity and the subarachnoid space; alternatively, the cavity can be fenestrated. Cases due to intramedullary spinal cord tumor are generally managed by resection of the tumor. SECTION III Diseases of the Central Nervous System FIGURE 30-7 CHRONIC MYELOPATHY OF MULTIPLE MRI of syringomyelia associated with a Chiari malforma- SCLEROSIS tion. Sagittal T1-weighted image through the cervical and upper thoracic spine demonstrates descent of the cerebellar A chronic progressive myelopathy is the most frequent tonsils and vermis below the level of the foramen magnum cause of disability in both primary progressive and sec- (black arrows). Within the substance of the cervical and tho- ondary progressive forms of MS. Involvement is typically racic spinal cord, a CSF collection dilates the central canal bilateral but asymmetric and produces motor, sensory, (white arrows). and bladder/bowel disturbances. Fixed motor disability appears to result from extensive loss of axons in the cor- or above). In cases with Chiari malformations, cough- ticospinal tracts; thus, the symptoms are not simply due induced headache and neck, arm, or facial pain are reported. to demyelination. Diagnosis is facilitated by identifica- Extension of the syrinx into the medulla, syringobulbia, tion of earlier attacks such as optic neuritis. MRI, CSF, causes palatal or vocal cord paralysis, dysarthria, horizon- and evoked response testing are confirmatory. Therapy tal or vertical nystagmus, episodic dizziness, and tongue with interferon β, glatiramer acetate, or natalizumab is weakness. indicated for patients with progressive myelopathy who also have coexisting MS relapses. These therapies are MRI scans accurately identify developmental and sometimes also offered to patients without relapses, acquired syrinx cavities and their associated spinal cord despite the lack of evidence supporting their value in enlargement (Fig. 30-7). MRI scans of the brain and this setting. MS is discussed in Chap. 34. the entire spinal cord should be obtained to delineate the full longitudinal extent of the syrinx, assess posterior SUBACUTE COMBINED DEGENERATION fossa structures for the Chiari malformation, and deter- (VITAMIN B12 DEFICIENCY) mine whether hydrocephalus is present. This treatable myelopathy presents with subacute paresthe- Treatment: sias in the hands and feet, loss of vibration and position SYRINGOMYELIA sensation, and a progressive spastic and ataxic weakness. Treatment of syringomyelia is generally unsatisfactory. Loss of reflexes due to an associated peripheral neuropathy The Chiari tonsillar herniation is usually decompressed, in a patient who also has Babinski signs, is an important generally by suboccipital craniectomy, upper cervical diagnostic clue. Optic atrophy and irritability or other laminectomy, and placement of a dural graft. Obstruc- mental changes may be prominent in advanced cases and tion of fourth ventricular outflow is reestablished by this are rarely the presenting symptoms. The myelopathy of procedure. If the syrinx cavity is large, some surgeons subacute combined degeneration tends to be diffuse rather recommend direct decompression or drainage by one than focal; signs are generally symmetric and reflect pre- dominant involvement of the posterior and lateral tracts, including Romberg’s sign. The diagnosis is confirmed by the finding of macrocytic red blood cells, a low serum B12 concentration, elevated serum levels of homocysteine and methylmalonic acid, and in uncertain cases a positive Schilling test.Treatment is by replacement therapy, beginning

with 1000 μg of intramuscular vitamin B12 repeated at insufficiency beginning in childhood and then develop a 397 CHAPTER 30 Diseases of the Spinal Cord regular intervals or by subsequent oral treatment. progressive spastic (or ataxic) paraparesis beginning in early adulthood; some patients also have a mild periph- HYPOCUPRIC MYELOPATHY eral neuropathy. Female heterozygotes may develop a slower, insidiously progressive spastic myelopathy begin- This recently described myelopathy is virtually identical ning later in adulthood and without adrenal insuffi- to subacute combined degeneration (described above) ciency. Diagnosis is usually made by demonstration of and probably explains many cases previously described elevated levels of very long chain fatty acids in plasma with normal serum levels of B12. Low levels of serum and in cultured fibroblasts.The responsible gene encodes copper are found and often there is also a low level of ADLP, a peroxisomal membrane transporter that is a serum ceruloplasmin. Some cases follow gastrointestinal member of the ATP-binding cassette (ABC) family. procedures that result in impaired copper absorption, Steroid replacement is indicated if hypoadrenalism is but many others are idiopathic. Improvement or at least present, and bone marrow transplantation and nutri- stabilization may be expected with reconstitution of tional supplements have been attempted for this condi- copper stores by oral supplementation. The pathophysi- tion without clear evidence of efficacy. ology and pathology are not known. OTHER CHRONIC MYELOPATHIES TABES DORSALIS Primary lateral sclerosis (Chap. 27) is a degenerative dis- The classic syndromes of tabes dorsalis and meningovascu- order characterized by progressive spasticity with weak- lar syphilis of the spinal cord are now less frequent than in ness, eventually accompanied by dysarthria and dyspho- the past but must be considered in the differential diagno- nia; bladder symptoms occur in approximately half of sis of spinal cord disorders.The characteristic symptoms of patients. Sensory function is spared.The disorder resem- tabes are fleeting and repetitive lancinating pains, primarily bles ALS and is considered a variant of the motor neu- in the legs or less often in the back, thorax, abdomen, ron degenerations, but without the characteristic lower arms, and face. Ataxia of the legs and gait due to loss of motor neuron disturbance. Some cases may represent position sense occurs in half of patients. Paresthesias, blad- familial spastic paraplegia, particularly autosomal reces- der disturbances, and acute abdominal pain with vomiting sive or X-linked varieties in which a family history may (visceral crisis) occur in 15–30% of patients. The cardinal be absent. signs of tabes are loss of reflexes in the legs; impaired posi- tion and vibratory sense; Romberg’s sign; and, in almost all There are a number of rare toxic causes of spastic cases, bilateral Argyll Robertson pupils, which fail to con- myelopathy, including lathyrism due to ingestion of chick strict to light but accommodate. Diabetic polyradiculopa- peas containing the excitotoxin β-N-oxalylaminoalanine thy may simulate tabes. (BOAA), seen primarily in the developing world, and nitrous oxide inhalation producing a myelopathy identi- FAMILIAL SPASTIC PARAPLEGIA cal to subacute combined degeneration. SLE, Sjögren’s syndrome, and sarcoidosis may each cause a myelopathy Many cases of slowly progressive myelopathy are genetic without overt evidence of systemic disease. Cancer-related in origin (Chap. 27). More than 20 different causative causes of chronic myelopathy, besides the common neo- loci have been identified, including autosomal domi- plastic compressive myelopathy discussed earlier, include nant, autosomal recessive, and X-linked forms. Most a rare paraneoplastic myelopathy (Chap. 39) or radiation patients present with almost imperceptibly progressive injury (Chap. 32). It is notable that metastases to the spasticity and weakness in the legs, usually but not cord are probably more common than either of these. In always symmetrical. Sensory symptoms and signs are obscure cases, a cause can often be identified through absent or mild, but sphincter disturbances may be pre- periodic reassessment. sent. In some families additional neurologic signs are prominent, including nystagmus, ataxia, or optic atrophy. REHABILITATION OF SPINAL CORD The onset may be as early as the first year of life or as DISORDERS late as middle adulthood. Only symptomatic therapies for the spasticity are currently available. The prospects for recovery from an acute destructive spinal cord lesion fade after ~6 months. There are cur- ADRENOMYELONEUROPATHY rently no effective means to promote repair of injured spinal cord tissue; promising experimental approaches This X-linked disorder is a variant of adrenoleukodys- include the use of factors that influence reinnervation trophy. Affected males usually have a history of adrenal by axons of the corticospinal tract, nerve and neural

398 TABLE 30-4 EXPECTED NEUROLOGIC FUNCTION FOLLOWING COMPLETE CORD LESIONS LEVEL SELF-CARE TRANSFERS MAXIMUM MOBILITY High quadriplegia (C1-C4) Low quadriplegia (C5-C8) Dependent on others; Dependent on others Motorized wheelchair Paraplegia (below T1) requires respiratory support Partially independent with May be dependent or May use manual wheelchair, drive an adaptive equipment independent automobile with adaptive equipment Independent Independent Ambulates short distances with aids Source: Adapted from JF Ditunno, CS Formal: Chronic spinal cord injury. N Engl J Med 330:550, 1994; with permission. SECTION III Diseases of the Central Nervous System sheath graft bridges, and the local introduction of stem Patients with acute cord injury are at risk for venous cells. The disability associated with irreversible spinal thrombosis and pulmonary embolism. During the first cord damage is determined primarily by the level of the 2 weeks, use of calf-compression devices and anticoagu- lesion and by whether the disturbance in function is lation with heparin (5000 U subcutaneously every 12 h) complete or incomplete (Table 30-4). Even a complete or warfarin (INR, 2–3) are recommended. In cases of high cervical cord lesion may be compatible with a pro- persistent paralysis, anticoagulation should probably be ductive life. The primary goals are development of a continued for 3 months. rehabilitation plan framed by realistic expectations and attention to the neurologic, medical, and psychological Prophylaxis against decubitus ulcers should involve complications that commonly arise. frequent changes in position in a chair or bed, the use of special mattresses, and cushioning of areas where pres- Many of the usual symptoms associated with medical sure sores often develop, such as the sacral prominence illnesses, especially somatic and visceral pain, may be and heels. Early treatment of ulcers with careful cleans- lacking because of the destruction of afferent pain path- ing, surgical or enzyme debridement of necrotic tissue, ways. Unexplained fever, worsening of spasticity, or and appropriate dressing and drainage may prevent deterioration in neurologic function should prompt a infection of adjacent soft tissue or bone. search for infection, thrombophlebitis, or an intraab- dominal pathology.The loss of normal thermoregulation Spasticity is aided by stretching exercises to maintain and inability to maintain normal body temperature can mobility of joints. Drug treatment is effective but may produce recurrent fever (quadriplegic fever), although most result in reduced function, as some patients depend episodes of fever are due to infection of the urinary upon spasticity as an aid to stand, transfer, or walk. tract, lung, skin, or bone. Baclofen (15–240 mg/d in divided doses) is effective; it acts by facilitating GABA-mediated inhibition of motor Bladder dysfunction generally results from loss of reflex arcs. Diazepam acts by a similar mechanism and is supraspinal innervation of the detrusor muscle of the useful for leg spasms that interrupt sleep (2–4 mg at bladder wall and the sphincter musculature. Detrusor bedtime).Tizanidine (2–8 mg tid), an α2 adrenergic ago- spasticity is treated with anticholinergic drugs (oxybu- nist that increases presynaptic inhibition of motor neu- tinin, 2.5–5 mg qid) or tricyclic antidepressants with rons, is another option. For nonambulatory patients, the anticholinergic properties (imipramine, 25–200 mg/d). direct muscle inhibitor dantrolene (25–100 mg qid) may Failure of the sphincter muscle to relax during bladder be used, but it is potentially hepatotoxic. In refractory emptying (urinary dyssynergia) may be managed with cases, intrathecal baclofen administered via an implanted the α-adrenergic blocking agent terazosin hydrochlo- pump, botulinum toxin injections, or dorsal rhizotomy ride (1–2 mg tid or qid), with intermittent catheteriza- may be required to control spasticity. tion, or, if that is not feasible, by use of a condom catheter in men or a permanent indwelling catheter. Surgical A paroxysmal autonomic hyperreflexia may occur fol- options include the creation of an artificial bladder by iso- lowing lesions above the major splanchnic sympathetic lating a segment of intestine that can be catheterized outflow at T6. Headache, flushing, and diaphoresis above intermittently (enterocystoplasty) or can drain continu- the level of the lesion, as well as hypertension with brady- ously to an external appliance (urinary conduit). Bladder cardia or tachycardia, are the major symptoms.The trigger areflexia due to acute spinal shock or conus lesions is is typically a noxious stimulus—for example, bladder or best treated by catheterization. Bowel regimens and dis- bowel distention, a urinary tract infection, or a decubitus impaction are necessary in most patients to ensure at ulcer—below the level of the cord lesion.Treatment con- least biweekly evacuation and avoid colonic distention sists of removal of offending stimuli; ganglionic blocking or obstruction. agents (mecamylamine, 2.5–5 mg) or other short-acting antihypertensive drugs are useful in some patients.

Attention to these details allows longevity and a KALB RG: Getting the spinal cord to think for itself. Arch Neurol 399 productive life for patients with complete transverse myelopathies. 60:805, 2003 KRINGS T, GEIBPRASERT S: Spinal dural arteriovenous fistuals. AJNR: FURTHER READINGS Am J Neuroradiol. 30:639, 2009 COLE JS, PATCHELL RA: Metastatic epidural spinal cord compression. KUMAR N: Copper deficiency myelopathy (human swayback). Mayo Lancet Neurol. 7:459, 2008 Clin Proc 81:1371, 2006 JACOB A, WEINSHENKER BG: An approach to the diagnosis of acute TRANSVERSE MYELITIS CONSORTIUM WORKING GROUP: Proposed transverse myelitis. Semin Neurol 28:95, 2008 diagnostic criteria and nosology of acute transverse myelitis. Neurology 59:499, 2002 TRAUL DE et al: Part I: Spinal-cord neoplasms—intradural neo- plasms. Lancet Oncol 8:35, 2007 CHAPTER 30 Diseases of the Spinal Cord

CHAPTER 31 CONCUSSION AND OTHER HEAD INJURIES Allan H. Ropper I Types of Head Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 I Clinical Syndromes and Treatment of Concussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 400 Head Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Contusion, Brain Hemorrhage, and Axonal Minor Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Shearing Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Injury of Intermediate Severity . . . . . . . . . . . . . . . . . . . . . . . . 406 Skull Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 Severe Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 Cranial Nerve Injuries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 Grading and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406 Seizures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 Postconcussion Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 407 Subdural and Epidural Hematomas . . . . . . . . . . . . . . . . . . . 403 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 407 Almost 10 million head injuries occur annually in the or report feeling “star struck.”The mechanics of concus- United States, about 20% of which are serious enough sion involve a blunt forward impact that creates sudden to cause brain damage. Among men <35 years, acci- deceleration of the head and an anterior-posterior dents, usually motor vehicle collisions, are the chief movement of the brain within the skull. Severe concus- cause of death, and >70% of these involve head injury. sion may precipitate a brief convulsion or autonomic Furthermore, minor head injuries are so common that signs such as facial pallor, bradycardia, faintness with almost all physicians will be called upon to provide mild hypotension, or sluggish pupillary reaction, but immediate care or to see patients who are suffering from most patients are soon neurologically normal. The loss various sequelae. of consciousness in concussion is believed to be a tran- sient electrophysiologic dysfunction of the reticular acti- Medical personnel caring for head injury patients vating system in the upper midbrain caused by rotation should be aware that (1) spinal injury often accompanies of the cerebral hemispheres on the relatively fixed brain- head injury and care must be taken to prevent compres- stem (Chap. 14). sion of the spinal cord due to instability of the spinal column; (2) intoxication is an important accompaniment Gross- and light-microscopic changes in the brain are of traumatic brain injury and, when appropriate, testing usually absent following concussion, but biochemical should be carried out for drugs and alcohol; and (3) and ultrastructural changes, such as mitochondrial ATP accompanying systemic injuries, including rupture of depletion and local disruption of the blood-brain bar- abdominal organs, may produce vascular collapse or res- rier, suggest that transient abnormalities occur. CT and piratory compromise requiring immediate attention. MRI scans are usually normal; however, a small number of patients will be found to have an intracranial hemor- TYPES OF HEAD INJURIES rhage or brain contusion. CONCUSSION A brief period of both retrograde and anterograde amnesia is typical of concussion and disappears rapidly This classically refers to an immediate but transient loss in alert patients. The memory loss spans the moments of consciousness that is associated with a short period of before impact but with severe injuries loss of memory amnesia. Some patients do not lose consciousness after a may encompass the previous days or weeks (rarely minor head injury and instead may appear dazed, confused months). The extent of retrograde amnesia roughly cor- relates with the severity of injury. Memory is regained 400

in an orderly way from the most distant to recent mem- 401CHAPTER 31 Concussion and Other Head Injuries ories, with islands of amnesia occasionally remaining.The mechanism of amnesia is not known. Hysterical post- FIGURE 31-1 traumatic amnesia is not uncommon after head injury Traumatic cerebral contusion. Noncontrast CT scan demon- and should be suspected when inexplicable abnormalities strating a hyperdense hemorrhagic region in the anterior of behavior occur, such as recounting events that cannot temporal lobe. be recalled on later testing, a bizarre affect, forgetting one’s own name, or a persistent anterograde deficit that reactions result in scarred, hemosiderin-stained depres- is excessive in comparison with the degree of injury. A sions on the cortex (plaques jaunes) that are the main further discussion of amnesia is provided in Chap. 15. source of posttraumatic epilepsy. A single, uncomplicated concussion only infrequently Torsion or shearing forces within the brain cause produces permanent neurobehavioral changes in patients hemorrhages of the basal ganglia and other deep who are free of preexisting psychiatric problems and sub- regions. Large hemorrhages after minor trauma suggest stance abuse. Nonetheless, residual minor problems in that there is a bleeding diathesis or cerebrovascular amy- memory and concentration may have an anatomic corre- loidosis. For unexplained reasons, deep cerebral hemor- late in microscopic cerebral lesions (see later). rhages may not develop until several days after injury. Sudden neurologic deterioration in a comatose patient CONTUSION, BRAIN HEMORRHAGE, AND or a sudden rise in intracranial pressure (ICP) should AXONAL SHEARING LESIONS therefore prompt investigation with a CT scan. A surface bruise of the brain, or contusion, consists of Another type of deep white matter lesion consists of varying degrees of petechial hemorrhage, edema, and widespread acute disruption, or shearing, of axons at the tissue destruction. Contusions and deeper hemorrhages time of impact. Most characteristic are small areas of tis- result from mechanical forces that displace and compress sue injury in the corpus callosum and dorsolateral pons. the hemispheres forcefully and by deceleration of the The presence of widespread axonal damage in both brain against the inner skull, either under a point of hemispheres, a state called diffuse axonal injury, is pro- impact (coup lesion) or, as the brain swings back, in the posed to explain persistent coma and the vegetative state antipolar area (contrecoup lesion). Trauma sufficient to after closed head injury (Chap. 14), but small ischemic- cause prolonged unconsciousness usually produces some hemorrhagic lesions in the midbrain and thalamus are as degree of contusion. Blunt deceleration impact, as from often the cause of this clinical state. Only severe shearing an automobile dashboard or from falling forward while lesions that contain blood are visualized by CT, usually in drunk, causes contusions on the orbital surfaces of the the corpus callosum and centrum semiovale (Fig. 31-2); frontal lobes and the anterior and basal portions of the however, special imaging sequences of the MRI can temporal lobes.With lateral forces, as from impact on an demonstrate such lesions throughout the white matter. automobile door frame, the contusions are situated on the lateral convexity of the hemisphere. The clinical SKULL FRACTURES signs are determined by the location and size of the A blow to the skull causes fracture if the elastic tolerance contusion; often, there are no focal neurologic abnor- of the bone is exceeded. Intracranial lesions accompany malities. A hemiparesis or gaze preference is fairly typical roughly two-thirds of skull fractures, and the presence of of moderately sized contusions. Large bilateral contu- a skull fracture increases manyfold the chances of an sions produce coma with extensor posturing, while those limited to the frontal lobes cause a taciturn state. Contusions in the temporal lobe may cause delirium or an aggressive, combative syndrome. Contusions are easily visible on CT and MRI scans, appearing as inhomogeneous hyperdensities on CT and as hyperintensities on MRI; the signal changes reflect small scattered areas of cortical and subcortical blood and localized brain edema (Fig. 31-1); there is usually some subarachnoid bleeding detected by scans or lum- bar puncture. Blood in the cerebrospinal fluid (CSF) resulting from trauma may provoke a mild inflammatory reaction. Over a few days, contusions acquire a sur- rounding contrast enhancement and edema that may be mistaken for tumor or abscess. Glial and macrophage

SECTION III Diseases of the Central Nervous System402 Sellar fractures, even those associated with serious neuroendocrine dysfunction, may be radiologically FIGURE 31-2 occult or are evident by an air-fluid level in the sphe- Multiple small areas of hemorrhage and tissue disruption noid sinus. Fractures of the dorsum sella cause sixth or in the white matter of the frontal lobes on noncontrast CT seventh nerve palsies or optic nerve damage. scan. These appear to reflect an extreme type of the diffuse axonal shearing lesions that occur with closed head injury. Petrous bone fractures, especially those oriented along the long axis of the bone, may be associated with facial underlying subdural or epidural hematoma. Conse- palsy, disruption of ear ossicles, and CSF otorrhea.Trans- quently, fractures are primarily markers of the site and verse petrous fractures are less common; they almost severity of injury. They also provide potential pathways always damage the cochlea or labyrinths and often the for entry of bacteria (meningitis) or air (pneumocephalus) facial nerve as well. External bleeding from the ear is to the CSF and for leakage of CSF out through the usually from local abrasion of the external canal but can dura. also result from petrous fracture. Most fractures are linear and extend from the point of Fractures of the frontal bone are usually depressed, impact toward the base of the skull. Basilar skull fractures involving the frontal and paranasal sinuses and the orbits; are often extensions of adjacent linear fractures over the permanent anosmia results if the olfactory filaments in convexity of the skull but may occur independently the cribriform plate are disrupted. Depressed skull frac- owing to stresses on the floor of the middle cranial fossa tures are typically compound, but they are often asymp- or occiput. Basilar fractures are usually parallel to the tomatic because the impact energy is dissipated in petrous bone or along the sphenoid bone and directed breaking the bone; however, a few have underlying brain toward the sella turcica and ethmoidal groove. Although contusions. Debridement and exploration of compound most basilar fractures are uncomplicated, they can cause fractures are required in order to avoid infection; simple CSF leakage, pneumocephalus, and cavernous-carotid fis- fractures do not require surgery. tulas. Hemotympanum (blood behind the tympanic membrane), delayed ecchymosis over the mastoid process CRANIAL NERVE INJURIES (Battle sign), or periorbital ecchymosis (“raccoon sign”) are associated signs. Because routine x-ray examination The cranial nerves most often injured with head trauma may fail to disclose basilar fractures, they should be sus- are the olfactory, optic, oculomotor, and trochlear; the pected if these clinical signs are present. first and second branches of the trigeminal nerve; and the facial and auditory nerves. Anosmia and an apparent CSF may leak through the cribriform plate or the loss of taste (actually a loss of perception of aromatic fla- adjacent sinus and allow a watery discharge from the vors, with elementary taste perception retained) occur in nose (CSF rhinorrhea). Persistent rhinorrhea and recur- ~10% of persons with serious head injuries, particularly rent meningitis are indications for surgical repair of torn after falls on the back of the head. This is the result of dura underlying the fracture.The site of the leak is often displacement of the brain and shearing of the olfactory difficult to determine, but useful diagnostic tests include nerve filaments and may occur in the absence of a frac- the instillation of water-soluble contrast into the CSF ture. At least partial recovery of olfactory and gustatory followed by CT with the patient in various positions, or function is the rule, but if bilateral anosmia persists for injection of radionuclide compounds or fluorescein into several months, the prognosis is poor. Partial optic nerve the CSF and the insertion of absorptive nasal pledgets. injuries from closed trauma result in blurring of vision, The site of an intermittent leak is rarely delineated, and central or paracentral scotomas, or sector defects. Direct many resolve spontaneously. orbital injury may cause short-lived blurred vision for close objects due to reversible iridoplegia. Diplopia lim- ited to downward gaze and corrected when the head is tilted away from the side of the affected eye indicates trochlear nerve damage. It occurs frequently as an iso- lated problem after minor head injury or may develop after a delay of several days without pathophysiologic explanation. Direct facial nerve injury caused by a basi- lar fracture is present immediately in up to 3% of severe injuries; it may also be delayed 5–7 days. Fractures through the petrous bone, particularly the less common transverse type, are liable to produce facial palsy. Delayed palsy, the mechanism of which is unknown, has a good prognosis. Injury to the eighth cranial nerve from a frac- ture of the petrous bone causes loss of hearing, vertigo,

and nystagmus immediately after injury. Deafness from 403 eighth nerve injury must be distinguished from that due to rupture of the eardrum, blood in the middle ear, or disruption of the ossicles from fracture through the mid- dle ear. Dizziness and high-tone hearing loss occur with direct cochlear concussion. SEIZURES FIGURE 31-3 CHAPTER 31 Concussion and Other Head Injuries Acute subdural hematoma. Noncontrast CT scan reveals a Convulsions are surprisingly uncommon immediately hyperdense clot which has an irregular border with the brain after a head injury, but a brief period of tonic extensor and causes more horizontal displacement (mass effect) than posturing or a few clonic movements of the limbs just might be expected from its thickness. The disproportionate after the moment of impact can occur. However, the mass effect is the result of the large rostral-caudal extent of cortical scars that evolve from contusions are highly these hematomas. Compare to Fig. 31-4. epileptogenic and may later manifest as seizures, even after many years (Chap. 20). The severity of injury hematomas may be asymptomatic and usually do not roughly determines the risk of future seizures. It has require evacuation. been estimated that 17% of individuals with brain con- tusion, subdural hematoma, or prolonged loss of con- A subacutely evolving syndrome due to subdural sciousness will develop a seizure disorder and that this hematoma occurs days or weeks after injury with risk extends for an indefinite period of time, whereas drowsiness, headache, confusion, or mild hemiparesis; it the risk is ≤2% after mild injury. The majority of con- usually arises in alcoholics and in the elderly, often after vulsions in the latter group occurs within 5 years of only minor trauma. injury but may be delayed for decades. Penetrating injuries have a much higher rate of subsequent epilepsy. On imaging studies subdural hematomas appear as crescentic collections over the convexity of one or both SUBDURAL AND EPIDURAL HEMATOMAS hemispheres, most commonly in the frontotemporal region, and less often in the inferior middle fossa or over Hemorrhages beneath the dura (subdural) or between the occipital poles (Fig. 31-3). Interhemispheric, poste- the dura and skull (epidural) each have characteristic rior fossa, or bilateral convexity hematomas are less fre- clinical and radiologic features. They are associated with quent and are difficult to diagnose clinically, although underlying contusions and other injuries, often making drowsiness and the signs expected for damage in each it difficult to determine the relative contribution of each region can usually be detected. The bleeding that causes component to the clinical state. The mass effect and larger hematomas is primarily venous in origin, although raised ICP caused by these hematomas may be life additional arterial bleeding sites are sometimes found at threatening, making it imperative to identify them operation and a few large hematomas have a purely arte- rapidly by CT or MRI scan and to remove them when rial origin. appropriate. Epidural Hematoma Acute Subdural Hematoma (Fig. 31-4) These evolve more rapidly than subdural (Fig. 31-3) Up to one-third of patients have a lucid hematomas and are correspondingly more treacherous. interval lasting minutes to hours before coma super- They occur in up to 10% of cases of severe head injury venes, but most are drowsy or comatose from the but are associated with underlying cortical damage less moment of injury. Direct cranial trauma may be minor often than are subdural hematomas. Most patients are and is not required for acute subdural hemorrhage to unconscious when first seen. A “lucid interval” of several occur, especially in the elderly and those taking antico- minutes to hours before coma supervenes is most char- agulant medications. Acceleration forces alone, as from acteristic of epidural hemorrhage, but it is still uncom- whiplash, are sometimes sufficient to produce subdural mon, and epidural hemorrhage is by no means the only hemorrhage. A unilateral headache and slightly enlarged pupil on the same side are frequently but not invariably present. Stupor or coma, hemiparesis, and unilateral pupillary enlargement are signs of larger hematomas. In an acutely deteriorating patient, burr (drainage) holes or an emergency craniotomy are required. Small subdural

404 SECTION III Diseases of the Central Nervous System FIGURE 31-4 FIGURE 31-5 Acute epidural hematoma. The tightly attached dura is CT scan of chronic bilateral subdural hematomas of dif- stripped from the inner table of the skull, producing a charac- ferent ages. The collections began as acute hematomas and teristic lenticular-shaped hemorrhage on noncontrast CT have become hypodense in comparison to the adjacent brain scan. Epidural hematomas are usually caused by tearing of after a period during which they were isodense and difficult the middle meningeal artery following fracture of the tempo- to appreciate. Some areas of resolving blood are contained ral bone. on the more recently formed collection on the left (arrows). cause of this temporal sequence. Rapid surgical evacua- Skull x-rays are usually normal except for a shift of the tion and ligation or cautery of the damaged vessel that is calcified pineal body to one side or an occasional unex- the source of bleeding, usually the middle meningeal pected fracture. In long-standing cases an irregular calcifi- artery that has been lacerated by an overlying skull frac- cation of membranes that surround the hematoma may ture, is indicated. be appreciated. CT without contrast infusion shows a low-density mass over the convexity of the hemisphere Chronic Subdural Hematoma (Fig. 31-5), but between 2 and 6 weeks after the initial bleeding the hemorrhage becomes isodense compared to A history of trauma may or may not be elicited in rela- adjacent brain and is then inapparent. Many subdural tion to chronic subdural hematoma.The causative injury hematomas that are a week or more in age contain areas may have been trivial and forgotten; 20–30% of patients of blood adjacent to intermixed serous fluid. Bilateral recall no head injury, particularly the elderly and those chronic hematomas may fail to be detected because of the with clotting disorders. Headache is common but not absence of lateral tissue shifts; this circumstance is sug- invariable. Additional features may include slowed think- gested by a “hypernormal” CT scan with fullness of the ing, vague change in personality, seizure, or a mild cortical sulci and small ventricles in an older patient.The hemiparesis.The headache may fluctuate in severity, some- infusion of contrast material demonstrates enhancement times with changes in head position. Bilateral chronic of the vascular fibrous capsule surrounding the collection. subdural hematomas produce perplexing clinical syn- MRI reliably identifies subacute and chronic hematomas. dromes. Focal signs such as hemiparesis may be lacking, and the initial clinical impression may be of a stroke, Clinical observation coupled with serial imaging is a brain tumor, drug intoxication, depression, or a dement- reasonable approach to patients with few symptoms and ing illness because drowsiness, inattentiveness, and inco- small chronic subdural collections. Treatment with glu- herence of thought are more prominent than focal signs cocorticoids alone is sufficient for some hematomas, but such as hemiparesis. Patients with undetected bilateral surgical evacuation is more often successful. The fibrous subdural hematomas have a low tolerance for surgery, membranes that grow from the dura and encapsulate the anesthesia, and drugs that depress the nervous system, collection require removal to prevent recurrent fluid remaining drowsy or confused for long periods. Chronic accumulation. Small hematomas are resorbed, leaving hematomas rarely cause brief episodes of hemiparesis or only the organizing membranes. On imaging studies aphasia that are indistinguishable from transient ischemic very chronic subdural hematomas may be difficult to attacks; on occasion a chronic collection can expand distinguish from hygromas, which are collections of CSF over a period of days or weeks and clinically resemble a from a rent in the arachnoid membrane. As noted, corti- brain tumor. cal damage underlying a chronic hematoma may serve as the origin of seizures.

CLINICAL SYNDROMES AND TABLE 31-1 405 TREATMENT OF HEAD INJURY GUIDELINES FOR MANAGEMENT OF CONCUSSION CHAPTER 31 Concussion and Other Head Injuries MINOR INJURY IN SPORTS The patient who is fully alert and attentive minutes after Severity of Concussion head injury but who has one or more symptoms of headache, dizziness, faintness, nausea, a single episode of Grade 1: Transient confusion, no loss of consciousness emesis, difficulty with concentration, or slight blurring (LOC), all symptoms resolve within 15 min. of vision has a good prognosis with little risk of subse- quent deterioration. Such patients have usually sustained Grade 2: Transient confusion, no LOC, but concussive a concussion and are expected to have a brief amnestic symptoms or mental status abnormalities persist longer period. Children are particularly prone to drowsiness, than 15 min. vomiting, and irritability, which are sometimes delayed for several hours after apparently minor injuries.Vasova- Grade 3: Any LOC, either brief (seconds) or prolonged gal syncope that follows injury may cause undue concern. (minutes). Constant generalized or frontal headache is common in the following days. It may be migrainous (throbbing and On-site Evaluation hemicranial) in nature or aching and bilateral. After several hours of observation, patients with minor injury 1. Mental status testing may be accompanied home and observed for a day by a a. Orientation—time, place, person, circumstances of family member or friend; written instructions to return injury if symptoms worsen should be provided. b. Concentration—digits backward, months of year in reverse order Persistent severe headache and repeated vomiting in c. Memory—names of teams, details of contest, recent the context of normal alertness and no focal neurologic events, recall of three words and objects at 0 and 5 min signs are usually benign, but radiologic studies should be obtained and a period of observation in the hospital is 2. Finger-to-nose with eyes open and closed justified. The decision to perform imaging tests depends 3. Pupillary symmetry and reaction largely on clinical signs that indicate the impact was 4. Romberg and tandem gait severe (e.g., prolonged concussion, periorbital or mas- 5. Provocative testing—40-yard sprint, 5 push ups, 5 sit ups, toid hematoma, repeated vomiting, palpable skull frac- ture), on the seriousness of other bodily injuries, and on 5 knee bends (development of dizziness, headaches, or the degree of surveillance that can be anticipated after other symptoms is abnormal) discharge. Two prospective studies have suggested that older age, two or more episodes of vomiting, >30 min Management Guidelines of retrograde or persistent anterograde amnesia, seizure, and concurrent drug or alcohol intoxication are sensi- Grade 1: Remove from contest. Examine immediately and at tive (but not specific) indicators of intracranial hemor- 5 min intervals. May return to contest if exam clears within rhage that justify CT scanning. It is appropriate to be 15 min. A second grade 1 concussion eliminates player for more liberal in obtaining CT scans in children since a 1 week, with return contingent upon normal neurologic small number, even without loss of consciousness, will assessment at rest and with exertion. display intracranial lesions. Grade 2: Remove from contest, cannot return for at least Concussion in Sports 1 week. Examine at frequent intervals on sideline. Formal neurologic exam the next day. If headache or other symp- In the current absence of adequate data, a common toms persist for 1 week or longer, CT or MRI scan is indi- sense approach has been taken to returning an athlete cated. After 1 full asymptomatic week, repeat neurologic who has suffered a concussion to physical activities. It is assessment at rest and with exercise before cleared to generally advisable to avoid contact sports for several resume play. A second grade 2 concussion eliminates player days at least, and for weeks after a severe concussion or for at least 2 weeks following complete resolution of after more than one minor concussion or if there are symptoms at rest or with exertion. If imaging shows protracted neurologic symptoms (Table 31-1). These abnormality, player is removed from play for the season. guidelines are designed to avoid cognitive decline and an extremely rare complication of recurrent head injury, Grade 3: Transport by ambulance to emergency department if termed the second impact syndrome, in which cerebral still unconscious or worrisome signs are present; cervical swelling follows a minor head injury. There is some spine stabilization may be indicated. Neurologic exam and, when indicated, CT or MRI scan will guide subsequent management. Hospital admission indicated when signs of pathology are present or if mental status remains abnormal. If findings are normal at the time of the initial medical evaluation, the athlete may be sent home, but daily exams as an outpatient are indicated. A brief (LOC for seconds) grade 3 concussion eliminates player for 1 week, and a prolonged (LOC for minutes) grade 3 concussion for 2 weeks, following complete resolution of symptoms. A second grade 3 concussion should eliminate player from sports for at least 1 month following resolution of symptoms. Any abnormality on CT or MRI scans should result in termination of the season for the athlete, and return to play at any future time should be discouraged. Source: Modified from Quality Standards Subcommittee of the American Academy of Neurology: The American Academy of Neurology Practice Handbook. The American Academy of Neurol- ogy, St. Paul, MN, 1997.

SECTION III Diseases of the Central Nervous System406 evidence that repeated concussions in football and soc- complications that follow severe brain injury can be cer players are associated with mild but cumulative cog- treated. Hypoxia should be reversed and normal saline nitive deficits, but this topic is controversial. used as the preferred resuscitation fluid. The finding of an epidural or subdural hematoma or large intracerebral INJURY OF INTERMEDIATE SEVERITY hemorrhage is an indication for prompt surgery and intracranial decompression in an otherwise salvageable Patients who have persistent confusion, behavioral patient.The use of prophylactic anticonvulsants has been changes, subnormal alertness, extreme dizziness, or focal recommended by some neurosurgeons but there is little neurologic signs such as hemiparesis should be admitted supportive data. Management of raised ICP, a frequent to the hospital and soon thereafter have a CT scan. Usu- feature of severe head injury, is discussed in Chap. 22. ally a cerebral contusion or hematoma is found. The common clinical syndromes in this group include (1) GRADING AND PROGNOSIS delirium with a disinclination to be examined or moved, expletive speech, and resistance if disturbed (anterior In severe head injury, the clinical features of eye open- temporal lobe contusions); (2) a quiet, disinterested, slowed ing, motor responses of the limbs, and verbal output mental state (abulia) with dull facial expression alternat- have been found to be generally predictive of outcome. ing with irascibility (inferior frontal and frontopolar These three features are summarized in the Glasgow contusions); (3) a focal deficit such as aphasia or mild Coma Scale; a score between 3 and 15 is assigned based hemiparesis (due to subdural hematoma or convexity on responses (Table 31-2). Over 85% of patients with contusion, or, less often but frequently missed, carotid aggregate scores of <5 die within 24 h. However, a num- artery dissection); (4) confusion and inattention, poor ber of patients with slightly higher scores and a poor performance on simple mental tasks, and fluctuating or initial prognosis, including a few without pupillary light slightly erroneous orientation (associated with several responses, survive, suggesting that an initially aggressive types of injuries, including those described above as well approach is justified in most patients. Patients <20 years, as medial frontal contusions and interhemispheric sub- particularly children, may make remarkable recoveries dural hematoma); (5) repetitive vomiting, nystagmus, after having grave early neurologic signs. In one large drowsiness, and unsteadiness (usually from labyrinthine study of severe head injury, 55% of children had a good concussion, but occasionally due to a posterior fossa outcome at 1 year, compared with 21% of adults. Older subdural hematoma or vertebral artery dissection); and age, increased ICP, early hypoxia or hypotension, and (6) diabetes insipidus (damage to the median eminence evidence on imaging of compression of the cisterns sur- or pituitary stalk). Injuries of this degree are often complicated rounding the brainstem and shift of midline structures by drug or alcohol intoxication, and clinically inapparent cervi- are all poor prognostic signs. A delay in the evacuation cal spine injury may be present. of large intracerebral hemorrhages is also associated with a poorer prognosis. Most patients in this category, after appropriate surgi- cal removal of hematomas, improve over several days or TABLE 31-2 weeks. During the first week the state of alertness, memory, and other cognitive functions often fluctuates, GLASGOW COMA SCALE FOR HEAD INJURY and irascibility or agitation is common. Behavioral changes are worse at night, as with many other Eye opening (E) 4 Verbal response (V) 5 encephalopathies, and may be treated with small doses Spontaneous 3 Oriented 4 of antipsychotic medications. Subtle abnormalities of To loud voice 2 Confused, disoriented 3 attention, intellect, spontaneity, and memory tend to To pain 1 Inappropriate words 2 return to normal weeks or months after the injury, Nil Incomprehensible sounds 1 sometimes surprisingly abruptly. Persistent problems in 6 Nil cognition are discussed below. Best motor 5 response (M) 4 SEVERE INJURY Obeys 3 Localizes Patients who are comatose from the onset require Withdraws (flexion) 2 immediate neurologic attention and resuscitation. After Abnormal flexion 1 intubation, with care taken to immobilize the cervical posturing spine, the depth of coma, pupillary size and reactivity, Extension posturing limb movements, and Babinski responses are assessed. As Nil soon as vital functions permit and cervical spine x-rays and a CT scan have been obtained, the patient should Note: Coma score = E + M + V. Patients scoring 3 or 4 have an 85% be transported to a critical care unit where systemic chance of dying or remaining vegetative, whereas scores >11 indi- cate only a 5–10% likelihood of death or vegetative state and 85% chance of moderate disability or good recovery. Intermediate scores correlate with proportional chances of recovery.

POSTCONCUSSION SYNDROME prolonged use of drugs that produce dependence. 407 Vestibular exercises (Chap. 9) and small doses of vestibu- The postconcussion syndrome refers to a state of nervous lar suppressants such as phenergan may be helpful instability following mild or moderate head injury. The when dizziness is the main problem. Patients who after main features are fatigue, dizziness, headache, and diffi- minor or moderate injury report difficulty with memory culty in concentration.The syndrome is at times difficult or with complex cognitive tasks at work may also be to distinguish from asthenia and depression. Based largely reassured that these problems usually improve over on experimental models, it has been proposed that subtle 6–12 months. It is helpful to obtain serial and quantified axonal shearing lesions or as yet undefined biochemical neuropsychological testing in order to adjust the work alterations account for the cognitive symptoms. In mod- environment to the patient’s current abilities and to erate and severe trauma, neuropsychological changes document improvement over time. Whether cognitive such as difficulty with attention, memory, and other exercises are useful is uncertain, but patients certainly cognitive deficits are undoubtedly present, sometimes report them to be so. Previously energetic individuals severe, but many deficits identified by formal testing do usually have the best recoveries. In patients with persis- not impact daily functioning.Test scores tend to improve tent symptoms, the possibility exists of malingering or rapidly during the first 6 months after injury, then more prolongation as a result of litigation. slowly for years. CHAPTER 31 Concussion and Other Head Injuries Treatment: FURTHER READINGS CONCUSSION DISCHINGER PC et al: Early predictors of postconcussive syndrome Management of the various symptoms of the postcon- in a population of trauma patients with mild traumatic brain cussive syndrome requires the identification and treat- injury. J Trauma 66:289, 2009 ment of depression, sleeplessness, anxiety, persistent headache, and dizziness. A clear explanation of the LOVELL M: The management of sports-related concussion: current problems that may follow concussion has been shown status and future trends. Clin Sports Med 28:95, 2009 to reduce subsequent complaints. Care is taken to avoid ROPPER AH (ed): Neurological and Neurosurgical Intensive Care, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2004 ——— GORSON KC: Concussion. N Engl J Med 356:166, 2007

CHAPTER 32 PRIMARY AND METASTATIC TUMORS OF THE NERVOUS SYSTEM Stephen M. Sagar ■ Mark A. Israel ■ Primary Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 Tuberous Sclerosis (Bourneville’s Disease) . . . . . . . . . . . . . . 417 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 Von Hippel–Lindau Syndrome . . . . . . . . . . . . . . . . . . . . . . . . 417 Astrocytomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 ■ Tumors Metastatic to Brain . . . . . . . . . . . . . . . . . . . . . . . . . . 418 Oligodendrogliomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Mechanisms of Brain Metastases . . . . . . . . . . . . . . . . . . . . . 418 Ependymomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413 Evaluation of Metastases from Known Cancer . . . . . . . . . . . 418 Medulloblastomas and Primitive Neuroectodermal Brain Metastases Without a Known Primary Tumor . . . . . . . . 418 Tumors (PNET) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 ■ Leptomeningeal Metastases . . . . . . . . . . . . . . . . . . . . . . . . . 420 CNS Lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 414 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 420 Meningiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 Laboratory and Imaging Evaluation . . . . . . . . . . . . . . . . . . . . 420 Schwannomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 ■ Malignant Spinal Cord Compression . . . . . . . . . . . . . . . . . . . 421 Other Benign Brain Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . 416 ■ Metastases to the Peripheral Nervous System . . . . . . . . . . . 421 ■ Complications of Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 ■ Neurocutaneous Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . 417 Radiation Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 421 Neurofibromatosis Type 1 Toxicities of Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . 422 (Von Recklinghausen’s Disease) . . . . . . . . . . . . . . . . . . . . . 417 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422 Neurofibromatosis Type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . 417 Malignant primary tumors of the central nervous system of a focal neurologic deficit; (2) seizure; or (3) nonfocal (CNS) occur in ~16,500 individuals and account for an esti- neurologic disorder such as headache, dementia, person- mated 13,000 deaths in the United States annually, a mortal- ality change, or gait disorder. The presence of systemic ity rate of 6 per 100,000.The age-adjusted incidence appears symptoms such as malaise, weight loss, anorexia, or fever to be about the same worldwide. An approximately equal suggests a metastatic rather than a primary brain tumor. number of benign tumors of the CNS are diagnosed, with a much lower mortality rate. Glial tumors account for 50–60% Progressive focal neurologic deficits result from of primary brain tumors, meningiomas for 25%, schwanno- compression of neurons and white matter tracts by mas for 10%, and other CNS tumors for the remainder. expanding tumor and surrounding edema. Less com- monly, a brain tumor presents with a sudden stroke- Brain and vertebral metastases from systemic cancer like onset of a focal neurologic deficit. Although this are far more prevalent than primary CNS tumors. About presentation may be caused by hemorrhage into the 15% of patients who die of cancer (80,000 individuals tumor, often no hemorrhage can be demonstrated and each year in the United States) have symptomatic brain the mechanism is obscure. Tumors frequently associ- metastases; an additional 5% suffer spinal cord involve- ated with hemorrhage include high-grade gliomas, ment. Brain and spinal metastases therefore pose a major metastatic melanoma, and choriocarcinoma. problem in the management of systemic cancer. Seizures may result from disruption of cortical circuits. Approach to the Patient: Tumors that invade or compress the cerebral cortex, even BRAIN TUMORS small meningiomas, are more likely to be associated with seizures than subcortical neoplasms. Nonfocal neurologic CLINICAL FEATURES Brain tumors usually present dysfunction usually reflects increased intracranial pressure with one of three syndromes: (1) subacute progression (ICP), hydrocephalus, or diffuse tumor spread.Tumors in some areas of the brain may produce behavioral disorders; 408

for example, frontal lobe tumors may present with per- pattern of edema, with accumulation of excess water 409 sonality change, dementia, or depression. in surrounding white matter. Contrast enhancement reflects a breakdown of the blood-brain barrier within Headache may result from focal irritation or dis- the tumor, permitting leakage of contrast agent. placement of pain-sensitive structures (Chap. 6) or Low-grade gliomas typically do not exhibit contrast from a generalized increase in ICP. A headache that enhancement. worsens rather than abates with recumbency is sug- gestive of a mass lesion. Headaches from increased Positron emission tomography (PET) and single- ICP are usually holocephalic and episodic, occurring photon emission tomography (SPECT) have ancillary more than once a day. They typically develop rapidly roles in the imaging of brain tumors, primarily in dis- over several minutes, persist for 20–40 min, and sub- tinguishing tumor recurrence from tissue necrosis that side quickly. They may awaken the patient from a can occur after irradiation (see below). Functional sound sleep, generally 60–90 min after retiring.Vom- imaging with PET, MRI, or magnetoencephalography iting may occur with severe headaches. As elevated may be of use in surgical or radiosurgical planning to ICP becomes sustained, the headache becomes con- define the anatomic relationship of the tumor to critical tinuous but varying in intensity. Elevated ICP may brain regions such as the primary motor or language cause papilledema (Chap. 17), although it is often not cortex. present in infants or patients >55 years. LABORATORY EXAMINATION Primary brain CHAPTER 32 Primary and Metastatic Tumors of the Nervous System The Karnofsky performance scale is useful in assess- tumors typically do not produce serologic abnormali- ing patients with brain tumors (Table 32-1). A score ties such as an elevated sedimentation rate or tumor- Ն70 indicates that the patient is ambulatory and inde- specific antigens. In contrast, metastases to the nervous pendent in self-care activities; it is often taken as a system, depending on the type and extent of the pri- level of function justifying aggressive therapy. mary tumor, may be associated with systemic signs of malignancy. Lumbar puncture is generally not useful in NEUROIMAGING CT and MRI can reveal mass the diagnosis of brain tumors. The cerebrospinal fluid effect and contrast enhancement. Mass effect reflects (CSF) rarely contains malignant cells, with the impor- the volume of neoplastic tissue as well as surrounding tant exceptions of leptomeningeal metastases; primary edema. Brain tumors typically produce a vasogenic CNS lymphoma; and primitive neuroectodermal tumors, including medulloblastoma.The primary use of lumbar TABLE 32-1 puncture in the evaluation of a brain tumor is to KARNOFSKY PERFORMANCE INDEX exclude other diagnoses, such as infection or demyeli- nating disease. Moreover, lumbar puncture may precip- PERFORMANCE FUNCTIONAL CAPABILITY OF itate brain herniation in patients with mass lesions and STATUS THE PATIENT should be performed only in patients in whom imag- 100 ing studies have demonstrated the basilar cisterns to be Normal; no complaints; no evidence of patent. 90 disease 80 Treatment: 70 Able to carry on normal activity; minor BRAIN TUMORS 60 signs or symptoms of disease 50 SYMPTOMATIC Glucocorticoids decrease the volume 40 Normal activity with effort; some signs of edema surrounding brain tumors and improve neuro- 30 or symptoms of disease logic function; dexamethasone (initially 12–20 mg/d in divided doses PO or IV) is used because it has relatively 20 Cares for self; unable to carry on little mineralocorticoid activity. Because of the toxicities normal activity or do active work of long-term glucocorticoid administration, the dexam- 10 Requires occasional assistance but is ethasone dose is rapidly tapered to the lowest dose that 0 able to care for most needs relieves symptoms. Requires considerable assistance and frequent medical care The treatment of epilepsy associated with brain Disabled; requires special care and tumors is identical to the treatment of other forms of assistance partial epilepsy. The first-line agents phenytoin, carba- Severely disabled; hospitalization is mazepine, and valproic acid are equally effective; levirac- indicated although death is not tam and oxcarbazepine are also coming into wide use imminent Very sick; hospitalization necessary; active supportive treatment is necessary Moribund, fatal processes progressing rapidly Dead

SECTION III Diseases of the Central Nervous System410 (Chap. 20). It is common practice to administer anti- patients with hereditary predisposition syndromes (Table 32-2), most brain tumors do not occur in patients with epileptic drugs prophylactically to all patients with supra- such recognizable syndromes. As is the case in all other tentorial brain tumors, although there are no good data tumor types, somatic mutations are almost invariably supporting this practice. present in malignant brain tumor tissue. Amplification of the EGFR gene occurs in approximately one-third of Gliomas and primary CNS lymphomas are associated cases of glioblastoma multiforme (GBM), the highest with an increased risk for deep vein thrombosis and pul- grade astrocytoma. Moreover, cytogenetic analysis often monary embolism, probably because these tumors reveals characteristic changes that can signal the alter- secrete procoagulant factors into the systemic circulation. ation in cancer-related genes within these chromosomal Even though hemorrhage within gliomas is a frequent regions. In astrocytic tumors, DNA is commonly lost on histopathologic finding, patients are at no increased risk chromosomes 10p, 17p, 13q, and 9. Oligodendrogliomas for symptomatic intracranial bleeding following treat- frequently have deletions of 1p and 19q, resulting from a ment with an anticoagulant. Prophylaxis with low-dose centromeric translocation and loss of one of the translo- SC heparin should be employed for patients with brain cated chromosomes. In meningiomas portions of 22q, tumors who have lower limb immobility, which places which contains the gene for neurofibromatosis (NF) them at risk for deep venous thrombosis. type 2, are often lost. PRIMARY BRAIN TUMORS The particular constellation of genetic alterations varies among individual gliomas, even those that are ETIOLOGY histologically indistinguishable. Moreover, gliomas are genetically unstable. Genetic abnormalities tend to accu- Exposure to ionizing radiation is the only well- mulate with time, and these changes correspond with an documented environmental risk factor for the develop- increasingly malignant phenotype.There are at least two ment of gliomas. A number of hereditary syndromes genetic routes for the development of GBM (Fig. 32-1). are associated with an increased risk of brain tumors One route involves the progression, generally over years, (Table 32-2). Genes that contribute to the development from a low-grade astrocytoma with deletions of chro- of brain tumors, as well as other malignancies, fall into mosome 17 and inactivation of the p53 gene to a highly two general classes, tumor-suppressor genes and oncogenes. malignant glioma with additional chromosomal alter- Whereas germ-line mutations of such genes do occur in ations.The second route is characterized by the de novo appearance of a malignant glioma with amplification of TABLE 32-2 HEREDITARY SYNDROMES ASSOCIATED WITH BRAIN TUMORS SYNDROME GENE (LOCUS) GENE PRODUCT (FUNCTION) NERVOUS SYSTEM NEOPLASMS NF1 (17q) Neurofibromin (GTPase Neurofibromatosis type 1 Neuroma, schwannoma, (von Recklinghausen’s NF2 (22q) activating protein) meningioma, optic glioma Disease)a Merlin (cytoskeletal protein) Schwannoma, glioma, Neurofibromatosis type 2a ependymoma, meningioma Astrocytoma Tuberous sclerosis TSC1 (9q) Hamartin (unknown function) Hemangioblastoma of retina, von Hippel-Lindaua TSC2 (16p) Tuberin (GTPase activating protein) cerebellum and spinal cord; Li-Fraumenia VHL (3p) pVHL (modulator of cellular pheochromocytoma Retinoblastomaa hypoxic response) Malignant glioma p53 (17p) TP53 (cell cycle and transcriptional regulator) Retinoblastoma, pineoblastoma, RB1 (13q) RB (cell cycle regulator) malignant glioma Medulloblastoma, Turcot APC (5q) APC (cell adhesion) malignant glioma (adenomatous Gorlin (basal cell nevus polyposis coli) PTH (developmental regulator) Medulloblastoma syndrome) PTCH (9q) Menin (cofactor for transcription) (patched) Pituitary adenoma, malignant Multiple endocrine neoplasia MEN1 (11q13) schwannoma 1 (Werner syndrome)a aGenetic testing possible.

Cell of origin Cell of origin 411 EGFR amplification LOH 17p (p53) LOH 10 (PTEN) Astrocytoma CDK4 amplification WHO Grade II MDM2 amplification LOH 19q LOH 9p (INK4a) Astrocytoma WHO Grade III Other LOH (e.g., DCC) LOH 10q (PTEN) Other LOH (eg.,DCC) Other amplification (e.g., PDGFR) Other amplification (e.g., PDGFR) de novo: GBM, Secondary: GBM, FIGURE 32-2 CHAPTER 32 Primary and Metastatic Tumors of the Nervous System WHO Grade IV WHO Grade IV Malignant astrocytoma (glioblastoma). Coronal proton density–weighted MR scan through the temporal lobes FIGURE 32-1 demonstrates a heterogeneous right temporal lobe mass Model for the pathogenesis of human astrocytoma. (arrows) compressing the third and lateral ventricles. The Glioblastoma multiforme (GBM) typically presents without area of hypointense signal (double arrows) indicates either evidence of a precursor lesion, referred to as de novo GBM, hemorrhage or calcification. Heterogeneous MR signal inten- frequently associated with amplification of the epidermal sity is typical of glioblastoma. growth factor receptor (EGFR) gene. Less commonly, GBM arises in association with progressive genetic alterations cytoplasmic atypia, endothelial proliferation, mitotic activ- after the diagnosis of a lower grade astrocytoma. These ity, and necrosis. Endothelial proliferation and necrosis are tumors are referred to as secondary GBM. The most widely strong predictors of aggressive behavior. described alterations are mutations of p53 and INK4a. Other genes implicated in the development of these primary brain Quantitative measures of mitotic activity also corre- tumors include CDK4, MDM2, DDC, and PDGFR. LOH, loss late with prognosis.The proliferation index can be deter- of heterozygosity. mined by immunohistochemical staining with antibodies to the proliferating cell nuclear antigen (PCNA) or with the EGFR gene and an intact p53 gene in association a monoclonal antibody termed Ki-67, which recognizes with other genetic abnormalities. a histone protein expressed in proliferating but not qui- escent cells. ASTROCYTOMAS The prognosis of brain tumor patients is closely asso- Tumors with astrocytic cytologic features are the most ciated with the histologic grade of the tumor. In a repre- common primary intracranial neoplasms (Fig. 32-2). sentative Finnish population, the median survival was 93.5 The most widely used histologic grading system is the months for patients with grade I or II astrocytomas, 12.4 World Health Organization four-tiered grading system. months for patients with grade III (anaplastic astrocy- Grade I is reserved for special histologic variants of toma), and 5.1 months for patients with grade IV (GBM) astrocytoma that occur mainly in childhood and can tumors.Although these survival rates are somewhat lower have an excellent prognosis after surgical excision.These than are generally reported, they represent a population- include juvenile pilocytic astrocytoma, subependymal giant cell based experience and are not influenced by selection astrocytoma (which most often occurs in patients with bias. Clinical features correlating with poor prognosis tuberous sclerosis), and pleiomorphic xanthoastrocytoma. At include age >65 years and a poor functional status, as the other extreme is grade IV GBM, a clinically aggres- defined by the Karnofsky performance scale. sive tumor. Astrocytoma (grade II) and anaplastic astrocy- toma (grade III) are intermediate in their histologic and Low-Grade Astrocytoma clinical manifestations. The histologic features associated with higher grade are hypercellularity, nuclear and Low-grade astrocytomas are more common in children than adults. Pilocytic astrocytoma, named for its character- istic spindle-shaped cells, is the most common childhood

SECTION III Diseases of the Central Nervous System412 brain tumor and is typically benign. It frequently occurs primary glial tumors, radiation is generally administered in the cerebellum and is well demarcated from adjacent to the tumor mass, as defined by contrast enhancement brain. Complete surgical excision usually produces long- on a CT or MRI scan, plus a 2-cm margin. A total dose term, disease-free survival. of 5000–7000 cGy is administered in 25–35 equal frac- The median overall survival of grade II astrocytoma is tions, 5 days per week. 5–6 years. The optimum timing of surgery and radiation therapy for these patients is unknown. Since astrocytomas The roles of stereotaxic radiosurgery and interstitial infiltrate surrounding brain, total surgical excision is brachytherapy in glioma treatment are uncertain. Stereo- impossible. Moreover, they are genetically unstable and taxic radiosurgery is the administration of a focused high accumulate mutations over time, leading to more aggres- dose of radiation to a precisely defined volume of tissue sive behavior. For patients who are symptomatic from mass in a single treatment. Stereotaxic radiosurgery can poten- effect or poorly controlled epilepsy, surgical excision can tially achieve tumor ablation within the treated volume. relieve symptoms. For patients who are asymptomatic or A major limitation of stereotaxic radiosurgery is that minimally symptomatic at presentation, a diagnostic biopsy it can be used for only relatively small tumors, generally should be performed and, when surgically feasible, the <4 cm in maximum diameter. Interstitial brachytherapy, the tumor may be resected. Whether radiation therapy is implantation of radioactive material into the tumor mass, administered immediately postoperatively or at the time of is generally reserved for tumor recurrence because of its tumor progression is not thought to affect overall survival, associated toxicity, necrosis of adjacent brain tissue. but immediate radiation therapy does delay tumor pro- gression. No role for chemotherapy in the management of Chemotherapy is marginally effective and is often low-grade astrocytoma has been defined. used as an adjuvant therapy following surgery and radia- tion therapy. Temozolomide, an orally administered High-Grade Astrocytoma alkylating agent, has replaced nitrosureas, including car- mustine (BCNU) and lomustine (CCNU), as the most The large majority of astrocytomas arising in adults are widely used chemotherapeutic agent for high-grade high grade, supratentorial, and do not have a clearly defined gliomas.Temozolomide is generally better tolerated than margin between normal and malignant tissue. Neoplastic nitrosoureas, notably producing less fatigue and pulmonary cells migrate away from the main tumor mass and infiltrate toxicity, and has the advantage of oral administration. adjacent brain, often tracking along white matter pathways. Moreover, a randomized trial of radiation therapy plus Imaging studies do not indicate the full extent of the temozolomide for the adjuvant treatment of GBM com- tumor.These tumors are almost all eventually fatal. Median pared to radiation therapy alone was the first clinical survival of patients with grade III astrocytoma is <3 years trial to demonstrate a clear-cut advantage of adjuvant and for those with a grade IV tumor, <1 year. Longer sur- chemotherapy for that disease. The patients who vival correlates with younger age, better performance sta- received radiation therapy plus temozolomide had a tus, and greater extent of surgical resection. Late in their median survival 21/2 months longer than those who course, astrocytomas, especially those located in the poste- received radiation therapy alone. The modest survival rior fossa, can metastasize along CSF pathways to the spine. benefit appears to be restricted to a subgroup of patients Metastases outside the CNS are rare. with methylation and silencing of the promoter for the MGMT gene coding for O6-methylguanine-DNA High-grade astrocytomas are managed with gluco- methyltransferase. corticoids, surgery, radiation therapy, and chemotherapy. Dexamethasone is generally administered at the time of An alternative approach to the chemotherapy of diagnosis and continued for the duration of radiation high-grade gliomas that has shown survival benefit in therapy. After completion of radiation therapy, dexam- controlled trials is the surgical implantation directly into ethasone is tapered to the lowest possible dose. the tumor resection cavity of polymer wafers that release BCNU locally into surrounding brain. The efficacy of Because astrocytomas infiltrate adjacent normal brain, this approach is similar to but probably slightly less than total surgical excision is not possible. Nevertheless, retro- that of temozolomide, although without the attendant spective studies indicate that the extent of tumor resection systemic toxicity of chemotherapy. correlates with survival in younger patients. Therefore, accessible astrocytomas are generally resected aggressively. Experimental approaches to brain tumor chemother- Surgery is indicated to obtain tissue for pathologic diag- apy include efforts to bypass the blood-brain barrier nosis and to control mass effect. using local injection of chemotherapeutic agents into the tumor mass or the intraarterial injection of chemotherapy Postoperative radiation therapy prolongs survival and following osmotic disruption of the blood-brain barrier. improves quality of life. Treated with dexamethasone Molecularly targeted therapies are also being tested in alone following surgery, the mean survival of patients patients with GBM. In particular, since mutation or <65 years with glioblastoma is 7–9 months. Survival is overexpression of EGFR is common in GBM, EGFR prolonged to 11–13 months with radiation therapy. For antagonists or inhibitors of its signaling pathways are being evaluated in patients with GBM in clinical trials.

Gliomatosis cerebri is a rare form of astrocytoma in Surgery, at minimum a stereotaxic biopsy, is necessary 413CHAPTER 32 Primary and Metastatic Tumors of the Nervous System which there is diffuse infiltration of the brain by malig- to establish a diagnosis. Many oligodendrogliomas are nant astrocytes without a focal enhancing mass. It gener- amenable to gross total surgical resection. In addition, ally presents as a multifocal CNS syndrome or a more oligodendrogliomas may respond dramatically to systemic generalized disorder including dementia, personality combination chemotherapy with procarbazine, lomustine, change, or seizures. Neuroimaging studies are often non- and vincristine (PCV), or to temozolomide, which, specific, and biopsy is required to establish the diagnosis. although not approved by the U.S. Food and Drug Gliomatosis cerebri is treated with whole-brain radiation Administration (FDA) for this indication, is currently therapy or temozolomide; in selected patients, radiation to much more widely used than PCV. Oligodendrogliomas the entire neuroaxis is employed. with deletions of chromosome 1p always respond to chemotherapy, but only ~25% of oligodendrogliomas OLIGODENDROGLIOMAS lacking the 1p deletion respond. The simultaneous dele- tion of 1p and 19q, which results from a centromeric Oligodendrogliomas, which comprise about 15% of translocation of chromosomes 1 and 19, predicts a durable gliomas in adults, have a more benign course and are response to chemotherapy (>31 months on average) and more responsive to cytotoxic treatment than astrocy- a much longer survival. It appears that the chromosomal tomas. For grade II oligodendrogliomas, the median sur- translocation identifies a subgroup of anaplastic oligoden- vival is 7–8 years, and there are a substantial number of drogliomas with a less aggressive natural course, and patients with prolonged survival (>10 years). For grade response to chemotherapy is another marker of that III or anaplastic oligodendrogliomas, median survival is favorable phenotype. ~5 years. Oligodendrogliomas occur chiefly in supraten- torial locations; in adults, ~30% contain areas of calcifi- EPENDYMOMAS cation (Fig. 32-3). In adults, the most frequent histologic type is myxopapil- As a rule, oligodendrogliomas are less infiltrative than lary ependymoma, which typically arises from the filum astrocytomas, permitting more complete surgical exci- terminale of the spinal cord and appears in the lum- sion. Histologic features of mitoses, necrosis, and nuclear bosacral region. The term myxopapillary refers to the atypia are associated with a more aggressive clinical course. papillary arrangement of tumor cells, which produce If these features are prominent, the tumor is termed an mucin. Ependymomas in adults may also occur intracra- anaplastic oligodendroglioma. Some gliomas contain mixtures nially or at higher levels of the spinal cord. On CT or of cells with astrocytic and oligodendroglial features. If MRI, ependymomas typically appear as diffusely this mixed histology is prominent, the tumor is termed enhancing masses relatively well demarcated from adja- a mixed glioma, or an oligoastrocytoma. The greater the cent neural tissue. Following gross total resection, the oligodendroglial component, the more benign the clini- prognosis is good, with >80% 5-year disease-free survival. cal course. AB FIGURE 32-3 Oligodendroglioma. A. Noncontrast CT scan reveals a calcified mass involving the left temporal lobe (arrows) associated with mild mass effect but little edema. B. An MR T2- weighted image demonstrates a het- erogeneous mass with hypointense signal (black arrows) surrounded by a zone of higher signal intensity (white arrows), consistent with a calcified temporal lobe mass. The tumor extends into the left medial temporal lobe and compresses the midbrain.

SECTION III Diseases of the Central Nervous System414 Ependymomas that cannot be totally resected are treated mainstay of definitive therapy is chemotherapy. A single with stereotaxic radiosurgery or with a course of exter- dose of rituximab is generally administered prior to cyto- nal beam radiation therapy. toxic chemotherapy as long as an enhancing mass lacking a blood-tumor barrier is present. Chemotherapy includes MEDULLOBLASTOMAS AND PRIMITIVE high-dose methotrexate, but multiagent chemotherapy, NEUROECTODERMAL TUMORS (PNET) usually adding vincristine and procarbazine, appears to be more effective than methotrexate alone. Chemotherapy is These highly cellular malignant tumors are thought to followed in patients <60 years with whole-brain radiation arise from neural precursor cells. Medulloblastomas occur therapy (WBRT). WBRT is postponed as long as possible in the posterior fossa and, along with astrocytomas, are or administered at reduced doses in patients >60 years the most frequent malignant brain tumors of children. because of the risk of dementia, gait disorder, and inconti- PNET is a term applied to tumors histologically indis- nence as manifestations of late-delayed radiation toxicity. tinguishable from medulloblastoma but occurring either Consolidation therapy is typically with high-dose cytara- in adults or supratentorially in children. In adults, >50% bine. Intraarterial chemotherapy with or without blood- present in the posterior fossa. These tumors frequently brain barrier disruption is an alternative. Intrathecal disseminate along CSF pathways. chemotherapy with methotrexate can be added if lep- tomeningeal disease is present, but it has not proven to offer If possible, these tumors should be surgically excised; added benefit if high-dose methotrexate is used. Despite the less residual tumor left behind, the better the prog- aggressive therapy, >90% of patients develop recurrent nosis. In adults, surgical excision of a PNET should be CNS disease.The median survival of patients who tolerate followed by irradiation of the entire neuraxis, with a treatment with high-dose methotrexate is >3 years. boost in radiation dose to the primary tumor. If the tumor is not disseminated at presentation, the prognosis In immunodeficient patients, primary CNS lym- is generally favorable. Aggressive treatment can result in phoma may be ring-enhancing rather than diffusely prolonged survival, although half of adult patients enhancing on CT or MRI (Fig. 32-4). It may therefore relapse within 5 years of treatment.Whereas chemother- be impossible by imaging criteria to distinguish primary apy is widely used in medulloblastoma and PNET in CNS lymphoma from metastatic malignancies or infec- children, its role in adults is not yet defined. tions, particularly toxoplasmosis. The standard approach to this dilemma in a neurologically stable patient is to CNS LYMPHOMA administer antibiotics to treat toxoplasmosis for 2–3 weeks and then repeat neuroimaging. If the imaging shows Primary CNS Lymphoma clear improvement, antibiotic treatment is continued. If not, a stereotaxic brain biopsy, which has substantially Primary CNS lymphoma is typically a high-grade B cell more risk in an immunodeficient than an immunocom- malignancy that presents within the neuraxis without petent patient, is performed. Alternatively, when the evidence of systemic lymphoma. These occur most fre- clinical situation permits a safe lumbar puncture, a CSF quently in immunocompromised individuals, specifically examination demonstrating Epstein-Barr virus DNA in organ transplant recipients and patients with AIDS CSF in an immunodeficient patient with neuroimaging (Chap. 37). In immunocompromised patients, CNS lym- findings consistent with lymphoma is diagnostic of pri- phomas are invariably associated with Epstein-Barr virus mary CNS lymphoma. In organ transplant recipients, infection of the tumor cells. reversal of the immunosuppressed state can improve outcome. Survival with AIDS-related primary CNS In immunocompetent patients, neuroimaging studies lymphoma is very poor, generally Յ3 months; pretreat- most often reveal a uniformly enhancing mass lesion. ment performance status, the degree of immunosuppres- Stereotaxic needle biopsy can be used to establish the sion, and the extent of CNS dissemination at diagnosis diagnosis.There is no benefit of surgical resection unless all appear to influence outcome. there is a need for immediate decompression of a life- threatening mass effect. Leptomeningeal involvement is Secondary CNS Lymphoma present in ~15% of patients at presentation and in 50% at some time during the course of the illness. Moreover, Secondary CNS lymphoma is a manifestation of sys- the disease extends to the eyes in up to 15% of patients. temic disease and almost always occurs in adults with Therefore, a slit-lamp examination and, if indicated, progressive B cell lymphoma or B cell leukemia who anterior chamber paracentesis or vitreous biopsy is nec- have tumor involvement of bone, bone marrow, testes, essary to define radiation ports. or the cranial sinuses. The leptomeninges are the most common site of CNS metastasis. Leptomeningeal lym- The prognosis of primary CNS lymphoma is poor phoma is usually detectable with contrast-enhanced CT compared to histologically similar lymphoma occurring or gadolinium-enhanced MRI of the brain and spine outside the CNS. Many patients experience a dramatic clinical and radiographic response to glucocorticoids; how- ever, relapse almost invariably occurs within weeks. The

415 AB C CHAPTER 32 Primary and Metastatic Tumors of the Nervous System FIGURE 32-4 lymphoma or toxoplasmosis; the presence of multiple lesions CNS lymphoma. A. Proton density–weighted MR image favors toxoplasmosis. C. In a different patient with lymphoma- through the temporal lobe demonstrates a low signal inten- tous meningitis, an axial postcontrast T1-weighted MRI sity nodule (small arrows) surrounded by a ring of high signal through the midbrain demonstrates multiple areas of abnor- intensity edema (larger arrows). B. T1-weighted contrast- mal enhancement in periventricular and subependymal enhanced axial MRI demonstrates ring enhancement sur- regions (arrows). Lymphoma tends to spread subependy- rounded by a nonenhanced rim of edema. In this patient with mally at interfaces of CSF and brain parenchyma. AIDS, a solitary lesion of this type is consistent with either or by CSF examination. Treatment consists of systemic Total surgical resection of benign meningiomas is chemotherapy, intrathecal chemotherapy, and CNS irradi- curative. If a total resection cannot be achieved, local ation. It is usually possible to suppress the leptomeningeal external beam radiotherapy or stereotaxic radiosurgery disease effectively, although the overall prognosis is deter- reduces the recurrence rate to <10%. For meningiomas mined by the course of the systemic lymphoma. Intra- that are not surgically accessible, radiosurgery is the parenchymal lymphoma metastases may be treated with treatment of choice. Small asymptomatic meningiomas radiation therapy or systemic chemotherapy. incidentally discovered in older patients can safely be followed radiologically; these tumors grow at an average MENINGIOMAS rate of a few millimeters in diameter per year and only rarely become symptomatic. Meningiomas are derived from mesoderm, probably from cells giving rise to the arachnoid granulations.These tumors Rare meningiomas invade the brain or have histologic are usually benign and attached to the dura. They may evidence of malignancy such as nuclear pleomorphism invade the skull but only infrequently invade the brain. and cellular atypia. A high mitotic index is also predictive Meningiomas most often occur along the sagittal sinus, of aggressive behavior. Hemangiopericytoma, although not over the cerebral convexities, in the cerebellar-pontine strictly a meningioma, is a meningeal tumor with an angle, and along the dorsum of the spinal cord.They are especially aggressive behavior. Meningiomas with fea- more frequent in women than men, with a peak inci- tures of aggressiveness and hemangiopericytomas, even if dence in middle age. totally excised by gross inspection, frequently recur and should receive postoperative radiotherapy. Chemotherapy Meningiomas may be found incidentally on a CT or has no proven benefit. MRI scan or may present with a focal seizure, a slowly progressive neurologic deficit, or symptoms of raised SCHWANNOMAS ICP. The radiologic image of a dural-based, extraaxial mass with dense, uniform contrast enhancement is These tumors are also called neuromas, neurinomas, or neu- essentially diagnostic, although a dural metastasis must rolemmomas.They arise from Schwann cells of nerve roots, also be considered (Fig. 32-5). A meningioma may have most frequently in the eighth cranial nerve (vestibular a “dural tail,” a streak of dural enhancement flanking the schwannoma, formerly termed acoustic schwannoma or main tumor mass; however, this finding may also be pre- acoustic neuroma).The fifth cranial nerve is the second most sent with other dural tumors. frequent site; however, schwannomas may arise from any

SECTION III Diseases of the Central Nervous System416 vestibular system adapts to slow destruction of the eighth nerve, patients with vestibular schwannomas characteris- FIGURE 32-5 tically present with progressive unilateral hearing loss rather Meningioma. Coronal postcontrast T1-weighted MR image than with dizziness or other vestibular symptoms. Unex- demonstrates an enhancing extraaxial mass arising from the plained unilateral hearing loss merits evaluation with falx cerebri (arrows). There is a “dural tail” of contrast enhance- audiometry and an MRI scan (Chap. 18). As a vestibular ment extending superiorly along the intrahemispheric septum. schwannoma grows, it can compress the cerebellum, pons, or facial nerve.With rare exceptions schwannomas cranial or spinal root except the optic and olfactory are histologically and clinically benign. nerves, which are myelinated by oligodendroglia rather than Schwann cells. Neurofibromatosis (NF) type 2 (see Whenever possible, schwannomas should be surgi- below) strongly predisposes to vestibular schwannoma. cally excised. When the tumors are small, it is usually Schwannomas of spinal nerve roots also occur in patients possible to preserve hearing in the involved ear. In the with NF type 2 as well as patients with NF type 1. case of large tumors, the patient is usually deaf at presen- tation; nonetheless, surgery is indicated to prevent fur- Eighth cranial nerve schwannomas typically arise from ther compression of posterior fossa structures. Stereotaxic the vestibular division of the nerve. On MRI they are radiosurgery is also effective treatment for schwannoma densely and uniformly enhancing neoplasms (Fig. 32-6). and has a complication rate equivalent to that of surgery. Vestibular schwannomas enlarge the internal auditory canal, an imaging feature that helps distinguish them OTHER BENIGN BRAIN TUMORS from other cerebellopontine angle masses. Because the Epidermoid tumors are cystic tumors with proliferative epi- dermal cells at the periphery and more mature epidermal cells towards the center of the cyst. The mature cells desquamate into the liquid center of the cyst. Epider- moid tumors are thought to arise from embryonic epi- dermal rests within the cranium. They occur extraaxially near the midline, in the middle cranial fossa, the suprasel- lar region, or the cerebellopontine angle. These well- demarcated lesions are amenable to complete surgical excision. Postoperative radiation therapy is unnecessary. Dermoid cysts are thought to arise from embryonic rests of skin tissue trapped within the CNS during clo- sure of the neural tube. The most frequent locations are in the midline supratentorially or at the cerebellopon- tine angle. Histologically, they are composed of multiple elements of the dermis including epidermis, hair folli- cles, and sweat glands; they frequently calcify. Treatment is surgical excision. AB FIGURE 32-6 Vestibular schwannoma. A. Axial noncontrast MR scan through the cerebellopontine angle demon- strates an extraaxial mass that extends into a widened internal auditory canal, displacing the pons (arrows). B. Postcontrast T1-weighted image demonstrates intense enhancement of the vestibu- lar schwannoma (white arrow). Abnormal enhance- ment of the left fifth nerve (black arrow) most likely represents another schwannoma in this patient with neurofibromatosis type 2.

Craniopharyngiomas are thought to arise from remnants NEUROFIBROMATOSIS TYPE 2 417 of Rathke’s pouch, the mesodermal structure from which the anterior pituitary gland is derived (Chap. 33). Cranio- NF2 is characterized by the development of bilateral CHAPTER 32 Primary and Metastatic Tumors of the Nervous System pharyngiomas typically present as suprasellar masses. vestibular schwannomas in >90% of individuals who Because of their location, they may present as growth fail- inherit the gene. Patients with NF2 also have a predispo- ure in children, endocrine dysfunction in adults, or visual sition for the development of meningiomas, gliomas, and loss in either age group. Histologically, craniopharyn- schwannomas of cranial and spinal nerves. In addition, a giomas resemble epidermoid tumors; they are usually characteristic type of cataract, juvenile posterior subcap- cystic, and in adults 80% are calcified. Treatment is surgi- sular lenticular opacity, occurs in NF2. Multiple café au cal excision; postoperative external beam radiation or lait spots and peripheral neurofibromas occur rarely. stereotaxic radiosurgery is added if total surgical removal cannot be achieved. In patients with NF2, vestibular schwannomas are usu- ally associated with progressive unilateral deafness early in Colloid cysts are benign tumors of unknown cellular the third decade of life. Bilateral vestibular schwannomas origin that occur within the third ventricle and can are generally detectable by MRI at that time (Fig. 32-6). obstruct CSF flow. Other rare benign primary brain tumors Surgical management is designed to treat the underlying include neurocytomas, subependymomas, and pleomor- tumor and preserve hearing as long as possible. phic xanthoastrocytomas. Surgical excision of these neo- plasms is the primary treatment and can be curative. This syndrome is caused by mutation of the NF2 Pituitary tumors are discussed in Chap. 33. gene on chromosome 22q. NF2 encodes a protein called neurofibromin 2, schwannomin, or merlin, with homology to NEUROCUTANEOUS SYNDROMES a family of cytoskeletal proteins that includes moesin, ezrin, and radixin. This group of genetic disorders, also known as the phako- matoses, produces a variety of developmental abnormalities TUBEROUS SCLEROSIS (BOURNEVILLE’S of skin along with an increased risk of nervous system DISEASE) tumors (Table 32-2). These disorders are inherited as autosomal dominant conditions with variable penetrance. Tuberous sclerosis is characterized by cutaneous lesions, seizures, and mental retardation. The cutaneous lesions NEUROFIBROMATOSIS TYPE 1 include adenoma sebaceum (facial angiofibromas), ash (VON RECKLINGHAUSEN’S DISEASE) leaf–shaped hypopigmented macules (best seen under ultraviolet illumination with a Wood’s lamp), shagreen NF1 is characterized by cutaneous neurofibromas, pig- patches (yellowish thickenings of the skin over the lum- mented lesions of the skin called café au lait spots, freckling bosacral region of the back), and depigmented nevi. in non-sun-exposed areas such as the axilla, hamartomas Recognizable by neuroimaging studies, the presence of of the iris termed Lisch nodules, and pseudoarthrosis of the subependymal nodules, which may be calcified, is char- tibia. Neurofibromas are benign peripheral nerve tumors acteristic.Tuberous sclerosis patients are at increased risk composed of proliferating Schwann cells and fibroblasts. of developing ependymomas and childhood astrocy- They present as multiple, palpable, rubbery, cutaneous tomas, of which >90% are subependymal giant cell astrocy- tumors.They are generally asymptomatic; however, if they tomas. These are benign neoplasms that may develop in grow in an enclosed space, e.g., the intervertebral fora- the retina or along the border of the lateral ventricles. men, they may produce a compressive radiculopathy or They may obstruct the foramen of Monro and produce neuropathy. Aqueductal stenosis with hydrocephalus, scol- hydrocephalus. Rhabdomyomas of the myocardium and iosis, short stature, hypertension, epilepsy, and mental angiomyomas of the kidney, liver, adrenals, and pancreas retardation may also occur. may also occur. Patients with NF1 are at increased risk of developing Treatment is symptomatic.Anticonvulsants for seizures, nervous system neoplasms, including plexiform neurofibro- shunting for hydrocephalus, and behavioral and educa- mas, optic pathway gliomas, ependymomas, meningiomas, tional strategies for mental retardation are the mainstays astrocytomas, and pheochromocytomas. Neurofibromas may of management. Severely affected individuals generally undergo secondary malignant degeneration and become die before 30 years of age. sarcomatous. Mutations in either the TSC-1 gene at 9q or the Mutation of the NF1 gene on chromosome 17 causes TSC-2 gene at 16p are associated with tuberous sclero- von Recklinghausen’s disease.The NF1 gene is a tumor- sis. These genes encode tuberins, proteins that modulate suppressor gene; it encodes a protein, neurofibromin, which the GTPase activity of other cellular signaling proteins. modulates signal transduction through the ras GTPase pathway. VON HIPPEL–LINDAU SYNDROME This syndrome consists of retinal, cerebellar, and spinal hemangioblastomas, which are slowly growing cystic

SECTION III Diseases of the Central Nervous System418 tumors. Hypernephroma, renal cell carcinoma, pheochro- surrounding a central mass of nonenhancing necrotic tis- mocytoma, and benign cysts of the kidneys, pancreas, epi- sue that develops as the metastasis outgrows its blood sup- didymis, or liver may also occur. Erythropoietin produced ply. Metastases are surrounded by variable amounts of by hemangioblastomas may result in polycythemia. edema. Blood products may also be seen, reflecting hem- Mutation of the von Hippel–Lindau (VHL) gene on orrhage of abnormal tumor vessels. chromosome 3p, a tumor-suppressor gene, causes this dis- order. VHL encodes a protein with multiple functions, The radiologic appearance of a brain metastasis is not including modulation of signal transduction in response specific. The differential diagnosis of ring-enhancing to cellular hypoxia. lesions includes brain abscess, radiation necrosis, toxo- plasmosis, granulomas, tuberculosis, sarcoidosis, demyeli- TUMORS METASTATIC TO BRAIN nating lesions, primary brain tumors, primary CNS lymphoma, stroke, hemorrhage, and trauma. Contrast- MECHANISMS OF BRAIN METASTASES enhanced CT scanning is less sensitive than MRI for the detection of brain metastases. Cytologic examination of Brain metastases arise from hematogenous spread. The the CSF is not indicated, since intraparenchymal brain anatomic distribution of brain metastases generally metastases almost never shed cells into the CSF. parallels regional cerebral blood flow, with a predilec- tion for the gray matter–white matter junction and for BRAIN METASTASES WITHOUT A KNOWN the border zone between middle cerebral and poste- PRIMARY TUMOR rior cerebral artery distributions. The lung is the most common origin of brain metastases; both primary lung In general hospital populations, up to one-third of cancer and cancers metastatic to the lung frequently patients presenting with brain metastases do not have a metastasize to the brain. Breast cancer (especially ductal previously known underlying cancer.These patients gen- carcinoma) has a propensity to metastasize to the cere- erally present with either a seizure or a progressive neu- bellum and the posterior pituitary gland. Other common rologic deficit. Neuroimaging studies typically demonstrate origins of brain metastases are gastrointestinal malignan- one or multiple ring-enhancing lesions. In individuals cies and melanoma (Table 32-3). Certain less common who are not immunocompromised and not at risk for tumors have a special propensity to metastasize to brain, brain abscesses, this radiologic pattern is most likely due including germ cell tumors and thyroid cancer. By con- to brain metastasis. trast, prostate cancer, ovarian cancer, and Hodgkin’s dis- ease rarely metastasize to the brain. Diagnostic evaluation begins with a search for the primary tumor. Blood tests should include carcinoem- EVALUATION OF METASTASES FROM bryonic antigen and liver function tests. Examination of KNOWN CANCER the skin for melanoma and the thyroid gland for masses should be carried out. The search for a primary cancer On MRI scans brain metastases typically appear as well- most often discloses lung cancer (particularly small cell demarcated, approximately spherical lesions that are lung cancer) or melanoma. In 30% of patients no pri- hypointense or isointense relative to brain on T1-weighted mary tumor can be identified, even after extensive eval- images and bright on T2-weighted images.They invariably uation. A CT scan of the chest, abdomen, and pelvis enhance with gadolinium, reflecting extravasation of should be obtained. If these are all negative, further gadolinium through tumor vessels that lack a blood-tumor imaging studies, including bone scan, other radionuclide barrier (Fig. 32-7). Small metastases often enhance uni- scans, mammography, and upper and lower gastrointesti- formly. Larger metastases typically produce ring enhancement nal barium studies, are unlikely to be productive. A tissue diagnosis is essential. If a primary tumor is found, it will usually be more accessible to biopsy than a TABLE 32-3 FREQUENCY OF NERVOUS SYSTEM METASTASES BY COMMON PRIMARY TUMORS SITE OF PRIMARY BRAIN LEPTOMENINGEAL SPINAL CORD TUMOR METASTASES, % METASTASES, % COMPRESSION, % Lung 40 24 18 Breast 19 41 24 Melanoma 10 12 4 Gastrointestinal tract 13 6 Genitourinary tract 7 18 Other 7 10 30 17

419 AB FIGURE 32-7 Brain metastasis. A. Axial T2-weighted MRI through the lateral ventricles reveals two iso- dense masses, one in the subependymal region and one near the cortex (arrows). B. T1-weighted postcontrast image at the same level as A reveals enhancement of the two masses seen on the T2-weighted image as well as a third mass in the left frontal lobe (arrows). brain lesion. If a single brain lesion is found in a surgically visualized by neuroimaging studies, WBRT is usually CHAPTER 32 Primary and Metastatic Tumors of the Nervous System accessible location, if a primary tumor is not found, or if used. Its benefit has been established in controlled the primary tumor is in a location difficult to biopsy, the studies, but no clear dose response has been shown. brain metastasis should be biopsied or resected. Usually, 30–37.5 Gy is administered in 10–15 fractions; an additional dose (“boost”) of focal irradiation to a single or Treatment: large metastasis may also be administered. Stereotaxic TUMORS METASTATIC TO BRAIN radiosurgery is of benefit in patients with four or fewer Once a systemic cancer metastasizes to the brain it is, metastases demonstrable by MRI. The addition of WBRT with rare exception, incurable. Therapy is therefore pal- to stereotaxic radiosurgery delays tumor recurrence in liative, designed to prevent disability and suffering and, the brain but does not prolong survival. if possible, to prolong life. Published outcome studies have focused on survival as the primary endpoint, leaving Surgery Up to 40% of patients with brain metastases questions regarding quality of life unanswered. There is, have only a single tumor mass identified by CT. Accessible however, widespread agreement that glucocorticoids, single metastases may be surgically excised as a anticonvulsants, radiation therapy, and surgery (see palliative measure. If the systemic disease is under below) can contribute to the management of these control, total resection of a single brain lesion has been patients. demonstrated to improve survival and minimize disability. Survival is further improved if surgery is followed by GENERAL MEASURES Glucocorticoids frequently WBRT. ameliorate symptoms of brain metastases. Improvement is often dramatic, occurring within 24 h, and is sustained Chemotherapy Brain metastases of certain tumors, with continued administration, although the toxicity including breast cancer, small cell lung cancer, and of glucocorticoids is cumulative. Therefore, if possible, germ cell tumors, are often responsive to systemic a more definitive therapy for metastases should be chemotherapy. Although metastases frequently do not instituted to permit withdrawal of glucocorticoid respond as well as the primary tumor, dramatic responses therapy. One-third of patients with brain metastases to systemic chemotherapy or hormonal therapy may have one or more seizures; anticonvulsants are used occur in some cases. In patients who are neurologically empirically for seizure prophylaxis. asymptomatic, two to four cycles of systemic chemother- apy may be administered initially to reduce tumor mass SPECIFIC MEASURES and render the residual tumor more amenable to Radiation Therapy Radiation therapy is the radiation therapy. Even if a complete radiologic remission primary treatment for brain metastases. Since multiple is achieved from chemotherapy, WBRT should then be microscopic deposits of tumor cells throughout the administered. Gene therapy, immunotherapy, intraarterial brain are likely to be present in addition to metastases chemotherapy, and chemotherapy administered following osmotic disruption of the blood-brain barrier are currently under investigation.

SECTION III Diseases of the Central Nervous System420 LEPTOMENINGEAL METASTASES FIGURE 32-8 Carcinomatous meningitis. Sagittal postcontrast MRI Leptomeningeal metastases are also called carcinomatous through the lower thoracic region demonstrates diffuse pial meningitis, meningeal carcinomatosis, and, in the case of spe- enhancement along the surface of the spinal cord (arrows), cific tumors, leukemic meningitis or lymphomatous meningitis. typical of CSF spread of neoplasm. Clinical evidence of leptomeningeal metastases is present in 8% of patients with metastatic solid tumors; at Treatment: necropsy, the prevalence is as high as 19%. Among solid LEPTOMENINGEAL METASTASES tumors, adenocarcinomas of the breast, lung, and gastroin- Although the prognosis of patients with leptomeningeal testinal tract and melanoma are the most common cause metastases is poor, ~20% of patients treated aggressively of leptomeningeal metastases (Table 32-3). In one-quarter can expect a response of Ն6 months. Intrathecal therapy of patients the systemic cancer is under control, and exposes meningeal tumor implants to high concentra- especially in these patients the effective control of lep- tions of chemotherapy with minimal systemic toxicity. tomeningeal disease can improve the quality and duration Methotrexate can be safely administered intrathecally of life. and is effective against leptomeningeal metastases from a variety of solid tumors including lymphoma; cytara- Cancer usually metastasizes to the meninges via the bine and thiotepa are alternative agents. Liposomal bloodstream. Alternatively, cells may invade the subarach- cytarabine provides prolonged cytotoxic levels of noid space directly from a superficially located parenchy- cytarabine in the CSF, requiring administration only mal brain metastasis. Some tumors, including squamous every 2 weeks, in contrast to weekly or twice weekly cell carcinoma of the skin and some non-Hodgkin’s lym- administration of other agents. Intrathecal chemother- phomas, have a propensity to grow along peripheral apy may be administered either by repeated lumbar nerves and may seed the meninges by that route. puncture or through an indwelling Ommaya reservoir, which consists of a catheter in one lateral ventricle CLINICAL FEATURES attached to a reservoir implanted under the scalp. If there is a question of patency of CSF pathways, a Leptomeningeal metastases present with signs and radionuclide flow study through the reservoir may be symptoms at multiple levels of the nervous system, performed. most often in a setting of known systemic malignancy. Large, nodular deposits of tumor on the meninges or Encephalopathy is frequent, and cranial neuropathy or along nerve roots are unlikely to respond to intrathecal spinal radiculopathy from nodular nerve root compression chemotherapy, as the barrier to diffusion is too great. is characteristic. Hydrocephalus can result from obstruc- tion of CSF outflow. Focal neurologic deficits reflect coexisting intraparenchymal metastases. LABORATORY AND IMAGING EVALUATION Leptomeningeal metastases are diagnosed by cytologic demonstration of malignant cells in the CSF, by MRI demonstration of nodular tumor deposits or diffuse enhancement in the meninges (Fig. 32-8), and by meningeal biopsy. CSF findings are usually those of an inflammatory meningitis consisting of lymphocytic pleocytosis, elevated protein levels, and normal or low CSF glucose. A positive CSF cytology is unequivocal evidence of tumor spread to the subarachnoid space. CSF examination is more likely to be informative when larger volumes of CSF are submitted for cytology and when up to three CSF examinations are per- formed. A complete MRI examination of the neuraxis is indicated in all cases of suspected leptomeningeal metastases; in addition to nodular meningeal lesions, hydrocephalus due to obstruction of CSF pathways may be found.

Therefore, external beam radiation is employed, and In patients with cancer who have brachial or lum- 421 these patients may also benefit from systemic bosacral plexopathy, it may be difficult to distinguish chemotherapy. Hydrocephalus is treated with a ven- tumor invasion from radiation injury. High radiation triculoperitoneal shunt, although seeding of the peri- dose or the presence of myokymia (rippling contractions toneum by tumor is a risk. of muscle) suggests radiation injury, whereas pain suggests tumor. Radiographic imaging studies may be equivocal, and surgical exploration is sometimes required. MALIGNANT SPINAL CORD COMPLICATIONS OF THERAPY CHAPTER 32 Primary and Metastatic Tumors of the Nervous System COMPRESSION RADIATION TOXICITY Spinal cord compression from solid tumor metastases usu- ally results from growth of a vertebral metastasis into the The nervous system is vulnerable to injury by therapeutic epidural space. Primary tumors that frequently metastasize radiation. Histologically, there is demyelination, degener- to bone include lung, breast, and prostate cancer. Back ation of small arterioles, and eventually brain infarction pain is usually the first symptom and is prominent at pre- and necrosis. sentation in 90% of patients. The pain is typically dull, aching, and may be associated with localized tenderness. If Acute radiation injury to the brain occurs during or a nerve root is compressed, radicular pain is also present. immediately after therapy. It is rarely seen with current The thoracic cord is most often affected. Weakness, sen- protocols of external beam radiation but may occur after sory loss, and autonomic dysfunction (urinary urgency stereotaxic radiosurgery. Manifestations include headache, and incontinence, fecal incontinence, and sexual impo- sleepiness, and worsening of preexisting neurologic deficits. tence in men) are hallmarks of spinal cord compression. Once signs of spinal cord compression appear, they tend Early delayed radiation injury occurs within 4 months to progress rapidly. It is thus essential to recognize and of therapy. It is associated with an increased white mat- treat this serious complication of malignancy promptly to ter T2 signal on MRI scans. In children, the somnolence prevent irreversible neurologic deficits. Diagnosis and syndrome is a common form of early delayed radiation management are discussed in Chap. 30. injury in which somnolence and ataxia develop after WBRT. Irradiation of the cervical spine may cause METASTASES TO THE PERIPHERAL Lhermitte’s phenomenon, an electricity-like sensation NERVOUS SYSTEM evoked by neck flexion. Symptoms resulting from acute and early delayed radiation injury often respond to glu- Systemic cancer may compress or invade peripheral cocorticoid administration, are self-limited, and usually nerves. Compression of the brachial plexus may occur resolve without residual deficits. These injuries do not by direct extension of Pancoast’s tumors (cancer of the increase the risk of late radiation injury. apex of the lung), by lymphoma, or by extension of local lymph node metastases in breast or lung cancer. Late delayed radiation injury produces permanent dam- The lumbosacral plexus may be compressed by age to the nervous system. It occurs >4 months (gener- retroperitoneal tumor invasion such as occurs in cases of ally 8–24 months) after completion of therapy; onset prostate or ovarian cancer or lymphoma. Skull metas- as late as 15 years after therapy has been described. tases may compress cranial nerve branches as they pass Following focal brain irradiation, radiation necrosis can through the skull, and pituitary metastases may extend occur within the radiation field, producing a contrast- into the cavernous sinus. enhancing (frequently ring-enhancing) mass with sur- rounding white matter signal abnormalities (Fig. 32-9). The epineurium generally provides an effective bar- MRI or CT scans are often unable to distinguish radia- rier to invasion of the peripheral nerves by solid tumors, tion necrosis from recurrent tumor, but PET or SPECT but certain tumors characteristically invade and spread scans may demonstrate the increased glucose metabolism along peripheral nerves. Squamous cell carcinoma of the typical of tumor tissue or the decreased metabolism of skin may spread along the trigeminal nerve and extend necrotic tissue. Magnetic resonance spectroscopy may intracranially. Non-Hodgkin’s lymphoma may be neu- demonstrate a high lactate concentration with relatively rotrophic and cause polyradiculopathy or a syndrome low choline concentration in areas of necrosis. Biopsy is resembling mononeuropathy multiplex (Chap. 40). Focal frequently required to establish the correct diagnosis. external beam radiation may reduce pain, prevent irre- Peripheral nerves, including the brachial and lum- versible loss of peripheral nerve function, and possibly bosacral plexuses, may also develop late delayed radiation restore function. injury. If untreated, radiation necrosis of the CNS may act as an expanding mass lesion. Symptoms may resolve spon- taneously or respond to treatment with glucocorticoids.

422 SECTION III Diseases of the Central Nervous System AB C FIGURE 32-9 (B) demonstrates a mass in the right frontal lobe with sur- Radiation injury. A. Late delayed radiation injury 1 year after rounding vasogenic edema. Abnormal signal changes are whole-brain radiation (5500 cGy). T2-weighted MR image at also present on the left. T1-weighted postcontrast MRI the level of the temporal lobes reveals high signal intensity (C) reveals a heterogeneously enhancing mass in the right abnormality in periventricular white matter (arrows). B and C. cingulate gyrus. Focal radiation necrosis 3 years after radiotherapy (7000 cGy) for carcinoma of the nasopharynx. Axial T2-weighted MRI Progressive radiation necrosis is best treated with surgi- are associated with the development of altered mental cal resection if the patient has a life expectancy of at states (e.g., confusion, depression), ataxia, and seizures. least 6 months and a Karnofsky performance score >70. Chemotherapy for systemic malignancy is a more fre- There are anecdotal reports that anticoagulation with quent cause of nervous system toxicity and is more heparin or warfarin may be beneficial. After WBRT, pro- often toxic to the peripheral than the central nervous gressive dementia can occur, often accompanied by gait system. Cisplatin commonly produces tinnitus and high- apraxia and urinary incontinence. Radiation injury of frequency bilateral hearing loss, especially in younger large arteries also accelerates the development of athero- patients. At cumulative doses >450 mg/m2, cisplatin can sclerosis, but an increase in the risk of stroke becomes produce a symmetric, large-fiber axonal neuropathy that significant only years after radiation treatment. is predominantly sensory; paclitaxel (Taxol) produces a similar picture. Fluorouracil and high-dose cytarabine Endocrine dysfunction resulting in hypopituitarism can cause cerebellar dysfunction that resolves after dis- frequently follows exposure of the hypothalamus or continuation of therapy.Vincristine, which is commonly pituitary gland to therapeutic radiation. Growth hor- used to treat lymphoma, may cause an acute ileus and is mone is the pituitary hormone most sensitive to radia- frequently associated with development of a progressive tion therapy, and thyroid-stimulating hormone is the distal, symmetric sensory motor neuropathy with foot least sensitive; ACTH, prolactin, and the gonadotropins drop and paresthesias. have an intermediate sensitivity. FURTHER READINGS Development of a second neoplasm is another risk of therapeutic radiation that generally occurs many years DEANGELIS L: Chemotherapy for brain tumors—a new beginning. after radiation exposure. Depending on the irradiated N Engl J Med 352:1036, 2005 field, the risk of gliomas, meningiomas, sarcomas, and thyroid cancer is increased. KEIME-GUIBERT F et al: Radiotherapy for glioblastoma in the elderly. N Engl J Med 356:1527, 2007 TOXICITIES OF CHEMOTHERAPY MORRIS PG, ABREY LE: Therapeutic challenges in primary CNS Chemotherapy regimens used to treat primary brain lymphoma. Lancet Neurol 8:581, 2009 tumors generally include alkylating agents, either temo- zolomide or nitrosoureas, and are relatively well toler- PUROW B, SCHIFF D: Advances in the genetics of gliobastoma: are we ated. Infrequently, drugs used to treat CNS neoplasms reaching critical mass? Nat Rev Neurol 5:419, 2009 SANAI N et al: Functional outcome after language mapping for glioma resection N Engl J Med 358:18, 2008

CHAPTER 33 NEUROLOGIC DISORDERS OF THE PITUITARY AND HYPOTHALAMUS Shlomo Melmed I J. Larry Jameson I Gary L. Robertson I Anatomy and Development . . . . . . . . . . . . . . . . . . . . . . . . . . 423 Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423 I Hypothalamic and Anterior Pituitary Insufficiency . . . . . . . . . . 424 I Developmental and Genetic Causes of Hypopituitarism . . . . 425 Acquired Hypopituitarism . . . . . . . . . . . . . . . . . . . . . . . . . . . 425 Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . 426 Laboratory Investigation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 426 I Hypothalamic, Pituitary, and Other Sellar Masses . . . . . . . . . 428 Pituitary Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 428 Other Sellar Masses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429 I Metabolic Effects of Hypothalamic Lesions . . . . . . . . . . . . . . 431 I Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 431 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 The anterior pituitary is often referred to as the “master manifestations and performing the correct laboratory gland” because, together with the hypothalamus, it orches- diagnostic tests. trates the complex regulatory functions of multiple other endocrine glands.The anterior pituitary gland produces six ANATOMY AND DEVELOPMENT major hormones: (1) prolactin (PRL), (2) growth hor- mone (GH), (3) adrenocorticotropin hormone (ACTH), ANATOMY (4) luteinizing hormone (LH), (5) follicle-stimulating hor- mone (FSH), and (6) thyroid-stimulating hormone (TSH). The pituitary gland weighs ~600 mg and is located within the sella turcica ventral to the diaphragma sella; it com- Pituitary hormones are secreted in a pulsatile manner, prises anatomically and functionally distinct anterior and reflecting stimulation by an array of specific hypothala- posterior lobes. The sella is contiguous to vascular and mic releasing factors. Each of these pituitary hormones neurologic structures, including the cavernous sinuses, cra- elicits specific responses in peripheral target tissues. The nial nerves, and optic chiasm. Thus, expanding intrasellar hormonal products of these peripheral glands, in turn, pathologic processes may have significant central mass exert feedback control at the level of the hypothalamus effects in addition to their endocrinologic impact. and pituitary to modulate pituitary function (Fig. 33-1). Pituitary tumors cause characteristic hormone excess Hypothalamic neural cells synthesize specific releas- syndromes. Hormone deficiency may be inherited or ing and inhibiting hormones that are secreted directly acquired. Fortunately, efficacious treatments exist for the into the portal vessels of the pituitary stalk. Blood supply various pituitary hormone excess and deficiency syn- of the pituitary gland is derived from the superior and dromes. Nonetheless, these diagnoses are often elusive, inferior hypophyseal arteries (Fig. 33-2). The hypothal- emphasizing the importance of recognizing subtle clinical amic-pituitary portal plexus provides the major blood 423

424 TRH GHRH Hypothalamus GnRH Neuroendocrine Third ventricle – CRH cell nuclei Hypothalamus Dopamine Pituitary + + + – + Superior Stalk – hypophyseal artery Inferior hypophyseal Long portal artery vessels Target ACTH Trophic organs + hormone TSH secreting cells SECTION III Diseases of the Central Nervous System Cortisol LH PRL GH Posterior + + Anterior pituitary Cell homeostasis FSH pituitary and function + Adrenal Short portal glands vessel T4/T3 Hormone Thermogenesis secretion metabolism Thyroid + Liver FIGURE 33-2 Testosterone glands Diagram of hypothalamic-pituitary vasculature. The hypo- Inhibin thalamic nuclei produce hormones that traverse the portal Spermatogenesis Lactation system and impinge on anterior pituitary cells to regulate pituitary hormone secretion. Posterior pituitary hormones are + derived from direct neural extensions. Testes Estradiol Ovaries Chrondrocytes LH mlU/mL GnRH pg/mL Progesterone Linear and Inhibin organ growth Ovulation IGF-1 FIGURE 33-1 GnRH pulses Diagram of pituitary axes. Hypothalamic hormones regulate anterior pituitary trophic hormones that, in turn, determine LH pulses target gland secretion. Peripheral hormones feed back to regulate hypothalamic and pituitary hormones. For abbrevia- FIGURE 33-3 tions, see text. Hypothalamic gonadotropin-releasing hormone (GnRH) pulses induce secretory pulses of luteinizing hormone (LH). source for the anterior pituitary, allowing reliable trans- mission of hypothalamic peptide pulses without signifi- HYPOTHALAMIC AND ANTERIOR cant systemic dilution; consequently, pituitary cells are PITUITARY INSUFFICIENCY exposed to releasing or inhibiting factors and in turn Hypopituitarism results from impaired production of release their hormones as discrete pulses (Fig. 33-3). one or more of the anterior pituitary trophic hormones. Reduced pituitary function can result from inherited The posterior pituitary is supplied by the inferior disorders; more commonly, it is acquired and reflects the hypophyseal arteries. In contrast to the anterior pitu- mass effects of tumors or the consequences of inflamma- itary, the posterior lobe is directly innervated by hypo- tion or vascular damage.These processes may also impair thalamic neurons (supraopticohypophyseal and tubero- synthesis or secretion of hypothalamic hormones, with hypophyseal nerve tracts) via the pituitary stalk. Thus, resultant pituitary failure (Table 33-1). posterior pituitary production of vasopressin [antidi- uretic hormone (ADH)] and oxytocin is particularly sensitive to neuronal damage by lesions that affect the pituitary stalk or hypothalamus.

TABLE 33-1 Increasing evidence suggests that patients with brain 425 CHAPTER 33 Neurologic Disorders of the Pituitary and Hypothalamus injury including trauma, subarachnoid hemorrhage, and ETIOLOGY OF HYPOPITUITARISMa irradiation have transient hypopituitarism and require intermittent long-term endocrine follow-up, as perma- Development/structural nent hypothalamic or pituitary dysfunction will develop Transcription factor defect in 25–40% of these patients. Pituitary dysplasia/aplasia Congenital CNS mass, encephalocele Hypothalamic Infiltration Disorders Primary empty sella Congenital hypothalamic disorders (septo-optic dysplasia, These disorders—including sarcoidosis, histiocytosis X, Prader-Willi syndrome, Laurence-Moon-Biedl amyloidosis, and hemochromatosis—frequently involve syndrome, Kallmann syndrome) both hypothalamic and pituitary neuronal and neuro- chemical tracts. Consequently, diabetes insipidus occurs Traumatic in one-half of patients with these disorders. Growth Surgical resection retardation is seen if attenuated GH secretion occurs Radiation damage before pubertal epiphyseal closure. Hypogonadotropic Head injuries hypogonadism and hyperprolactinemia are also common. Neoplastic Inflammatory Lesions Pituitary adenoma Parasellar mass (meningioma, germinoma, Pituitary damage and subsequent dysfunction can be ependymoma, glioma) seen with chronic infections such as tuberculosis, with Rathke’s cyst opportunistic fungal infections associated with AIDS, Craniopharyngioma and in tertiary syphilis. Other inflammatory processes, Hypothalamic hamartoma, gangliocytoma such as granulomas or sarcoidosis, may mimic the fea- Pituitary metastases (breast, lung, colon carcinoma) tures of a pituitary adenoma. These lesions may cause Lymphoma and leukemia extensive hypothalamic and pituitary damage, leading to Meningioma trophic hormone deficiencies. Infiltrative/inflammatory Cranial Irradiation Lymphocytic hypophysitis Hemochromatosis Cranial irradiation may result in long-term hypothalamic Sarcoidosis and pituitary dysfunction, especially in children and adoles- Histiocytosis X cents, as they are more susceptible to damage following Granulomatous hypophysitis whole-brain or head and neck therapeutic irradiation.The development of hormonal abnormalities correlates strongly Vascular with irradiation dosage and the time interval after comple- Pituitary apoplexy tion of radiotherapy. Up to two-thirds of patients ultimately Pregnancy-related (infarction with diabetes; develop hormone insufficiency after a median dose of postpartum necrosis) 50 Gy (5000 rad) directed at the skull base. The develop- Sickle cell disease ment of hypopituitarism occurs over 5–15 years and usu- Arteritis ally reflects hypothalamic damage rather than primary destruction of pituitary cells. Although the pattern of hor- Infections mone loss is variable, GH deficiency is most common, Fungal (histoplasmosis) followed by gonadotropin and ACTH deficiency. When Parasitic (toxoplasmosis) deficiency of one or more hormones is documented, the Tuberculosis possibility of diminished reserve of other hormones is Pneumocystis carinii likely. Accordingly, anterior pituitary function should be evaluated over the long term in previously irradiated aTrophic hormone failure associated with pituitary compression or patients, and replacement therapy instituted when appro- destruction usually occurs sequentially GH > FSH > LH > TSH > priate (see later). ACTH. During childhood, growth retardation is often the presenting feature, and in adults hypogonadism is the earliest symptom. Lymphocytic Hypophysitis DEVELOPMENTAL AND GENETIC This often occurs in postpartum women; it usually pre- CAUSES OF HYPOPITUITARISM sents with hyperprolactinemia and MRI evidence of a prominent pituitary mass often resembling an adenoma, ACQUIRED HYPOPITUITARISM Hypopituitarism may be caused by accidental or neuro- surgical trauma; vascular events such as apoplexy; pituitary or hypothalamic neoplasms such as pituitary adenomas, craniopharyngiomas, lymphoma, or metastatic tumors; inflammatory disease such as lymphocytic hypophysitis; infiltrative disorders such as sarcoidosis, hemochromatosis, and tuberculosis; or irradiation.

SECTION III Diseases of the Central Nervous System426 with mildly elevated PRL levels. Pituitary failure however, may develop insidiously. Pituitary masses may caused by diffuse lymphocytic infiltration may be tran- undergo clinically silent infarction with development of sient or permanent but requires immediate evaluation a partial or totally empty sella by cerebrospinal fluid and treatment. Rarely, isolated pituitary hormone defi- (CSF) filling the dural herniation. Rarely, small but ciencies have been described, suggesting a selective functional pituitary adenomas may arise within the rim autoimmune process targeted to specific cell types. of pituitary tissue, and these are not always visible on Most patients manifest symptoms of progressive mass MRI. effects with headache and visual disturbance. The ery- throcyte sedimentation rate is often elevated. As the PRESENTATION AND DIAGNOSIS MRI image may be indistinguishable from that of a pituitary adenoma, hypophysitis should be considered The clinical manifestations of hypopituitarism depend in a postpartum woman with a newly diagnosed pitu- on which hormones are lost and the extent of the hor- itary mass before embarking on unnecessary surgical mone deficiency. GH deficiency causes growth disorders intervention. The inflammatory process often resolves in children and leads to abnormal body composition in after several months of glucocorticoid treatment, and adults (see below). Gonadotropin deficiency causes pituitary function may be restored, depending on the menstrual disorders and infertility in women and extent of damage. decreased sexual function, infertility, and loss of sec- ondary sexual characteristics in men. TSH and ACTH Pituitary Apoplexy deficiency usually develop later in the course of pitu- itary failure. TSH deficiency causes growth retardation Acute intrapituitary hemorrhagic vascular events can in children and features of hypothyroidism in children cause substantial damage to the pituitary and surround- and in adults. The secondary form of adrenal insuffi- ing sellar structures. Pituitary apoplexy may occur ciency caused by ACTH deficiency leads to hypocorti- spontaneously in a preexisting adenoma; post-partum solism with relative preservation of mineralocorticoid (Sheehan’s syndrome); or in association with diabetes, production. PRL deficiency causes failure of lactation. hypertension, sickle cell anemia, or acute shock. The When lesions involve the posterior pituitary, polyuria hyperplastic enlargement of the pituitary during preg- and polydipsia reflect loss of vasopressin secretion. nancy increases the risk for hemorrhage and infarction. Epidemiologic studies have documented an increased Apoplexy is an endocrine emergency that may result in mortality rate in patients with longstanding pituitary severe hypoglycemia, hypotension, central nervous sys- damage, primarily from increased cardiovascular and tem (CNS) hemorrhage, and death. Acute symptoms cerebrovascular disease. may include severe headache with signs of meningeal irritation, bilateral visual changes, ophthalmoplegia, LABORATORY INVESTIGATION and, in severe cases, cardiovascular collapse and loss of consciousness. Pituitary computed tomography (CT) or Biochemical diagnosis of pituitary insufficiency is MRI may reveal signs of intratumoral or sellar hemor- made by demonstrating low levels of trophic hor- rhage, with deviation of the pituitary stalk and com- mones in the setting of low target hormone levels. For pression of pituitary tissue. example, low free thyroxine in the setting of a low or inappropriately normal TSH level suggests secondary Patients with no evident visual loss or impaired con- hypothyroidism. Similarly, a low testosterone level sciousness can be observed and managed conservatively without elevation of gonadotropins suggests hypogo- with high-dose glucocorticoids. Those with significant nadotropic hypogonadism. Provocative tests may be or progressive visual loss or loss of consciousness require required to assess pituitary reserve (Table 33-2). GH urgent surgical decompression. Visual recovery after responses to insulin-induced hypoglycemia, arginine, surgery is inversely correlated with the length of time l-dopa, growth hormone–releasing hormone (GHRH), after the acute event. Therefore, severe ophthalmoplegia or growth hormone–releasing peptides (GHRPs) can or visual deficits are indications for early surgery. be used to assess GH reserve. Corticotropin-releasing Hypopituitarism is very common after apoplexy. hormone (CRH) administration induces ACTH release, and administration of synthetic ACTH (cortrosyn) Empty Sella evokes adrenal cortisol release as an indirect indicator of pituitary ACTH reserve. ACTH reserve is most reliably A partial or apparently totally empty sella is often an assessed during insulin-induced hypoglycemia. How- incidental MRI finding.These patients usually have nor- ever, this test should be performed cautiously in mal pituitary function, implying that the surrounding patients with suspected adrenal insufficiency because rim of pituitary tissue is fully functional. Hypopituitarism,

TABLE 33-2 427 TESTS OF PITUITARY SUFFICIENCY HORMONE TEST BLOOD SAMPLES INTERPRETATION Growth hormone −30, 0, 30, 60, 120 min for Insulin tolerance test: Glucose < 40 mg/dL; Prolactin Regular insulin glucose and GH GH should be >3 μg/L (0.05–0.15 U/kg IV) 0, 15, 30, 45, 60, 120 min for GH GHRH test: 1 μg/kg IV 0, 30, 60, 120 min for GH Normal response is GH >3 μg/L L-Arginine test: 30 g IV 0, 30, 60, 120 min for GH Normal response is GH >3 μg/L over 30 min 0, 20, and 60 min for TSH L-dopa test: 500 mg PO and PRL Normal response is GH >3 μg/L −30, 0, 30, 60, 90 min for TRH test: 200–500 μg IV glucose and cortisol Normal prolactin is >2 μg/L and 0, 15, 30, 60, 90, 120 min increase >200% of baseline ACTH Insulin tolerance test: Regular insulin for ACTH and cortisol Glucose <40 mg/dL (0.05–0.15 U/kg IV) Plasma 11-deoxycortisol and Cortisol should increase by CHAPTER 33 Neurologic Disorders of the Pituitary and Hypothalamus CRH test: 1 μg/kg ovine >7 μg/dL or to >20 μg/dL CRH IV at 0800 h cortisol at 8 A.M.; ACTH can Basal ACTH increases 2- to 4-fold also be measured and peaks at 20–100 pg/mL Metyrapone test: Cortisol levels >20–25 μg/dL Metyrapone (30 mg/kg) 0, 30, 60 min for cortisol Plasma cortisol should be at midnight and aldosterone <4 μg/dL to assure an adequate response TSH Standard ACTH stimulation 0, 30, 60 min for cortisol Normal response is LH, FSH test: ACTH 1-24 11-deoxycortisol >7.5 μg/dL (Cosyntropin), 0.25 mg Basal tests or ACTH >75 pg/mL IM or IV Normal response is cortisol 0, 20, 60 min for TSH and PRLa >21 μg/dL and aldosterone Low-dose ACTH test: response of >4 ng/dL above ACTH 1-24 (Cosyntropin), Basal tests baseline 1 μg IV Cortisol should be >21 μg/dL 3-day ACTH stimulation 0, 30, 60 min for LH and FSH test consists of 0.25 mg Cortisol >21 μg/dL ACTH 1-24 given IV over −30, 0, 15, 30, 60, 90, 120 min 8 h each day for GH, ACTH, cortisol, Low free thyroid hormone levels LH, FSH, and TSH in the setting of TSH levels that Basal thyroid function are not appropriately increased tests: T4, T3, TSH TSH should increase by >5 mU/L unless thyroid TRH test: 200–500 μg IV hormone levels are increased LH, FSH, testosterone, Basal LH and FSH should be estrogen increased in postmenopausal women Multiple GnRH test: GnRH (100 μg) IV Low testosterone levels in the hormones setting of low LH and FSH Combined anterior pituitary In most adults, LH should increase test: GHRH (1 μg/kg), by 10 IU/L and FSH by 2 IU/L CRH (1 μg/kg), Normal responses are variable GnRH (100 μg), TRH (200 μg) Combined or individual releasing are given IV hormone responses must be elevated in the context of basal target gland hormone values and may not be uniformly diagnostic (see text) aEvoked PRL response indicates lactotrope integrity. Note: For abbreviations, see text.

428 of enhanced susceptibility to hypoglycemia and hypoten- HYPOTHALAMIC, PITUITARY, sion. Insulin-induced hypoglycemia is contraindicated in AND OTHER SELLAR MASSES patients with active coronary artery disease or seizure PITUITARY TUMORS disorders. Pituitary adenomas are the most common cause of pituitary hormone hypersecretion and hyposecretion SECTION III Diseases of the Central Nervous System Treatment: syndromes in adults. They account for ~15% of all HYPOPITUITARISM intracranial neoplasms. At autopsy, up to one-quarter of all pituitary glands harbor an unsuspected microade- Hormone replacement therapy, including glucocorti- noma (<10 mm diameter). Similarly, pituitary imaging coids, thyroid hormone, sex steroids, growth hormone, detects small clinically inapparent pituitary lesions in at and vasopressin, is usually safe and free of complica- least 10% of individuals. tions. Treatment regimens that mimic physiologic hor- mone production allow for maintenance of satisfactory Pathogenesis clinical homeostasis. Effective dosage schedules are out- lined in Table 33-3. Patients in need of glucocorticoid Pituitary adenomas are benign neoplasms that arise from replacement require careful dose adjustments during one of the five anterior pituitary cell types. The clinical stressful events such as acute illness, dental procedures, and biochemical phenotype of pituitary adenomas trauma, and acute hospitalization. depend on the cell type from which they are derived. Thus, tumors arising from lactotrope (PRL), somatotrope TABLE 33-3 (GH), corticotrope (ACTH), thyrotrope (TSH), or gonadotrope (LH, FSH) cells hypersecrete their respective HORMONE REPLACEMENT THERAPY FOR ADULT hormones (Table 33-4). Plurihormonal tumors that HYPOPITUITARISMa express combinations of GH, PRL,TSH, ACTH, and the TROPHIC HORMONE REPLACEMENT TABLE 33-4 HORMONE DEFICIT CLASSIFICATION OF PITUITARY ADENOMASa ACTH Hydrocortisone (10–20 mg A.M.; 5–10 mg P.M.) ADENOMA CELL HORMONE CLINICAL TSH Cortisone acetate ORIGIN PRODUCT SYNDROME FSH/LH (25 mg A.M.; 12.5 mg P.M.) PRL Prednisone Lactotrope Hypogonadism, GH (5 mg A.M.; 2.5 mg P.M.) FSH, LH, galactorrhea Vasopressin L-Thyroxine (0.075–0.15 mg daily) Gonadotrope subunits Silent or Males GH hypogonadism Testosterone enanthate Somatotrope Acromegaly/ (200 mg IM every 2 weeks) ACTH gigantism Testosterone skin patch (5 mg/d) Corticotrope GH, PRL Cushing’s disease Females Mixed growth Acromegaly, Conjugated estrogen Any hypogonadism, (0.65–1.25 mg qd for 25 days) hormone and galactorrhea Progesterone prolactin cell PRL, GH Mixed (5–10 mg qd) on days 16–25 Other plurihormonal Estradiol skin patch cell Hypogonadism, (0.5 mg, every other day) Acidophil stem cell galactorrhea, For fertility: Menopausal acromegaly gonadotropins, human Mammosomatotrope PRL, GH Hypogonadism, chorionic gonadotropins galactorrhea, Adults: Somatotropin Thyrotrope TSH acromegaly (0.1–1.25 mg SC qd) Null cell None Thyrotoxicosis Children: Somatotropin Oncocytoma None Pituitary failure [0.02–0.05 (mg/kg per day)] Pituitary failure Intranasal desmopressin (5–20 μg twice daily) aHormone-secreting tumors are listed in decreasing order of fre- Oral 300–600 μg qd quency. All tumors may cause local pressure effects, including visual disturbances, cranial nerve palsy, and headache. aAll doses shown should be individualized for specific patients and Note: For abbreviations, see text. should be reassessed during stress, surgery, or pregnancy. Male and Source: Adapted from S Melmed, in JL Jameson (ed): Principles of female fertility requirements should be managed. Molecular Medicine, Totowa, Humana Press, 1998. Note: For abbreviations, see text.

glycoprotein hormone α subunit may be diagnosed by PRL- and ACTH-producing adenomas and in some 429 CHAPTER 33 Neurologic Disorders of the Pituitary and Hypothalamus careful immunocytochemistry or may manifest as clinical nonfunctioning tumors. syndromes that combine features of these hormonal hypersecretory syndromes. Morphologically, these tumors Compelling evidence also favors growth factor promo- may arise from a single polysecreting cell type or com- tion of pituitary tumor proliferation. Basic fibroblast prise cells with mixed function within the same tumor. growth factor (bFGF) is abundant in the pituitary and has been shown to stimulate pituitary cell mitogenesis. Other Hormonally active tumors are characterized by factors involved in initiation and promotion of pituitary autonomous hormone secretion with diminished respon- tumors include loss of negative-feedback inhibition (as siveness to physiologic inhibitory pathways. Hormone seen with primary hypothyroidism or hypogonadism) and production does not always correlate with tumor size. estrogen-mediated or paracrine angiogenesis. Growth Small hormone-secreting adenomas may cause significant characteristics and neoplastic behavior may also be influ- clinical perturbations, whereas larger adenomas that pro- enced by several activated oncogenes, including RAS and duce less hormone may be clinically silent and remain pituitary tumor transforming gene (PTTG). undiagnosed (if no central compressive effects occur). About one-third of all adenomas are clinically nonfunc- Genetic Syndromes Associated tioning and produce no distinct clinical hypersecretory with Pituitary Tumors syndrome. Most of these arise from gonadotrope cells and may secrete small amounts of α- and β-glycoprotein Several familial syndromes are associated with pituitary hormone subunits or, very rarely, intact circulating tumors, and the genetic mechanisms for some of these gonadotropins. True pituitary carcinomas with docu- have been unraveled. mented extracranial metastases are exceedingly rare. Multiple endocrine neoplasia (MEN) 1 is an autosomal Almost all pituitary adenomas are monoclonal in ori- dominant syndrome characterized primarily by a gin, implying the acquisition of one or more somatic genetic predisposition to parathyroid, pancreatic islet, mutations that confer a selective growth advantage. In and pituitary adenomas. MEN1 is caused by inactivating addition to direct studies of oncogene mutations, this germline mutations in MENIN, a constitutively expressed model is supported by X-chromosomal inactivation tumor-suppressor gene located on chromosome 11q13. analyses of tumors in female patients heterozygous for Loss of heterozygosity, or a somatic mutation of the X-linked genes. Consistent with their clonal origin, remaining normal MENIN allele, leads to tumorigene- complete surgical resection of small pituitary adenomas sis. About half of affected patients develop prolactino- usually cures hormone hypersecretion. Nevertheless, mas; acromegaly and Cushing’s syndrome are less com- hypothalamic hormones, such as GHRH or CRH, also monly encountered. enhance mitotic activity of their respective pituitary tar- get cells, in addition to their role in pituitary hormone Carney syndrome is characterized by spotty skin pig- regulation. Thus, patients harboring rare abdominal or mentation, myxomas, and endocrine tumors including chest tumors elaborating ectopic GHRH or CRH may testicular, adrenal, and pituitary adenomas. Acromegaly present with somatotrope or corticotrope hyperplasia. occurs in about 20% of patients. A subset of patients have mutations in the R1α regulatory subunit of pro- Several etiologic genetic events have been implicated tein kinase A (PRKAR1A). in the development of pituitary tumors.The pathogene- sis of sporadic forms of acromegaly has been particularly McCune-Albright syndrome consists of polyostotic fibrous informative as a model of tumorigenesis. GHRH, after dysplasia, pigmented skin patches, and a variety of binding to its G protein–coupled somatotrope receptor, endocrine disorders, including GH-secreting pituitary utilizes cyclic AMP as a second messenger to stimulate tumors, adrenal adenomas, and autonomous ovarian func- GH secretion and somatotrope proliferation. A subset tion. Hormonal hypersecretion is the result of constitutive (~35%) of GH-secreting pituitary tumors contain spo- cyclic AMP production caused by inactivation of the radic mutations in Gsα (Arg 201 ¡ Cys or His; Gln 227 GTPase activity of Gsα.The Gsα mutations occur postzy- ¡Arg). These mutations inhibit intrinsic GTPase activ- gotically, leading to a mosaic pattern of mutant expression. ity, resulting in constitutive elevation of cyclic AMP, Pit-1 induction, and activation of cyclic AMP response Familial acromegaly is a rare disorder in which family element binding protein (CREB), thereby promoting members may manifest either acromegaly or gigantism. somatotrope cell proliferation and GH secretion. The disorder is associated with LOH at a chromosome 11q13 locus distinct from that of MENIN. Characteristic loss of heterozygosity (LOH) in vari- ous chromosomes has been documented in large or OTHER SELLAR MASSES invasive macroadenomas, suggesting the presence of putative tumor suppressor genes at these loci. LOH of Craniopharyngiomas are benign, suprasellar cystic masses chromosome regions on 11q13, 13, and 9 is present in that present with headaches, visual field deficits, and up to 20% of sporadic pituitary tumors including GH-, variable degrees of hypopituitarism. They are derived from Rathke’s pouch and arise near the pituitary stalk,

SECTION III Diseases of the Central Nervous System430 commonly extending into the suprasellar cistern. show evidence of calcification or bony erosion. Menin- Craniopharyngiomas are often large, cystic, and locally giomas may cause compressive symptoms. invasive. Many are partially calcified, providing a char- acteristic appearance on skull x-ray and CT images. Histiocytosis X comprises a variety of syndromes asso- More than one-half of all patients present before 20 ciated with foci of eosinophilic granulomas. Diabetes years of age, usually with signs of increased intracranial insipidus, exophthalmos, and punched-out lytic bone pressure, including headache, vomiting, papilledema, lesions (Hand-Schüller-Christian disease) are associated and hydrocephalus. Associated symptoms include visual with granulomatous lesions visible on MRI, as well as a field abnormalities, personality changes and cognitive characteristic axillary skin rash. Rarely, the pituitary stalk deterioration, cranial nerve damage, sleep difficulties, may be involved. and weight gain. Hypopituitarism can be documented in about 90% and diabetes insipidus occurs in about Pituitary metastases occur in ~3% of cancer patients. 10%. About one-half of affected children present with Blood-borne metastatic deposits are found almost growth retardation. MRI is generally superior to CT exclusively in the posterior pituitary. Accordingly, dia- to evaluate cystic structure and tissue components of betes insipidus can be a presenting feature of lung, gas- craniopharyngiomas. CT is useful to define calcifica- trointestinal, breast, and other pituitary metastases. About tions and to evaluate invasion into surrounding bony one-half of pituitary metastases originate from breast structures and sinuses. cancer; about 25% of patients with metastatic breast can- Treatment usually involves transcranial or transsphe- cer have such deposits. Rarely, pituitary stalk involve- noidal surgical resection followed by postoperative ment results in anterior pituitary insufficiency.The MRI radiation of residual tumor. Surgery alone is curative in diagnosis of a metastatic lesion may be difficult to distin- less than half of patients because of adherence to vital guish from an aggressive pituitary adenoma; the diagno- structures or because of small tumor deposits in the sis may require histologic examination of excised tumor hypothalamus or brain parenchyma. The goal of tissue. Primary or metastatic lymphoma, leukemias, and surgery is to remove as much tumor as possible with- plasmacytomas also occur within the sella. out risking complications associated with efforts to remove firmly adherent or inaccessible tissue. In the Hypothalamic hamartomas and gangliocytomas may arise absence of radiotherapy, about 75% of tumors recur, from astrocytes, oligodendrocytes, and neurons with vary- and 10-year survival is less than 50%. In patients with ing degrees of differentiation. These tumors may overex- incomplete resection, radiotherapy improves 10-year press hypothalamic neuropeptides including GnRH, survival to 70–90% but is associated with increased risk GHRH, or CRH. In GnRH-producing tumors, chil- of secondary malignancies. Most patients require life- dren present with precocious puberty, psychomotor long pituitary hormone replacement. delay, and laughing-associated seizures. Medical treatment Developmental failure of Rathke’s pouch obliteration of GnRH-producing hamartomas with long-acting may lead to Rathke’s cysts, which are small (<5 mm) cysts GnRH analogues effectively suppresses gonadotropin entrapped by squamous epithelium, and are found in secretion and controls premature pubertal development. about 20% of individuals at autopsy. Although Rathke’s Rarely, hamartomas are also associated with craniofacial cleft cysts do not usually grow and are often diagnosed abnormalities; imperforate anus; cardiac, renal, and lung incidentally, about a third present in adulthood with disorders; and pituitary failure as features of Pallister-Hall compressive symptoms, diabetes insipidus, and hyperpro- syndrome, which is caused by mutations in the carboxyter- lactinemia due to stalk compression. Rarely, internal minus of the GLI3 gene. Hypothalamic hamartomas are hydrocephalus develops. The diagnosis is suggested pre- often contiguous with the pituitary, and preoperative MRI operatively by visualizing the cyst wall on MRI, which diagnosis may not be possible. Histologic evidence of distinguishes these lesions from craniopharyngiomas. hypothalamic neurons in tissue resected at transsphe- Cyst contents range from CSF-like fluid to mucoid noidal surgery may be the first indication of a primary material. Arachnoid cysts are rare and generate an MRI hypothalamic lesion. image isointense with cerebrospinal fluid. Sella chordomas usually present with bony clival ero- Hypothalamic gliomas and optic gliomas occur mainly in sion, local invasiveness, and, on occasion, calcification. childhood and usually present with visual loss. Adults Normal pituitary tissue may be visible on MRI, distin- have more aggressive tumors; about a third are associated guishing chordomas from aggressive pituitary adenomas. with neurofibromatosis. Mucinous material may be obtained by fine-needle aspiration. Brain germ-cell tumors may arise within the sellar Meningiomas arising in the sellar region may be diffi- region.These include dysgerminomas, which are frequently cult to distinguish from nonfunctioning pituitary adeno- associated with diabetes insipidus and visual loss. They mas. Meningiomas typically enhance on MRI and may rarely metastasize. Germinomas, embryonal carcinomas, ter- atomas, and choriocarcinomas may arise in the parasellar region and produce hCG. These germ-cell tumors pre- sent with precocious puberty, diabetes insipidus, visual field defects, and thirst disorders. Many patients are GH-deficient with short stature.

METABOLIC EFFECTS TABLE 33-5 431 OF HYPOTHALAMIC LESIONS FEATURES OF SELLAR MASS LESIONSa Lesions involving the anterior and preoptic hypothalamic IMPACTED STRUCTURE CLINICAL IMPACT CHAPTER 33 Neurologic Disorders of the Pituitary and Hypothalamus regions cause paradoxical vasoconstriction, tachycardia, Pituitary and hyperthermia. Acute hyperthermia is usually due to Hypogonadism a hemorrhagic insult, but poikilothermia may also occur. Optic chiasm Hypothyroidism Central disorders of thermoregulation result from poste- Growth failure and adult rior hypothalamic damage. The periodic hypothermia syn- Hypothalamus drome comprises episodic attacks of rectal temperatures hyposomatotropism <30°C, sweating, vasodilation, vomiting, and bradycardia. Cavernous sinus Hypoadrenalism Damage to the ventromedial hypothalamic nuclei by Frontal lobe Loss of red perception craniopharyngiomas, hypothalamic trauma, or inflamma- Brain Bitemporal hemianopia tory disorders may be associated with hyperphagia and Superior or bitemporal obesity. This region appears to contain an energy-satiety center where melanocortin receptors are influenced by field defect leptin, insulin, POMC products, and gastrointestinal pep- Scotoma tides. Polydipsia and hypodipsia are associated with dam- Blindness age to central osmoreceptors located in preoptic nuclei. Temperature dysregulation Slow-growing hypothalamic lesions can cause increased Appetite and thirst disorders somnolence and disturbed sleep cycles as well as obesity, Obesity hypothermia, and emotional outbursts. Lesions of the Diabetes insipidus central hypothalamus may stimulate sympathetic neu- Sleep disorders rons, leading to elevated serum catecholamine and corti- Behavioral dysfunction sol levels. These patients are predisposed to cardiac Autonomic dysfunction arrhythmias, hypertension, and gastric erosions. Ophthalmoplegia with or EVALUATION without ptosis or diplopia Facial numbness Local Mass Effects Personality disorder Anosmia Clinical manifestations of sellar lesions vary, depending on Headache the anatomic location of the mass and direction of its Hydrocephalus extension (Table 33-5). The dorsal sellar diaphragm pre- Psychosis sents the least resistance to soft tissue expansion from the Dementia sella; consequently, pituitary adenomas frequently extend Laughing seizures in a suprasellar direction. Bony invasion may occur as well. aAs the intrasellar mass expands, it first compresses intrasellar pituitary Headaches are common features of small intrasellar tissue, then usually invades dorsally through the dura to lift the optic tumors, even with no demonstrable suprasellar exten- chiasm or laterally to the cavernous sinuses. Bony erosion is rare, as is sion. Because of the confined nature of the pituitary, direct brain compression. Microadenomas may present with headache. small changes in intrasellar pressure stretch the dural plate; however, headache severity correlates poorly with palsies as well as effects on the ophthalmic and maxillary adenoma size or extension. branches of the fifth cranial nerve (Chap. 29). Patients may present with diplopia, ptosis, ophthalmoplegia, and Suprasellar extension can lead to visual loss by several decreased facial sensation, depending on the extent of mechanisms, the most common being compression of the neural damage. Extension into the sphenoid sinus indicates optic chiasm, but direct invasion of the optic nerves or that the pituitary mass has eroded through the sellar floor. obstruction of CSF flow leading to secondary visual dis- Aggressive tumors rarely invade the palate roof and cause turbances also occurs. Pituitary stalk compression by a nasopharyngeal obstruction, infection, and CSF leakage. hormonally active or inactive intrasellar mass may com- Temporal and frontal lobe involvement may lead to unci- press the portal vessels, disrupting pituitary access to nate seizures, personality disorders, and anosmia. Direct hypothalamic hormones and dopamine; this results in hypothalamic encroachment by an invasive pituitary mass hyperprolactinemia and concurrent loss of other pituitary may cause important metabolic sequelae, including preco- hormones. This “stalk section” phenomenon may also be cious puberty or hypogonadism, diabetes insipidus, sleep caused by trauma, whiplash injury with posterior clinoid disturbances, dysthermia, and appetite disorders. stalk compression, or skull base fractures. Lateral mass inva- sion may impinge on the cavernous sinus and compress its MRI neural contents, leading to cranial nerve III, IV, and VI Sagittal and coronal T1-weighted MRI imaging, before and after administration of gadolinium, allow precise visualization of the pituitary gland with clear delineation of the hypothalamus, pituitary stalk, pituitary tissue and