Harrison Neurology in Clinical Medicine Second Edition

SECTION III Diseases of the Central Nervous System432 Ophthalmologic Evaluation FIGURE 33-4 Because optic tracts may be contiguous to an expanding Pituitary adenoma. Coronal T1-weighted postcontrast MR pituitary mass, reproducible visual field assessment that image shows a homogeneously enhancing mass (arrowheads) uses perimetry techniques should be performed on all in the sella turcica and suprasellar region compatible with a patients with sellar mass lesions that abut the optic chi- pituitary adenoma; the small arrows outline the carotid arteries. asm (Chap. 17). Bitemporal hemianopia or superior bitemporal defects are classically observed, reflecting the location of these tracts within the inferior and posterior part of the chiasm. Homonymous cuts reflect postchias- mal and monocular field cuts prechiasmal lesions. Loss of red perception is an early sign of optic tract pressure. Early diagnosis reduces the risk of blindness, scotomas, or other visual disturbances. Laboratory Investigation The presenting clinical features of functional pituitary ade- nomas (e.g., acromegaly, prolactinomas, or Cushing’s syn- drome) should guide the laboratory studies (Table 33-6). However, for a sellar mass with no obvious clinical features surrounding suprasellar cisterns, cavernous sinuses, sphe- TABLE 33-6 noid sinus, and optic chiasm. Pituitary gland height ranges from 6 mm in children to 8 mm in adults; during SCREENING TESTS FOR FUNCTIONAL PITUITARY pregnancy and puberty, the height may reach 10–12 mm. ADENOMAS The upper aspect of the adult pituitary is flat or slightly concave, but in adolescent and pregnant individuals, this TEST COMMENTS surface may be convex, reflecting physiologic pituitary enlargement. The stalk should be midline and vertical. Acromegaly Serum IGF-I Interpret IGF-I relative CT scan is indicated to define the extent of bony ero- sion or the presence of calcification. Prolactinoma to age- and Cushing’s Anterior pituitary gland soft tissue consistency is gender-matched slightly heterogeneous on MRI, and signal intensity disease resembles that of brain matter on T1-weighted imaging controls (Fig. 33-4). Adenoma density is usually lower than that of surrounding normal tissue on T1-weighted imaging, Oral glucose Normal subjects and the signal intensity increases with T2-weighted images. The high phospholipid content of the posterior tolerance test should suppress pituitary results in a “pituitary bright spot.” with GH obtained growth hormone Sellar masses are commonly encountered as incidental findings on MRI, and most of these are pituitary adeno- at 0, 30, and to <1 μg/L mas (incidentalomas). In the absence of hormone hyper- secretion, these small lesions can be safely monitored by 60 min MRI, which is performed annually and then less often if there is no evidence of growth. Resection should be Serum PRL Exclude medications considered for incidentally discovered macroadenomas, as about one-third become invasive or cause local pres- MRI of the sella sure effects. If hormone hypersecretion is evident, spe- cific therapies are indicated.When larger masses (>1 cm) should be ordered are encountered, they should also be distinguished from nonadenomatous lesions. Meningiomas are often associ- if prolactin is ated with bony hyperostosis; craniopharyngiomas may be calcified and are usually hypodense, whereas gliomas elevated are hyperdense on T2-weighted images. 24-h urinary Ensure urine free cortisol collection is total and accurate Dexamethasone Normal subjects (1 mg) at 11 P.M. suppress to and fasting <5 μg/dL plasma cortisol measured at 8 A.M. ACTH assay Distinguishes adrenal adenoma (ACTH suppressed) from ectopic ACTH or Cushing’s disease (ACTH normal or elevated) Note: For abbreviations, see text.

of hormone excess, laboratory studies are geared towards middle fossa, the optic nerves, or invading posteriorly 433 determining the nature of the tumor and assessing the behind the clivus. Intraoperative microscopy facilitates possible presence of hypopituitarism. When a pituitary visual distinction between adenomatous and normal CHAPTER 33 Neurologic Disorders of the Pituitary and Hypothalamus adenoma is suspected based on MRI, initial hormonal pituitary tissue, as well as microdissection of small evaluation usually includes (1) basal PRL; (2) insulin-like tumors that may not be visible by MRI (Fig. 33-5). growth factor (IGF) I; (3) 24-h urinary free cortisol (UFC) Transsphenoidal surgery also avoids the cranial invasion and/or overnight oral dexamethasone (1 mg) suppression and manipulation of brain tissue required by subfrontal test; (4) α subunit, FSH, and LH; and (5) thyroid function surgical approaches. Endoscopic techniques with three- tests. Additional hormonal evaluation may be indicated dimensional intraoperative localization have improved based on the results of these tests. Pending more detailed visualization and access to tumor tissue. assessment of hypopituitarism, a menstrual history, testos- terone and 8 A.M. cortisol levels, and thyroid function tests In addition to correction of hormonal hypersecretion, usually identify patients with pituitary hormone deficien- pituitary surgery is indicated for mass lesions that cies that require hormone replacement before further test- impinge on surrounding structures. Surgical decompres- ing or surgery. sion and resection are required for an expanding pituitary mass accompanied by persistent headache, progressive Histologic Evaluation visual field defects, cranial nerve palsies, internal hydro- cephalus, and, occasionally, intrapituitary hemorrhage and Immunohistochemical staining of pituitary tumor speci- apoplexy. Transsphenoidal surgery is sometimes used for mens obtained at transsphenoidal surgery confirms clin- pituitary tissue biopsy to establish a histologic diagnosis. ical and laboratory studies and provides a histologic diagnosis when hormone studies are equivocal and in cases of clinically nonfunctioning tumors. Occasionally, ultrastructural assessment by electron microscopy is required for diagnosis. Treatment: FIGURE 33-5 HYPOTHALAMIC, PITUITARY, Transsphenoidal resection of pituitary mass via the AND OTHER SELLAR MASSES endonasal approach. (Adapted from Fahlbusch R: Endocrinol Metab Clin 21:669, 1992.) OVERVIEW Successful management of sellar masses requires accurate diagnosis as well as selection of optimal therapeutic modalities. Most pituitary tumors are benign and slow-growing. Clinical features result from local mass effects and hormonal hypo- or hyper- secretion syndromes caused directly by the adenoma or as a consequence of treatment. Thus, lifelong manage- ment and follow-up are necessary for these patients. MRI technology with gadolinium enhancement for pituitary visualization, new advances in transsphenoidal surgery and in stereotactic radiotherapy (including gamma-knife radiotherapy), and novel therapeutic agents have improved pituitary tumor management. The goals of pituitary tumor treatment include normal- ization of excess pituitary secretion, amelioration of symptoms and signs of hormonal hypersecretion syn- dromes, and shrinkage or ablation of large tumor masses with relief of adjacent structure compression. Residual anterior pituitary function should be preserved and can sometimes be restored by removing the tumor mass. Ideally, adenoma recurrence should be prevented. TRANSSPHENOIDAL SURGERY Transsphe- noidal rather than transfrontal resection is the desired surgical approach for pituitary tumors, except for the rare invasive suprasellar mass surrounding the frontal or

SECTION III Diseases of the Central Nervous System434 Whenever possible, the pituitary mass lesion should be and in an attempt to prevent regrowth. Irradiation offers the only effective means for ablating significant postop- selectively excised; normal tissue should be manipulated erative residual nonfunctioning tumor tissue. In con- or resected only when critical for effective mass dissection. trast, PRL-, GH-, and sometimes ACTH-secreting tumor Nonselective hemihypophysectomy or total hypophysec- tissues are amenable to medical therapy. tomy may be indicated if no mass lesion is clearly dis- cernible, multifocal lesions are present, or the remaining Side Effects In the short term, radiation may cause nontumorous pituitary tissue is obviously necrotic. This transient nausea and weakness. Alopecia and loss of strategy, however, increases the likelihood of hypopitu- taste and smell may be more long-lasting. Failure of itarism and the need for lifelong hormonal replacement. pituitary hormone synthesis is common in patients who have undergone head and neck or pituitary-directed Preoperative mass effects, including visual field irradiation. More than 50% of patients develop loss of defects or compromised pituitary function, may be GH, ACTH, TSH, and/or gonadotropin secretion within reversed by surgery, particularly when these deficits are 10 years, usually due to hypothalamic damage. Lifelong not long-standing. For large and invasive tumors, it is follow-up with testing of anterior pituitary hormone necessary to determine the optimal balance between reserve is therefore necessary after radiation treatment. maximal tumor resection and preservation of anterior Optic nerve damage with impaired vision due to optic pituitary function, especially for preserving growth and neuritis is reported in about 2% of patients who reproductive function in younger patients. Similarly, undergo pituitary irradiation. Cranial nerve damage is tumor invasion outside of the sella is rarely amenable to uncommon now that radiation doses are ≤2 Gy (200 rad) surgical cure; the surgeon must judge the risk-benefit at any one treatment session and the maximum dose is ratio of extensive tumor resection. <50 Gy (5000 rad). The use of stereotactic radiotherapy may reduce damage to adjacent structures. Radiother- Side Effects Tumor size, the degree of invasive- apy of pituitary tumors has been associated with ness, and experience of the surgeon largely determine adverse mortality, mainly from cerebrovascular disease. the incidence of surgical complications. Operative mor- The cumulative risk of developing a secondary tumor tality is about 1%. Transient diabetes insipidus and after conventional radiation is 1.3% after 10 years and hypopituitarism occur in up to 20% of patients. Perma- 1.9% after 20 years. nent diabetes insipidus, cranial nerve damage, nasal septal perforation, or visual disturbances may be MEDICAL Medical therapy for pituitary tumors is encountered in up to 10% of patients. CSF leaks occur in highly specific and depends on tumor type. For pro- 4% of patients. Less common complications include lactinomas, dopamine agonists are the treatment of carotid artery injury, loss of vision, hypothalamic dam- choice. For acromegaly and TSH-secreting tumors, age, and meningitis. Permanent side effects are rare somatostatin analogues and, occasionally, dopamine after surgery for microadenomas. agonists are indicated. ACTH-secreting tumors and non- functioning tumors are generally not responsive to RADIATION Radiation is used either as a primary medications and require surgery and/or irradiation. therapy for pituitary or parasellar masses or, more com- monly, as an adjunct to surgery or medical therapy. FURTHER READINGS Focused megavoltage irradiation is achieved by precise MRI localization, using a high-voltage linear accelerator AIMARETTI G et al: Residual pituitary function after brain injury- and accurate isocentric rotational arcing. A major deter- induced hypopituitarism: A prospective 12-month study. J Clin minant of accurate irradiation is reproduction of the Endocrinol Metab 90:6085, 2005 patient’s head position during multiple visits and main- tenance of absolute head immobility. A total of <50 Gy CATUREGLI P et al: Autoimmune hypophysitis. Endocr Rev 26:599, (5000 rad) is given as 180-cGy (180-rad) fractions split 2005 over about 6 weeks. Stereotactic radiosurgery delivers a large single high-energy dose from a cobalt 60 source MELMED S: Acromegaly. N Engl J Med 355(24):2558, 2006 (gamma knife), linear accelerator, or cyclotron. Long-term MINNITI G et al: Risk of second brain tumor after conservative effects of gamma-knife surgery are as yet unknown. surgery and radiotherapy for pituitary adenomas: Update after an The role of radiation therapy in pituitary tumor man- additional 10 years. J Clin Endocrinol Metab 90:800, 2005 agement depends on multiple factors including the MOLITCH ME: Evaluation and treatment of adult growth hormone nature of the tumor, age of the patient, and the avail- deficiency: An Endocrine Society Clinical Practice Guideline. J ability of surgical and radiation expertise. Because of its Clin Endocrinol Metab 91:1621, 2006 relatively slow onset of action, radiation therapy is usu- PATIL CG et al: Non-surgical management of hormone-secreting ally reserved for postsurgical management. As an adju- pituitary tumors. J Clin Neurosci 16:985, 2009 vant to surgery, radiation is used to treat residual tumor TABAEE A et al: Endoscopic pituitary surgery: a systematic review and meta-analysis. J neurosurg 111:545, 2009

CHAPTER 34 MULTIPLE SCLEROSIS AND OTHER DEMYELINATING DISEASES Stephen L. Hauser ■ Douglas S. Goodin ■ Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 435 Genetic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 437 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 438 Disease Course . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 439 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 440 Diagnostic Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 442 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443 Clinical Variants of MS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449 ■ Acute Disseminated Encephalomyelitis (ADEM) . . . . . . . . . . . 449 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 450 Demyelinating disorders are characterized by inflamma- by perivenular cuffing with inflammatory mononuclear tion and selective destruction of central nervous system cells, predominantly T cells and macrophages, which also (CNS) myelin. The peripheral nervous system (PNS) is infiltrate the surrounding white matter. At sites of inflam- spared, and most patients have no evidence of an associ- mation, the blood-brain barrier (BBB) is disrupted, but ated systemic illness. unlike vasculitis, the vessel wall is preserved. In many lesions, myelin-specific autoantibodies are present, pre- MULTIPLE SCLEROSIS sumably promoting demyelination directly as well as stimulating macrophages and microglial cells (bone mar- Multiple sclerosis (MS) is characterized by a triad of row–derived CNS phagocytes) that scavenge the myelin inflammation, demyelination, and gliosis (scarring); the debris. As lesions evolve, there is prominent astrocytic course can be relapsing-remitting or progressive. Lesions of proliferation (gliosis). Surviving oligodendrocytes or MS typically occur at different times and in different CNS those that differentiate from precursor cells may partially locations (i.e., disseminated in time and space). MS affects remyelinate the surviving naked axons, producing so- ~350,000 individuals in the United States and 2.5 million called shadow plaques. In many lesions, oligodendrocyte individuals worldwide. In Western societies, MS is second precursors are present in large numbers but fail to only to trauma as a cause of neurologic disability begin- remyelinate. Ultrastructural studies of MS lesions suggest ning in early to middle adulthood. Manifestations of MS that fundamentally different underlying pathologies may vary from a benign illness to a rapidly evolving and inca- exist in different patients. Heterogeneity has been pacitating disease requiring profound lifestyle adjustments. observed in terms of (1) whether the inflammatory cell infiltrate is associated with antibody deposition and acti- PATHOGENESIS vation of complement, and (2) whether the target of the Anatomy immunopathologic process is the myelin sheath itself or the cell body of the oligodendrocyte. Although relative The lesions of MS (plaques) vary in size from 1 or 2 mm to sparing of axons is typical of MS, partial or total axonal several centimeters. Acute MS lesions are characterized destruction can also occur, especially within highly 435

SECTION III Diseases of the Central Nervous System436 inflammatory lesions. Evidence also suggests that axonal slowing occurs when the demyelinated segments support loss is a major contributor to irreversible neurologic dis- only (slow) continuous nerve impulse propagation. ability in MS (see Neurodegeneration, below). Epidemiology Physiology MS is approximately threefold more common in women Nerve conduction in myelinated axons occurs in a salta- than men. The age of onset is typically between 20 and tory manner, with the nerve impulse jumping from one 40 years (slightly later in men than in women), but the node of Ranvier to the next without depolarization of disease can present across the lifespan. Approximately the axonal membrane underlying the myelin sheath 10% of cases begin before 18 years, and extremes with between nodes (Fig. 34-1). This produces considerably onset as early as 1–2 years or as late as the eighth decade faster conduction velocities (~70 m/s) than the slow have been described. velocities (~1 m/s) produced by continuous propagation in unmyelinated nerves. Conduction block occurs when Geographical gradients have been repeatedly the nerve impulse is unable to traverse the demyelinated observed in MS, with prevalence rates increasing segment. This can happen when the resting axon mem- at higher latitudes.The highest known prevalence brane becomes hyperpolarized due to the exposure of for MS (250 per 100,000) occurs in the Orkney Islands, voltage-dependent potassium channels that are normally located north of Scotland, and similarly high rates are buried underneath the myelin sheath. A temporary con- found throughout northern Europe, the northern United duction block often follows a demyelinating event before States, and Canada. By contrast, the prevalence is low in sodium channels (originally concentrated at the nodes) Japan (6 per 100,000), in other parts of Asia, in equatorial redistribute along the naked axon (Fig. 34-1).This redis- Africa, and in the Middle East. tribution ultimately allows continuous propagation of One proposed explanation for the latitude effect on nerve action potentials through the demyelinated seg- MS is that there is a protective effect of sun exposure. ment. On occasion, conduction block is incomplete, Ultraviolet radiation from sun is the most important affecting, for example, high- but not low-frequency vol- source of vitamin D in most individuals, and low levels leys of impulses. Variable conduction block can occur of vitamin D are common at high latitudes where sun with raised body temperature or metabolic alterations exposure may be low, particularly during winter and may explain clinical fluctuations that vary from hour months. Prospective studies have confirmed that vitamin to hour or appear with fever or exercise. Conduction D deficiency is associated with an increase in MS risk. Immunoregulatory effects of vitamin D could explain Saltatory nerve impulse this possible relationship. Migration studies and identification of possible point Myelin sheath epidemics provide additional support for an environ- Axon mental effect on MS risk. Migration studies suggest that some MS-related exposure occurs in childhood and Na+ channels Node of Ranvier years before MS is clinically evident. In some studies, A migration early in life from a low- to high-risk area was found to increase MS risk, and conversely, migration Myelin sheath Continuous nerve impulse Myelin sheath from a high- to a low-risk area decreased risk. With Axon respect to possible point epidemics, the most convincing example occurred in the Faeroe Islands north of Den- Na+ channels mark after the British occupation during World War II. B The prevalence of MS appears to have steadily increased over the past century; furthermore, this increase FIGURE 34-1 has occurred primarily in women. Interestingly, recent Nerve conduction in myelinated and demyelinated axons. epidemiologic data suggests that the latitude effect on A. Saltatory nerve conduction in myelinated axons occurs MS may currently be decreasing, for unknown reasons. with the nerve impulse jumping from one node of Ranvier to MS risk also correlates with high socioeconomic status, the next. Sodium channels (shown as breaks in the solid black which may reflect improved sanitation and delayed initial line) are concentrated at the nodes where axonal depolariza- exposures to infectious agents. By analogy, some viral tion occurs. B. Following demyelination, additional sodium infections (e.g., poliomyelitis and measles viruses) produce channels are redistributed along the axon itself, thereby allow- neurologic sequelae more frequently when the age of ini- ing continuous propagation of the nerve action potential tial infection is delayed. Occasional reports seem to impli- despite the absence of myelin. cate a specific infectious agent such as human herpes virus type 6 (HHV-6) or Chlamydia pneumoniae, although, in general, the available reports have been inconsistent.

Most intriguingly, the evidence of a remote Epstein- Autoreactive T Lymphocytes 437 Barr virus (EBV) infection playing some role in MS is supported by a number of epidemiologic and laboratory Myelin basic protein (MBP) is an important T cell anti- studies. A higher risk of infectious mononucleosis (associated with relatively late EBV infection) and gen in EAE and probably also in human MS. Activated higher-antibody titers to latency-associated EBV nuclear antigen are associated with MS; conversely, individuals MBP-reactive T cells have been identified in the blood, never infected with EBV are at low MS risk. At this time, however, a causal role for EBV or for any specific in cerebrospinal fluid (CSF), and within MS lesions. infectious agent in MS remains uncertain. Moreover, DR2 may influence the autoimmune GENETIC CONSIDERATIONS response because it binds with high affinity to a frag- Evidence also supports an important genetic influ- ence on MS.Whites are inherently at higher risk for ment of MBP (spanning amino acids 89–96), stimulating MS than Africans or Asians, even when residing in a similar environment. MS also aggregates within some T cell responses to this self-protein. families, and adoption, half-sibling, twin, and spousal stud- ies indicate that familial aggregation is due to genetic, and Humoral Autoimmunity CHAPTER 34 Multiple Sclerosis and Other Demyelinating Diseases not environmental, factors (Table 34-1). Susceptibility to MS is polygenic, with each gene B cell activation and antibody responses also appear to contributing a relatively small amount to the overall be necessary for the full development of demyelinating risk. The major histocompatibility complex (MHC) on lesions to occur, both in experimental models and in chromosome 6 is the strongest MS susceptibility region human MS. Increased numbers of clonally expanded B in the genome. Fine mapping studies implicate primarily cells with properties of postgerminal center memory or the class II region of the MHC (encoding HLA mole- antibody-producing lymphocytes are present in MS cules involved in presenting peptide antigens to T cells) lesions and in CSF. Myelin-specific autoantibodies, some and specifically the DR2 (molecular designation directed against myelin oligodendrocyte glycoprotein DRB1*1501) allele. Other recently identified MS sus- (MOG), have been detected bound to vesiculated ceptibility genes encode receptors for two proinflamma- myelin debris in MS plaques. In the CSF, elevated levels tory cytokines, the IL-7 receptor alpha chain (CD127) of locally synthesized immunoglobulins and oligoclonal and the IL-2 receptor alpha chain (CD25); the MS asso- antibodies derived from expansion of clonally restricted ciated variant of the IL-7 receptor increases the amount plasma cells are also characteristic of MS.The pattern of of soluble compared to membrane bound receptor. It is oligoclonal banding is unique to each individual, and also likely that genetic heterogeneity is present in MS, attempts to identify the targets of these antibodies have meaning that there are different causative genes in dif- been largely unsuccessful, although one recent report ferent individuals. indicated that some bands recognized EBV antigens. Immunology Cytokines An autoimmune cause for MS is supported by the labo- Cytokines and chemokines appear to regulate many of ratory model of experimental allergic encephalomyelitis the cellular interactions that operate in MS. Proinflam- (EAE) and by studies of the immune system in MS matory TH1 cytokines including interleukin (IL) 2, patients. tumor necrosis factor (TNF) α, and interferon (IFN) γ play key roles in activating and maintaining autoimmune responses, and TNF-α and IFN-γ may directly injure oligodendrocytes or the myelin membrane. TABLE 34-1 Triggers RISK OF DEVELOPING MS Studies reveal that in patients with early relapsing remit- ting MS, serial MRI has demonstrated bursts of focal 1 in 3 If an identical twin has MS inflammatory disease activity occurring far more fre- 1 in 15 If a fraternal twin has MS quently than would have been predicted by the frequency 1 in 25 If a sibling has MS of relapses. Thus, early in MS, most disease activity is 1 in 50 If a parent or half-sibling has MS clinically silent. The triggers causing these bursts are 1 in 100 If a first cousin has MS unknown, although the fact that patients may experience 1 in 1000 If a spouse has MS relapses after nonspecific upper respiratory infections sug- 1 in 1000 If no one in the family has MS gests that either molecular mimicry between viruses and myelin antigens or viral superantigens activating patho- genic T cells may play a role in MS pathogenesis. Neurodegeneration Axonal damage occurs in every newly formed MS lesion, and cumulative axonal loss is considered to be the major cause of progressive and irreversible neurological disability

SECTION III Diseases of the Central Nervous System438 in MS. As many as 70% of axons are lost from the lateral The weakness is of the upper motor neuron type corticospinal tracts in patients with advanced paraparesis (Chap. 10) and is usually accompanied by other pyrami- from MS, and longitudinal MRI studies suggest there is dal signs such as spasticity, hyperreflexia and Babinski progressive axonal loss over time within established, inac- signs. Occasionally a tendon reflex may be lost (simulat- tive, lesions. Knowledge of the mechanisms responsible ing a lower motor neuron lesion) if an MS lesion dis- for axonal injury is incomplete, and it is even unclear rupts the afferent reflex fibers in the spinal cord. whether demyelination is a prerequisite for axonal injury in MS. Demyelination can result in reduced trophic Spasticity (Chap. 10) is often associated with sponta- support for axons, redistribution of ion channels, and neous and movement-induced muscle spasms. More than destabilization of action potential membrane potentials. 30% of MS patients have moderate to severe spasticity, Axons can initially adapt, but eventually distal and especially in the legs. This is often accompanied by retrograde degeneration occurs. Therefore the early pro- painful spasms, interfering with ambulation, work, or motion of remyelination and preservation of oligoden- self-care. Occasionally spasticity provides support for the drocytes remain important therapeutic goals in MS. Some body weight during ambulation, and in these cases treat- evidence suggests that axonal damage is mediated directly ment of spasticity may actually do more harm than good. by resident and invading inflammatory cells and their toxic products, in particular by microglia, macrophages, Optic neuritis (ON) presents as diminished visual acu- and CD8 T lymphocytes. Activated microglia are particu- ity, dimness, or decreased color perception (desaturation) larly likely to cause axonal injury through the release of in the central field of vision. These symptoms may be NO and oxygen radicals and via glutamate, which is toxic mild or may progress to severe visual loss. Rarely, there is to oligodendrocytes and neurons. complete loss of light perception. Visual symptoms are generally monocular but may be bilateral. Periorbital CLINICAL MANIFESTATIONS pain (aggravated by eye movement) often precedes or accompanies the visual loss. An afferent pupillary defect The onset of MS may be abrupt or insidious. Symptoms (Chap. 17) is usually present. Funduscopic examination may be severe or seem so trivial that a patient may not may be normal or reveal optic disc swelling (papillitis). seek medical attention for months or years. Indeed, at Pallor of the optic disc (optic atrophy) commonly fol- autopsy some individuals who were asymptomatic during lows ON. Uveitis is rare and should raise the possibility life will be found, unexpectedly, to have MS. In others, an of alternative diagnoses. MRI scan obtained for an unrelated reason may show evidence of asymptomatic MS. Symptoms of MS are Visual blurring in MS may result from ON or extremely varied and depend on the location and severity diplopia; if the symptom resolves when either eye is of lesions within the CNS (Table 34-2). Examination covered, the cause is diplopia. generally reveals evidence of neurologic dysfunction, often in asymptomatic locations. For example, a patient Diplopia may result from internuclear ophthalmople- may present with symptoms in one leg but signs in both. gia (INO) or from palsy of the sixth cranial nerve (rarely the third or fourth). An INO consists of impaired Weakness of the limbs may manifest as loss of strength adduction of one eye due to a lesion in the ipsilateral or dexterity, fatigue, or a disturbance of gait. Exercise- medial longitudinal fasciculus (Chap. 17). Prominent induced weakness is a characteristic symptom of MS. nystagmus is often observed in the abducting eye, along with a small skew deviation. A bilateral INO is particu- TABLE 34-2 larly suggestive of MS. Other common gaze disturbances INITIAL SYMPTOMS OF MS in MS include (1) a horizontal gaze palsy, (2) a “one and a half ” syndrome (horizontal gaze palsy plus an INO), PERCENT PERCENT and (3) acquired pendular nystagmus. SYMPTOM OF CASES SYMPTOM OF CASES Sensory symptoms are varied and include both paresthe- sias (e.g., tingling, prickling sensations, formications,“pins Sensory loss 37 Lhermitte 3 and needles,” or painful burning) and hypesthesia (e.g., Optic neuritis 36 Pain 3 reduced sensation, numbness, or a “dead” feeling). Weakness 35 Dementia 2 Unpleasant sensations (e.g., feelings that body parts are Paresthesias 24 Visual loss 2 swollen, wet, raw, or tightly wrapped) are also common. Diplopia 15 Facial palsy 1 Sensory impairment of the trunk and legs below a hori- Ataxia 11 Impotence 1 zontal line on the torso (a sensory level) indicates that Vertigo 6 Myokymia 1 the spinal cord is the origin of the sensory disturbance. It Paroxysmal attacks 4 Epilepsy 1 is often accompanied by a bandlike sensation of tightness Bladder 4 Falling 1 around the torso. Pain is a common symptom of MS, experienced by >50% of patients. Pain can occur any- Source: After WB Matthews et al, McAlpine’s Multiple Sclerosis, where on the body and can change locations over time. New York, Churchill Livingstone, 1991. Ataxia usually manifests as cerebellar tremors (Chap. 26). Ataxia may also involve the head and trunk or the voice,

producing a characteristic cerebellar dysarthria (scanning (see Acute Attacks or Initial Demyelinating Episodes, 439 CHAPTER 34 Multiple Sclerosis and Other Demyelinating Diseases speech). below). Such heat-related symptoms probably result from transient conduction block (see above). Bladder dysfunction is present in >90% of MS patients, and in a third of patients, dysfunction results in weekly Lhermitte’s symptom is an electric shocklike sensation or more frequent episodes of incontinence. During nor- (typically induced by flexion or other movements of the mal reflex voiding, relaxation of the bladder sphincter neck) that radiates down the back into the legs. Rarely, (α-adrenergic innervation) is coordinated with contrac- it radiates into the arms. It is generally self-limited but tion of the detrusor muscle in the bladder wall (mus- may persist for years. Lhermitte’s symptom can also carinic cholinergic innervation). Detrusor hyperreflexia, occur with other disorders of the cervical spinal cord due to impairment of suprasegmental inhibition, causes (e.g., cervical spondylosis). urinary frequency, urgency, nocturia, and uncontrolled bladder emptying. Detrusor sphincter dyssynergia, due to Paroxysmal symptoms are distinguished by their brief loss of synchronization between detrusor and sphincter duration (10 s to 2 min), high frequency (5–40 episodes muscles, causes difficulty in initiating and/or stopping per day), lack of any alteration of consciousness or the urinary stream, producing hesitancy, urinary reten- change in background electroencephalogram during tion, overflow incontinence, and recurrent infection. episodes, and a self-limited course (generally lasting weeks to months). They may be precipitated by hyper- Constipation occurs in >30% of patients. Fecal ventilation or movement. These syndromes may include urgency or bowel incontinence is less common (15%) but Lhermitte’s symptom; tonic contractions of a limb, face, can be socially debilitating. or trunk (tonic seizures); paroxysmal dysarthria and ataxia; paroxysmal sensory disturbances; and several other less Cognitive dysfunction can include memory loss, impaired well-characterized syndromes. Paroxysmal symptoms prob- attention, difficulties in problem solving, slowed informa- ably result from spontaneous discharges, arising at the tion processing, and problems shifting between cognitive edges of demyelinated plaques and spreading to adjacent tasks. Euphoria (elevated mood) was once thought to be white matter tracts. characteristic of MS but is actually uncommon, occurring in <20% of patients. Cognitive dysfunction sufficient to Trigeminal neuralgia, hemifacial spasm, and glossopharyngeal impair activities of daily living is rare. neuralgia (Chap. 29) can occur when the demyelinating lesion involves the root entry (or exit) zone of the fifth, Depression, experienced by approximately half of seventh, and ninth cranial nerve, respectively. Trigeminal patients, can be reactive, endogenous, or part of the illness neuralgia (tic douloureux) is a very brief lancinating facial itself and can contribute to fatigue. Suicide in MS patients pain often triggered by an afferent input from the face or is 7.5-fold more common than in age-matched controls. teeth. Most cases of trigeminal neuralgia are not MS- related; however, atypical features such as onset before age Fatigue is experienced by 90% of patients; this symp- 50 years, bilateral symptoms, objective sensory loss, or tom is the most common reason for work-related dis- nonparoxysmal pain should raise concerns that MS could ability in MS. Fatigue can be exacerbated by elevated be responsible. temperatures, by depression, by expending exceptional effort to accomplish basic activities of daily living, or by Facial myokymia consists of either persistent rapid sleep disturbances (e.g., from frequent nocturnal awak- flickering contractions of the facial musculature (espe- enings to urinate). cially the lower portion of the orbicularis oculus) or a contraction that slowly spreads across the face. It results Sexual dysfunction may manifest as decreased libido, from lesions of the corticobulbar tracts or brainstem impaired genital sensation, impotence in men, and dimin- course of the facial nerve. ished vaginal lubrication or adductor spasms in women. DISEASE COURSE Facial weakness due to a lesion in the pons may resem- ble idiopathic Bell’s palsy (Chap. 29). Unlike Bell’s palsy, Four clinical types of MS have been described (Fig. 34-2): facial weakness in MS is usually not associated with ipsi- lateral loss of taste sensation or retroauricular pain. 1. Relapsing/remitting MS (RRMS) accounts for 85% of MS cases at onset and is characterized by discrete Vertigo may appear suddenly from a brainstem lesion, attacks that generally evolve over days to weeks superficially resembling acute labyrinthitis (Chap. 9). (rarely over hours).There is often complete recovery Hearing loss may also occur in MS but is uncommon. over the ensuing weeks to months (Fig. 34-2A). However, when ambulation is severely impaired dur- Ancillary Symptoms ing an attack, approximately half will fail to improve. Between attacks, patients are neurologically stable. Heat sensitivity refers to neurologic symptoms produced by an elevation of the body’s core temperature. For 2. Secondary progressive MS (SPMS) always begins as example, unilateral visual blurring may occur during a RRMS (Fig. 34-2B). At some point, however, the hot shower or with physical exercise (Uhthoff’s symptom). It is also common for MS symptoms to worsen tran- siently, sometimes dramatically, during febrile illnesses

440 RRMS PPMS majority of RRMS ultimately evolves into SPMS. SPMS appears to represent a late stage of the same Disability Disability underlying illness as RRMS. 3. Primary progressive MS (PPMS) accounts for ~15% of Time Time cases. These patients do not experience attacks but SPMS PRMS only a steady functional decline from disease onset (Fig. 34-2C ). Compared to RRMS, the sex distrib- Disability Disability ution is more even, the disease begins later in life (mean age ~40 years), and disability develops faster Time Time (at least relative to the onset of the first clinical symptom). Whether PPMS is an uncommon form SECTION III Diseases of the Central Nervous System FIGURE 34-2 of the same underlying illness as RRMS or whether Clinical course of multiple sclerosis (MS). A. Relapsing/ these are distinct illnesses is uncertain. remitting MS. B. Secondary progressive MS. C. Primary pro- 4. Progressive/relapsing MS (PRMS) overlaps PPMS and gressive MS. D. Progressive/relapsing MS. SPMS and accounts for ~5% of MS patients. Like patients with PPMS, these patients experience a clinical course changes so that the patient experiences steady deterioration in their condition from disease a steady deterioration in function unassociated with onset. However, like SPMS patients, they experience acute attacks (which may continue or cease during occasional attacks superimposed upon their progres- the progressive phase). SPMS produces a greater sive course (Fig. 34-2D). amount of fixed neurologic disability than RRMS. For a patient with RRMS, the risk of developing DIAGNOSIS SPMS is ~2.5% each year, meaning that the great There is no definitive diagnostic test for MS. Diagnostic criteria for clinically definite MS require documentation of two or more episodes of symptoms and two or more signs that reflect pathology in anatomically noncontigu- ous white matter tracts of the CNS (Table 34-3). Symp- toms must last for >24 h and occur as distinct episodes that are separated by a month or more. At least one of the two required signs must be present on neurologic TABLE 34-3 DIAGNOSTIC CRITERIA FOR MS 1. Examination must reveal objective abnormalities of the CNS. 2. Involvement must reflect predominantly disease of white matter long tracts, usually including (a) pyramidal pathways, (b) cerebellar pathways, (c) medial longitudinal fasciculus, (d) optic nerve, and (e) posterior columns. 3. Examination or history must implicate involvement of two or more areas of the CNS. a. MRI may be used to document a second lesion when only one site of abnormality has been demonstrable on examination. A confirmatory MRI must have either four lesions involving the white matter or three lesions if one is periventricular in location. Acceptable lesions must be >3 mm in diameter. For patients older than 50 years, two of the following criteria must also be met: (a) lesion size >5 mm, (b) lesions adja- cent to the bodies of the lateral ventricles, and (c) lesion(s) present in the posterior fossa. b. Evoked response testing may be used to document a second lesion not evident on clinical examination. 4. The clinical pattern must consist of (a) two or more separate episodes of worsening involving different sites of the CNS, each lasting at least 24 h and occurring at least 1 month apart, or (b) gradual or stepwise progres- sion over at least 6 months if accompanied by increased IgG synthesis or two or more oligoclonal bands. MRI may be used to document dissemination in time if a new T2 lesion or a Gd-enhancing lesion is seen 3 or more months after a clinically isolated syndrome. 5. The patient’s neurologic condition could not better be attributed to another disease. DIAGNOSTIC CATEGORIES 1. Definite MS: All five criteria fulfilled. 2. Probable MS: All five criteria fulfilled except (a) only one objective abnormality despite two symptomatic episodes or (b) only one symptomatic episode despite two or more objective abnormalities. 3. At risk for MS: Criteria 1, 2, 3, and 5 fulfilled; patient has only one symptomatic episode and one objective abnormality. Note: CNS, central nervous system; MRI, magnetic resonance imaging; Gd, gadolinium.

examination.The second may be documented by abnor- found in >95% of patients. An increase in vascular per- 441 mal paraclinical tests such as MRI or evoked potentials meability from a breakdown of the BBB is detected by (EPs). Similarly, in the most recent diagnostic scheme, the leakage of intravenous gadolinium (Gd) into the second clinical event (in time) may be supported solely parenchyma. Such leakage occurs early in the develop- by paraclinical information, usually the development of ment of an MS lesion and serves as a useful marker of new focal white matter lesions on MRI. In patients who inflammation. Gd enhancement persists for approxi- experience gradual progression of disability for Ն6 mately 1 month, and the residual MS plaque remains months without superimposed relapses, documentation visible indefinitely as a focal area of hyperintensity of intrathecal IgG may be used to support the diagnosis. (a lesion) on spin-echo (T2-weighted) and proton-density images. Lesions are frequently oriented perpendicular to DIAGNOSTIC TESTS the ventricular surface, corresponding to the pathologic pattern of perivenous demyelination (Dawson’s fingers). Magnetic Resonance Imaging Lesions are multifocal within the brain, brainstem, and spinal cord. Lesions larger than 6 mm located in the cor- MRI has revolutionized the diagnosis and management pus callosum, periventricular white matter, brainstem, of MS (Fig. 34-3); characteristic abnormalities are CHAPTER 34 Multiple Sclerosis and Other Demyelinating Diseases FIGURE 34-3 corpus callosum are frequent in MS and rare in vascular dis- A. Axial first-echo image from T2-weighted sequence demon- ease. C. Sagittal T2-weighted fast spin echo image of the strates multiple bright signal abnormalities in white matter, thoracic spine demonstrates a fusiform high-signal-intensity typical for MS. B. Sagittal T2-weighted FLAIR (fluid attenu- lesion in the mid thoracic spinal cord. D. Sagittal T1-weighted ated inversion recovery) image in which the high signal of image obtained after the intravenous administration of CSF has been suppressed. CSF appears dark, while areas of gadolinium DTPA reveals focal areas of blood-brain barrier brain edema or demyelination appear high in signal as shown disruption, identified as high-signal-intensity regions (arrows). here in the corpus callosum (arrows). Lesions in the anterior

SECTION III Diseases of the Central Nervous System442 cerebellum, or spinal cord are particularly helpful diag- or more OCBs are found in 75–90% of patients with nostically. Different criteria for the use of MRI in the MS. OCBs may be absent at the onset of MS, and in diagnosis of MS have been proposed (Table 34-3). individual patients the number of bands may increase The total volume of T2-weighted signal abnormality with time. It is important that paired serum samples be (the “burden of disease”) shows a significant (albeit weak) studied to exclude a peripheral (i.e., non-CNS) origin correlation with clinical disability, as do measures of brain of any OCBs detected in the CSF. atrophy. Approximately one-third of T2-weighted lesions appear as hypointense lesions (black holes) on T1-weighted A mild CSF pleocytosis (>5 cells/μL) is present in imaging. Black holes may be a marker of irreversible ~25% of cases, usually in young patients with RRMS. A demyelination and axonal loss, although even this measure pleocytosis of >75 cells/μL, the presence of polymor- depends on the timing of the image acquisition (e.g., most phonuclear leukocytes, or a protein concentration of acute Gd-enhancing T2 lesions are T1 dark). >1.0 g/L (>100 mg/dL) in CSF should raise concern Newer MRI measures such as magnetization transfer that the patient may not have MS. ratio (MTR) imaging and proton magnetic resonance spectroscopic imaging (MRSI) may ultimately serve as DIFFERENTIAL DIAGNOSIS surrogate markers of clinical disability. For example, MRSI can quantitate molecules such as N-acetyl aspar- No single clinical sign or test is diagnostic of MS. The tate, which is a marker of axonal integrity, and MTR diagnosis is readily made in a young adult with relapsing may be able to distinguish demyelination from edema. and remitting symptoms involving different areas of CNS white matter. The possibility of an alternative diagnosis Evoked Potentials should always be considered (Table 34-4), particularly when (1) symptoms are localized exclusively to the pos- EP testing assesses function in afferent (visual, auditory, terior fossa, craniocervical junction, or spinal cord; (2) and somatosensory) or efferent (motor) CNS pathways. the patient is <15 or >60 years of age; (3) the clinical EPs use computer averaging to measure CNS electric course is progressive from onset; (4) the patient has never potentials evoked by repetitive stimulation of selected experienced visual, sensory, or bladder symptoms; or (5) peripheral nerves or of the brain.These tests provide the laboratory findings (e.g., MRI, CSF, or EPs) are atypical. most information when the pathways studied are clini- Similarly, uncommon or rare symptoms in MS (e.g., cally uninvolved. For example, in a patient with a remit- aphasia, parkinsonism, chorea, isolated dementia, severe ting and relapsing spinal cord syndrome with sensory deficits in the legs, an abnormal somatosensory EP fol- TABLE 34-4 lowing posterior tibial nerve stimulation provides little new information. By contrast, an abnormal visual EP in DISORDERS THAT CAN MIMIC MS this circumstance would permit a diagnosis of clinically definite MS (Table 34-3). Abnormalities on one or Acute disseminated encephalomyelitis (ADEM) more EP modalities occur in 80–90% of MS patients. Antiphospholipid antibody syndrome EP abnormalities are not specific to MS, although a Behçet’s disease marked delay in the latency of a specific EP component Cerebral autosomal dominant arteriopathy, subcortical (as opposed to a reduced amplitude or distorted wave- infarcts, and leukoencephalopathy (CADASIL) shape) is suggestive of demyelination. Congenital leukodystrophies (e.g., adrenoleukodystrophy, metachromatic leukodystrophy) Cerebrospinal Fluid Human immunodeficiency virus (HIV) infection Ischemic optic neuropathy (arteritic and nonarteritic) CSF abnormalities found in MS include a mononuclear Lyme disease cell pleocytosis and an increased level of intrathecally Mitochondrial encephalopathy with lactic acidosis and synthesized IgG.The total CSF protein is usually normal stroke (MELAS) or slightly elevated.Various formulas distinguish intrathe- Neoplasms (e.g., lymphoma, glioma, meningioma) cally synthesized IgG from IgG that may have entered Sarcoid the CNS passively from the serum. One formula, the Sjögren’s syndrome CSF IgG index, expresses the ratio of IgG to albumin in Stroke and ischemic cerebrovascular disease the CSF divided by the same ratio in the serum. The Syphilis IgG synthesis rate uses serum and CSF IgG and albumin Systemic lupus erythematosus and related collagen vas- measurements to calculate the rate of CNS IgG synthe- cular disorders sis. The measurement of oligoclonal banding (OCB) in Tropical spastic paraparesis (HTLV I/II infection) the CSF also assesses intrathecal production of IgG. Vascular malformations (especially spinal dural AV fistulas) OCBs are detected by agarose gel electrophoresis. Two Vasculitis (primary CNS or other) Vitamin B12 deficiency Note: HTLV, human T cell lymphotropic virus; AV, arteriovenous; CNS, central nervous system.

muscular atrophy, peripheral neuropathy, episodic loss of Effect of Pregnancy 443 consciousness, fever, headache, seizures, or coma) should increase concern about an alternative diagnosis. Diagno- Pregnant MS patients experience fewer attacks than sis is also difficult in patients with a rapid or explosive expected during gestation (especially in the last trimester), (strokelike) onset or with mild symptoms and a normal but more attacks than expected in the first 3 months post- neurologic examination. Rarely, intense inflammation partum.When considering the pregnancy year as a whole and swelling may produce a mass lesion that mimics a (i.e., 9 months pregnancy plus 3 months postpartum), the primary or metastatic tumor. The specific tests required overall disease course is unaffected. Decisions about child- to exclude alternative diagnoses will vary with each clin- bearing should thus be made based on (1) the mother’s ical situation; however, an erythrocyte sedimentation rate, physical state, (2) her ability to care for the child, and serum B12 level, ANA, and treponemal antibody should (3) the availability of social support. Disease-modifying probably be obtained in all patients with suspected MS. therapy is generally discontinued during pregnancy, although the actual risk from the interferons and glati- PROGNOSIS ramer acetate (see below) appears to be low. Most patients with MS ultimately experience progres- Treatment: CHAPTER 34 Multiple Sclerosis and Other Demyelinating Diseases sive neurologic disability. Fifteen years after onset, only MULTIPLE SCLEROSIS 20% of patients have no functional limitation; between one-third and one-half will have progressed to SPMS Therapy for MS can be divided into several categories: and will require assistance with ambulation. Twenty-five (1) treatment of acute attacks as they occur, (2) treat- years after onset, ~80% of MS patients will have reached ment with disease-modifying agents that reduce the this level of disability. In 1998, it was estimated that the biological activity of MS, and (3) symptomatic therapy. total annual economic burden of MS in the United Treatments that promote remyelination or neural States exceeded $6.8 billion. repair do not currently exist but would be highly desirable. However, even if the prognosis for disability is grave for the average patient, the prognosis in an individual is The Kurtzke Expanded Disability Status Score (EDSS) difficult to establish. Certain clinical features suggest a is a useful measure of neurologic impairment in MS more favorable prognosis, including ON or sensory (Table 34-5). Most patients with EDSS scores <3.5 have symptoms at onset; fewer than two relapses in the first RRMS, walk normally, and are generally not disabled; by year of illness; and minimal impairment after 5 years. By contrast, patients with EDSS scores >5.5 have progres- contrast, patients with truncal ataxia, action tremor, sive MS (SPMS or PPMS), are gait-impaired and, typically, pyramidal symptoms, or a progressive disease course are are occupationally disabled. more likely to become disabled. ACUTE ATTACKS OR INITIAL DEMYELINAT- Importantly, some MS patients have a benign variant ING EPISODES When patients experience acute of MS and never develop neurologic disability.The like- deterioration, it is important to consider whether this lihood of having benign MS is thought to be <20%. change reflects new disease activity or a “pseudoexacer- Patients with benign MS 15 years after onset who have bation”resulting from an increase in ambient temperature, entirely normal neurologic examinations are likely to fever, or an infection. In such instances, glucocorticoid maintain their benign course. treatment is inappropriate. Glucocorticoids are used to manage either first attacks or acute exacerbations. They In patients with their first demyelinating event (i.e., a provide short-term clinical benefit by reducing the clinically isolated syndrome), the brain MRI provides severity and shortening the duration of attacks. Whether prognostic information. With three or more typical T2- treatment provides any long-term benefit on the course weighted lesions, the risk of developing MS after 10 of the illness is less clear. Therefore, mild attacks are years is 70–80%. Conversely, with a normal brain MRI, often not treated. Physical and occupational therapy can the likelihood of developing MS is <20%. Similarly, two help with mobility and manual dexterity. or more Gd-enhancing lesions at baseline is highly pre- dictive of future MS, as is the appearance of either new Glucocorticoid treatment is usually administered as T2-weighted lesions or new Gd enhancement ≥3 months intravenous methylprednisolone, 500–1000 mg/d for after the initial episode. 3–5 days, either without a taper or followed by a course of oral prednisone beginning at a dose of 60–80 mg/d Mortality as a direct consequence of MS is uncom- and gradually tapered over 2 weeks. Outpatient treat- mon, although it has been estimated that the 25-year ment is usually possible. If intravenous therapy is survival is only 85% of expected. Death can occur dur- unavailable or inconvenient, oral glucocorticoids can be ing an acute MS attack, although this is distinctly rare. substituted. More commonly, death occurs as a complication of MS (e.g., pneumonia in a debilitated individual). Death also results from suicide.

444 TABLE 34-5 SCORING SYSTEMS FOR MS KURTZKE EXPANDED DISABILITY STATUS SCORE (EDSS) SECTION III Diseases of the Central Nervous System 0.0 = Normal neurologic exam [all grade 0 in functional 6.0 = Unilateral assistance required to walk about 100 m with status (FS)] or without resting 1.0 = No disability, minimal signs in one FS (i.e., grade 1) 6.5 = Constant bilateral assistance required to walk about 20 m 1.5 = No disability, minimal signs in more than one FS (more without resting than one grade 1) 7.0 = Unable to walk beyond about 5 m even with aid; 2.0 = Minimal disability in one FS (one FS grade 2, others essentially restricted to wheelchair; wheels self and transfers alone 0 or 1) 2.5 = Minimal disability in two FS (two FS grade 2, others 7.5 = Unable to take more than a few steps; restricted to wheelchair; may need aid to transfer 0 or 1) 3.0 = Moderate disability in one FS (one FS grade 3, others 8.0 = Essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most of day; retains many 0 or 1) or mild disability in three or four FS (three/four FS self-care functions; generally has grade 2, others 0 or 1) though fully ambulatory effective use of arms 3.5 = Fully ambulatory but with moderate disability in one FS (one grade 3) and one or two FS grade 2; or two FS grade 8.5 = Essentially restricted to bed much of the day; has some 3; or five FS grade 2 (others 0 or 1) effective use of arm(s); retains some self-care functions 4.0 = Ambulatory without aid or rest for Ն 500 m 4.5 = Ambulatory without aid or rest for Ն 300 m 9.0 = Helpless bed patient; can communicate and eat 5.0 = Ambulatory without aid or rest for Ն 200 m 9.5 = Totally helpless bed patient; unable to communicate 5.5 = Ambulatory without aid or rest for Ն 100 m or eat 10.0 = Death due to MS FUNCTIONAL STATUS (FS) SCORE A. Pyramidal functions 5 = Loss (essentially) of sensation in 1 or 2 limbs or moderate 0 = Normal decrease in touch or pain and/or loss of proprioception 1 = Abnormal signs without disability for most of the body below the head 2 = Minimal disability 3 = Mild or moderate paraparesis or hemiparesis, or severe 6 = Sensation essentially lost below the head monoparesis E. Bowel and bladder functions 4 = Marked paraparesis or hemiparesis, moderate quadriparesis, or monoplegia 0 = Normal 5 = Paraplegia, hemiplegia, or marked quadriparesis 1 = Mild urinary hesitancy, urgency, or retention 6 = Quadriplegia 2 = Moderate hesitancy, urgency, retention of bowel or B. Cerebellar functions bladder, or rare urinary incontinence 0 = Normal 3 = Frequent urinary incontinence 1 = Abnormal signs without disability 4 = In need of almost constant catheterization 2 = Mild ataxia 5 = Loss of bladder function 3 = Moderate truncal or limb ataxia 6 = Loss of bowel and bladder function 4 = Severe ataxia all limbs F. Visual (or optic) functions 5 = Unable to perform coordinated movements due to ataxia 0 = Normal 1 = Scotoma with visual acuity (corrected) better than 20/30 C. Brainstem functions 2 = Worse eye with scotoma with maximal visual acuity 0 = Normal 1 = Signs only (corrected) of 20/30 to 20/59 2 = Moderate nystagmus or other mild disability 3 = Worse eye with large scotoma, or moderate decrease in 3 = Severe nystagmus, marked extraocular weakness, or moderate disability of other cranial nerves fields, but with maximal visual acuity (corrected) of 20/60 4 = Marked dysarthria or other marked disability to 20/99 5 = Inability to swallow or speak 4 = Worse eye with marked decrease of fields and maximal acuity (corrected) of 20/100 to 20/200; grade 3 D. Sensory functions plus maximal acuity of better eye of 20/60 0 = Normal or less 1 = Vibration or figure-writing decrease only, in 1 or 2 limbs 5 = Worse eye with maximal visual acuity (corrected) less 2 = Mild decrease in touch or pain or position sense, and/or than 20/200; grade 4 plus maximal acuity of better eye moderate decrease in vibration in 1 or 2 limbs, or of 20/60 or less vibratory decrease alone in 3 or 4 limbs 6 = Grade 5 plus maximal visual acuity of better eye of 20/60 3 = Moderate decrease in touch or pain or position sense, or less and/or essentially lost vibration in 1 or 2 limbs, or mild G. Cerebral (or mental) functions decrease in touch or pain, and/or moderate decrease in 0 = Normal all proprioceptive tests in 3 or 4 limbs 1 = Mood alteration only (does not affect EDSS score) 4 = Marked decrease in touch or pain or loss of proprioception, 2 = Mild decrease in mentation alone or combined, in 1 or 2 limbs or moderate decrease 3 = Moderate decrease in mentation in touch or pain and/or severe proprioceptive decrease in 4 = Marked decrease in mentation more than 2 limbs 5 = Chronic brain syndrome—severe or incompetent Source: After JF Kurtzke: Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 33:1444, 1983.

TABLE 34-6 445 TWO-YEAR OUTCOMES FOR FDA-APPROVED THERAPIES FOR MULTIPLE SCLEROSISa OUTCOMESb MRI OUTCOMESc DOSE, ROUTE, ATTACK CHANGE IN NEW T2 TOTAL BURDEN AND SCHEDULE RATE, MEAN DISEASE SEVERITY LESIONSd OF DISEASE IFN-β-1b, 250 μg SC qod −34%e −29% (ns) −83%f −17%e IFN-β-1a, 30 μg IM qw −18%g −37%g −36%f −4% (ns) IFN-β-1a, 44 μg SC tiw −32%e −30%g −78%e −15%e GA, 20 mg SC qd −29%f −12% (ns) −38%f −8%f MTX, 12 mg/m2 IV q3mo −66%e −75%g −79%g nr NTZ, 300 mg IV qmo −68%e −42%e −83%e −18%e aPercentage reductions (or increases) have been calculated by dividing the reported rates in the treated group by CHAPTER 34 Multiple Sclerosis and Other Demyelinating Diseases the comparable rates in the placebo group, except for MRI disease burden, which was calculated as the differ- ence in the median % change between the treated and placebo groups. bSeverity = 1 point EDSS progression, sustained for 3 months (in the IFN-β-1a 30 μg qw trial, this change was sustained for 6 months; in the IFN-β-1b trial, this was over 3 years). cDifferent studies measured these MRI measures differently, making comparisons difficult (numbers for new T2 represent the best case scenario for each trial). dNew lesions seen on T2-weighted MRI. ep = .001. fp = .01. gp = .05. Note: IFN-β, interferon β; GA, glatiramer acetate; MTX, mitoxantrone; NTZ, natalizumab; IM, intramuscular; SC, subcutaneous; IV, intravenous; qod, every other day; qw, once per week; tiw, three times per week; qd, daily; q3mo, once every 3 months; qmo, once per month; ns, not significant; nr, not reported. Side effects of short-term glucocorticoid therapy lesions compared to placebo recipients (Table 34-6). include fluid retention, potassium loss, weight gain, Mitoxantrone (Novantrone), an immune suppressant, gastric disturbances, acne, and emotional lability. has also been approved in the United States, although it Concurrent use of a low-salt, potassium-rich diet and is generally reserved for patients with progressive dis- avoidance of potassium-wasting diuretics is advis- ability who have failed other treatments because of its able. Lithium carbonate (300 mg orally bid) may help potential toxicity. to manage emotional lability and insomnia associ- ated with glucocorticoid therapy. Patients with a his- Interferon β, Glatiramer Acetate, and Natal- tory of peptic ulcer disease may require cimetidine izumab IFN-β is a class I interferon originally identi- (400 mg bid) or ranitidine (150 mg bid). fied by its antiviral properties. Efficacy in MS probably results from immunomodulatory properties including Plasma exchange (seven exchanges: 40–60 mL/kg per (1) downregulating expression of MHC molecules on exchange, every other day for 14 days) may benefit antigen-presenting cells, (2) inhibiting proinflammatory patients with fulminant attacks of demyelination (not and increasing regulatory cytokine levels, (3) inhibition only MS) that are unresponsive to glucocorticoids. How- of T cell proliferation, and (4) limiting the trafficking of ever, the cost is high, and the evidence of efficacy is only inflammatory cells in the CNS. Glatiramer acetate is a preliminary. synthetic, random polypeptide composed of four amino acids (l-glutamic acid, l-lysine, l-alanine, and l-tyrosine). DISEASE-MODIFYING THERAPIES FOR Its mechanism of action may include (1) induction of RELAPSING FORMS OF MS (RRMS, SPMS antigen-specific suppressor T cells; (2) binding to MHC WITH EXACERBATIONS) Five such agents are molecules, thereby displacing bound MBP; or (3) altering approved in the United States: (1) IFN-β-1a (Avonex), (2) the balance between proinflammatory and regulatory IFN-β-1a (Rebif ), (3) IFN-β-1b (Betaseron), (4) glatiramer cytokines. Natalizumab is a humanized monoclonal anti- acetate (Copaxone), and (5) natalizumab (Tysabri). Each body directed against the α4 subunit of α4β1 integrin, a of these treatments is also used in SPMS patients who cellular adhesion molecule expressed on the surface of continue to experience attacks, because SPMS can be lymphocytes. It prevents lymphocytes from binding to difficult to distinguish from RRMS, and because clinical endothelial cells, thereby preventing lymphocytes from trials suggest that such patients also derive therapeutic penetrating the BBB and entering the CNS. benefit. In phase III clinical trials, recipients of IFN-β-1b, IFN-β-1a, glatiramer acetate, and natalizumab experi- IFN-β reduces the attack rate and improves dis- enced fewer clinical exacerbations and fewer new MRI ease severity measures such as EDSS progression

SECTION III Diseases of the Central Nervous System446 and MRI-documented disease burden. IFN-β should be The long-term efficacy of these treatments remains uncertain, although several recent studies suggest that considered in patients with either RRMS or SPMS with these agents can improve the long-term outcome of MS superimposed relapses. In patients with SPMS but with- when administered in the RRMS stage of the illness. Bene- out relapses, efficacy has not been established. Higher ficial effects seen in early MS include a reduction in the IFN-β doses appear to have slightly greater efficacy but relapse rate and a reduction in CNS inflammation as mea- are also more likely to induce neutralizing antibodies, sured by MRI. Unfortunately, already established progres- which may reduce the clinical benefit (see below). sive symptoms do not respond to treatment with these disease-modifying therapies. Because progressive symp- Glatiramer acetate also reduces the attack rate toms are likely to result from delayed effects of earlier (whether measured clinically or by MRI) in RRMS. Glati- focal demyelinating episodes, many experts now believe ramer acetate may also benefit disease severity mea- that very early treatment with a disease-modifying drug is sures, although this is less well-established than for the appropriate for most MS patients. It is reasonable to delay relapse rate. Therefore, glatiramer acetate should be initiating treatment in patients with (1) normal neurologic considered in RRMS patients. Its usefulness in progres- exams, (2) a single attack or a low attack frequency, and (3) sive disease is entirely unknown. a low burden of disease as assessed by brain MRI. Untreated patients should be followed closely with peri- Natalizumab dramatically reduces the attack rate and odic brain MRI scans; the need for therapy is reassessed if significantly improves all measures of disease severity in scans reveal evidence of ongoing, subclinical disease. MS. However, because of the development of progres- sive multifocal leukoencephalopathy (PML) in nearly Most treated patients with relapsing forms of MS two dozen patients treated with natalizumab, some in receive IFN-β or glatiramer acetate as first-line therapy. combination with other immunosuppressives, natal- Regardless of which agent is chosen first, treatment izumab is currently recommended only as monotherapy should probably be changed in patents who continue to for patients who have failed treatment with beta inter- have frequent attacks or progressive disability (Fig. 34-4). feron or glatiramer acetate, or who have particularly The value of combination therapy is unknown. aggressive presentations. Its usefulness in the treatment of progressive disease has not been studied. Relapsing-Remitting MS Progressive MS Acute neurologic change Stable Secondary Primary progressive MS progressive MS Exacerbation Pseudoexacerbation 1. Low attack frequency or Symptomatic therapy single attack Without relapses With relapses 2. Normal neurologic exam 3. Low disease burden by MRI Functional No functional 1. IFN-β1a, or No proven treatment impairment impairment 2. IFN-β1b No Yes Consider Intolerant or Methylprednisolone/ Symptomatic poor response prednisone therapy Prophylaxis Repeat clinical exam 1. IFN-β1a, or and MRI in 6 months 2. IFN-β1b, or 3. Glatiramer acetate Identify and treat any Clinical or No underlying infection or trauma MRI change change Consider Rx with one of the following: 1. Mitoxantrone 4. Pulse cyclophosphamide Good Intolerant or 2. Azathioprine 5. IVIg response poor response 3. Methotrexate 6. Pulse methylprednisolone Continue Successive trials Continue periodic B therapy of alternatives clinical/ MRI assessments Intolerant or poor response Natalizumab A FIGURE 34-4 Therapeutic decision-making for MS.

IFN-β-1a (Avonex), 30 μg, is administered by intra- trial in Europe, in addition to an even smaller phase II 447 muscular injection once every week. IFN-β-1a (Rebif ), study completed earlier. Mitoxantrone received (from 44 μg, is administered by subcutaneous injection three the FDA) the broadest indication of any current treat- CHAPTER 34 Multiple Sclerosis and Other Demyelinating Diseases times per week. IFN-β-1b (Betaseron), 250 μg, is adminis- ment for MS. Thus, mitoxantrone is indicated for use in tered by subcutaneous injection every other day. Glati- SPMS, in PRMS, and in patients with worsening RRMS ramer acetate, 20 mg, is administered by subcutaneous (defined as patients whose neurologic status remains injection every day. Natalizumab, 300 μg, is adminis- significantly abnormal between MS attacks). Despite this tered by IV infusion each month. Common side effects broad indication, however, the data supporting its effi- of IFN-β therapy include flulike symptoms (e.g., fevers, cacy are weaker than for other approved therapies. chills, and myalgias) and mild abnormalities on routine laboratory evaluation (e.g., elevated liver function tests Mitoxantrone can be cardiotoxic (e.g., cardiomyopa- or lymphopenia). Rarely, more severe hepatotoxicity thy, reduced left ventricular ejection fraction, and irre- may occur. Subcutaneous IFN-β also causes reactions at versible congestive heart failure). As a result, a cumula- the injection site (e.g., pain, redness, induration, or, tive dose >140 mg/m2 is not recommended. At currently rarely, skin necrosis). Side effects can usually be man- approved doses (12 mg/m2 every 3 months), the maxi- aged with concomitant nonsteroidal anti-inflammatory mum duration of therapy can be only 2–3 years. Further- medications and with the use of an autoinjector. more, >40% of women will experience amenorrhea, Depression, increased spasticity, and cognitive changes which may be permanent. Finally, there is risk of acute have been reported, although these symptoms can also leukemia, and this complication has already been be due to the underlying disease. In any event, side reported in several mitoxantrone-treated MS patients. effects to IFN-β therapy usually subside with time. Given these risks, mitoxantrone should not be used Approximately 2–10% of IFN-β-1a (Avonex) recipi- as a first-line agent in either RRMS or relapsing SPMS. It ents, 15–25% of IFN-β-1a (Rebif ) recipients, and 30–40% is reasonable to consider mitoxantrone in selected of IFN-β-1b (Betaseron) recipients develop neutralizing patients with a progressive course who have failed antibodies to IFN-β, which may disappear over time. other approved therapies. Some evidence suggests that neutralizing antibodies reduce efficacy, especially for MRI outcomes. The current DISEASE-MODIFYING THERAPIES FOR SPMS clinical data, however, are quite conflicted. Moreover, High-dose IFN-β probably has a beneficial effect in there are few situations where measurement of anti- patients with SPMS who are still experiencing acute bodies is necessary. Thus, for a patient doing well on relapses. IFN-β is probably ineffective in patients with therapy, the presence of antibodies should not affect SPMS who are not having acute attacks. Glatiramer treatment. Conversely, for a patient doing poorly on acetate and natalizumab have not been studied in this therapy, alternative treatment should be considered, patient population. even if there are no detectable antibodies. Although mitoxantrone has been approved for Injection-site reactions also occur with glatiramer patients with progressive MS, this is not the population acetate but are less severe than with IFN-β-1b. Approxi- studied in the pivotal trial. Therefore no evidence-based mately 15% of patients experience one or more episodes recommendation can be made with regard to its use in of flushing, chest tightness, dyspnea, palpitations, and this setting. anxiety after injection. This systemic reaction is unpre- dictable, brief (duration <1 h), and tends not to recur. PPMS No currently available therapies have shown any promise for treating PPMS at this time. A phase III Treatment with natalizumab is, in general, well toler- clinical trial of glatiramer acetate in PPMS was recently ated. A small percentage (<10%) of patients experience stopped because of lack of efficacy. Trials of mitox- hypersensitivity reactions (including anaphylaxis) and antrone and rituximab in PPMS are currently underway. ~6% develop neutralizing antibodies to the molecule. As noted above, of greater potential concern is the risk OFF-LABEL TREATMENT OPTIONS FOR RRMS of PML. AND SPMS Azathioprine (2–3 mg/kg per day) Mitoxantrone Hydrochloride Mitoxantrone has been used primarily in SPMS. Meta-analysis of pub- (Novantrone), an anthracenedione, exerts its antineo- lished trials suggests that azathioprine is marginally plastic action by (1) intercalating into DNA and produc- effective at lowering relapse rates, although a benefit on ing both strand breaks and interstrand cross-links, (2) disability progression has not been demonstrated. interfering with RNA synthesis, and (3) inhibiting topoi- somerase II (involved in DNA repair). The U.S. Food and Methotrexate (7.5–20 mg/wk) was shown in one Drug Administration (FDA) approved mitoxantrone on study to slow the progression of upper-extremity dys- the basis of a single (relatively small) phase III clinical function in SPMS. Because of the possibility of develop- ing irreversible liver damage, some experts recommend a blind liver biopsy after 2 years of therapy.

SECTION III Diseases of the Central Nervous System448 Cyclophosphamide (700 mg/m2, every other month) lioresal pump (delivering medication directly into the CSF) can provide substantial relief. may be helpful for treatment-refractory patients who are (1) otherwise in good health, (2) ambulatory, and Pain is treated with anticonvulsants (carbamazepine, (3) <40 years of age. Because cyclophosphamide can be 100–1000 mg/d; phenytoin, 300–600 mg/d; gabapentin, used for periods in excess of 3 years, it may be prefer- 300–3600 mg/d; or pregabalin, 50–300 mg/d ), antide- able to mitoxantrone in these circumstances. pressants (amitriptyline, 25–150 mg/d; nortriptyline, 25–150 mg/d; desipramine, 100–300 mg/d; or ven- Intravenous immunoglobulin (IVIg), administered in lafaxine, 75–225 mg/d), or antiarrhythmics (mexiletine, monthly pulses (up to 1 g/kg) for up to 2 years, appears 300–900 mg/d). If these approaches fail, patients to reduce annual exacerbation rates. However, its use is should be referred to a comprehensive pain manage- limited because of its high cost, questions about opti- ment program. mal dose, and uncertainty about its effect on long-term disability outcome. Bladder dysfunction management is best guided by urodynamic testing. Evening fluid restriction or frequent Methylprednisolone administered in one study as voluntary voiding may help detrusor hyperreflexia. If these monthly high-dose intravenous pulses, reduced disabil- methods fail, propantheline bromide (10–15 mg/d), oxy- ity progression (see above). butynin (5–15 mg/d), hyoscyamine sulfate (0.5–0.75 mg/d), tolterodine tartrate (2–4 mg/d), or solifenacin (5–10 mg/d) OTHER THERAPEUTIC CLAIMS Many pur- may help. Coadministration of pseudoephedrine (30–60 ported treatments for MS have never been subjected to mg) is sometimes beneficial. scientific scrutiny. These include dietary therapies (e.g., the Swank diet in addition to others), megadose Detrusor/sphincter dyssynergia may respond to phe- vitamins, low-dose naltrexone, calcium orotate, bee noxybenzamine (10–20 mg/d) or terazosin hydrochlo- stings, cow colostrum, hyperbaric oxygen, procarin (a ride (1–20 mg/d). Loss of reflex bladder wall contraction combination of histamine and caffeine), chelation, may respond to bethanechol (30–150 mg/d). However, acupuncture, acupressure, various Chinese herbal reme- both conditions often require catheterization. dies, and removal of mercury-amalgam tooth fillings, among many others. Patients should avoid costly or Urinary tract infections should be treated promptly. potentially hazardous unproven treatments. Many such Patients with large post-void residual urine volumes are treatments lack biologic plausibility. For example, no reli- predisposed to infections. Prevention by urine acidifica- able case of mercury poisoning resembling typical MS tion (with cranberry juice or vitamin C) inhibits some has ever been described. bacteria. Prophylactic administration of antibiotics is sometimes necessary but may lead to colonization by Although potential roles for EBV, HHV-6, or chlamydia resistant organisms. Intermittent catheterization may have been suggested for MS, these reports are uncon- help to prevent recurrent infections. firmed, and treatment with antiviral agents or antibi- otics is not currently appropriate. Treatment of constipation includes high-fiber diets and fluids. Natural or other laxatives may help. Fecal SYMPTOMATIC THERAPY Potassium channel incontinence may respond to a reduction in dietary fiber. blockers (e.g., 4-aminopyridine, 10–40 mg/d; and 3,4- di-aminopyridine, 40–80 mg/d) may be helpful for Depression should be treated. Useful drugs include weakness, especially for heat-sensitive symptoms. At the selective serotonin reuptake inhibitors (fluoxetine, high doses they may cause seizures. These agents are 20–80 mg/d, or sertraline, 50–200 mg/d); the tricyclic anti- not FDA-approved but can be obtained from com- depressants (amitriptyline, 25–150 mg/d, nortriptyline, pounding pharmacies around the United States. 25–150 mg/d, or desipramine, 100–300 mg/d); and the nontricyclic antidepressants (venlafaxine, 75–225 mg/d). Ataxia/tremor is often intractable. Clonazepam, 1.5–20 mg/d; mysoline, 50–250 mg/d; propranolol, Fatigue may improve with assistive devices, help in the 40–200 mg/d; or ondansetron, 8–16 mg/d may help. home, or successful management of spasticity. Patients Wrist weights occasionally reduce tremor in the arm or with frequent nocturia may benefit from anticholinergic hand. Thalamotomy or deep-brain stimulation has been medication at bedtime. Primary MS fatigue may respond tried with mixed success. to amantadine (200 mg/d), methylphenidate (5–25 mg/d), or modafinil (100–400 mg/d). Spasticity and spasms may improve with physical therapy, regular exercise, and stretching. Avoidance of Cognitive problems may respond to the cholinesterase triggers (e.g., infections, fecal impactions, bed sores) is inhibitor donepezil hydrochloride (10 mg/d). extremely important. Effective medications include liore- sal (20–120 mg/d), diazepam (2–40 mg/d), tizanidine Paroxysmal symptoms respond dramatically to low- (8–32 mg/d), dantrolene (25–400 mg/d), and cyclobenza- dose anticonvulsants (acetazolamide, 200–600 mg/d; prine hydrochloride (10–60 mg/d). For severe spasticity, a carbamazepine, 50–400 mg/d; phenytoin, 50–300 mg/d; or gabapentin, 600–1800 mg/d). Heat sensitivity may respond to heat avoidance, air- conditioning, or cooling garments.

Sexual dysfunction may be helped by lubricants to aid Disease-modifying therapies for MS have not been 449 CHAPTER 34 Multiple Sclerosis and Other Demyelinating Diseases in genital stimulation and sexual arousal. Management rigorously studied in NMO. Acute attacks are usually of pain, spasticity, fatigue, and bladder/bowel dysfunc- treated with high-dose glucocorticoids as for MS exacer- tion may also help. Sildenafil (50–100 mg) taken 1–2 h bations (see above). Because of the possibility that NMO before sex, is now the standard treatment for maintain- is antibody-mediated, plasma exchange has also been ing erections. used empirically for acute episodes that fail to respond to glucocorticoids. Immunosuppressants (cyclophosphamide PROMISING EXPERIMENTAL THERAPIES or azathioprine with glucocorticoids) are sometimes used Numerous clinical trials are currently underway. These in the hope that further relapses will be prevented. More include: (1) oral sphingosine-1-phosphate receptor recently, in a small open-case series, B cell depletion with modulators to sequester lymphocytes in the secondary anti-CD20 monoclonal antibody (rituxan) appeared to lymphoid organs; (2) oral cladribine, a purine nucleo- show promise in preventing relapses of NMO. side agonist; (3) monoclonal antibodies against CD20 to deplete B cells, against the IL-2 receptor on activated Acute MS (Marburg’s variant) is a fulminant demyeli- T- cells, or against CD52 to induce global lymphocyte nating process that in some cases progresses inexorably depletion; (4) use of MBP, or an altered peptide ligand to death within 1–2 years. Typically, there are no remis- resembling MBP, to induce antigen-specific tolerance; sions.When acute MS presents as a solitary, usually cavi- (5) use of statins as immunomodulators; (6) estriol to tary, lesion, a brain tumor is often suspected. In such induce a pregnancy-like state; and (7) bone marrow cases a brain biopsy is usually required to establish the transplantation. diagnosis. An antibody-mediated process appears to be responsible for most cases. Marburg’s variant does not CLINICAL VARIANTS OF MS seem to follow infection or vaccination, and it is unclear whether this syndrome represents an extreme form of Neuromyelitis optica (NMO), or Devic’s syndrome, consists MS or another disease altogether. No controlled trials of of separate attacks of acute ON and myelitis. ON may be therapy exist; high-dose glucocorticoids, plasma unilateral or bilateral and precede or follow an attack of exchange, and cyclophosphamide have been tried, with myelitis by days, months, or years. In contrast to MS, uncertain benefit. patients with NMO do not experience brainstem, cerebel- lar, and cognitive involvement, and the brain MRI is typi- ACUTE DISSEMINATED cally normal.A focal enhancing region of swelling and cav- ENCEPHALOMYELITIS (ADEM) itation, extending over three or more spinal cord segments, is typically seen on MRI. Histopathology of these lesions ADEM has a monophasic course and is frequently may reveal thickening of blood-vessel walls and deposition associated with antecedent immunization (postvacci- of antibody and complement. Occasional patients with nal encephalomyelitis) or infection (postinfectious apparent NMO also have brain MRI changes indicating encephalomyelitis).The hallmark of ADEM is the pres- involvement of the cerebral hemispheres. ence of widely scattered small foci of perivenular inflammation and demyelination. In its most explosive NMO, which is uncommon in whites compared with form, acute hemorrhagic leukoencephalitis, the lesions Asians and Africans, is best understood as a syndrome are vasculitic and hemorrhagic, and the clinical course with diverse causes. Some patients have a systemic is devastating. autoimmune disorder, often systemic lupus erythemato- sus, Sjögren’s syndrome, p-ANCA (perinuclear antineu- Postvaccinal encephalomyelitis may follow the trophil cytoplasmic antibody) associated vasculitis, or administration of smallpox and certain rabies vaccines. mixed connective tissue disease. In others, onset may be Postinfectious encephalomyelitis is most frequently asso- associated with acute infection with varicella-zoster ciated with the viral exanthems of childhood. Infection virus, EBV, HIV, or tuberculosis. More frequently, how- with measles virus is the most common antecedent ever, NMO is idiopathic and probably represents an MS (1 in 1000 cases). Worldwide, measles encephalomyelitis variant; in such cases the course can be monophasic but is still common, although use of the live measles vaccine is more often recurrent. has dramatically reduced its incidence in developed countries. An ADEM-like illness rarely follows vaccina- A highly specific autoantibody directed against the tion with live measles vaccine (1–2 in 106 immunizations). water channel protein aquaporin-4 is present in the sera ADEM is now most frequently associated with vari- of more than one-half of patients who have a clinical cella (chickenpox) infections (1 in 4000–10,000 cases). It diagnosis of NMO. Aquaporin-4 is localized to the foot may also follow infection with rubella, mumps, influenza, processes of astrocytes in close apposition to endothelial parainfluenza, infectious mononucleosis viruses, and surfaces. The role of aquaporin-4 antibodies in the Mycoplasma. Some patients may have a nonspecific upper pathogenesis of NMO, however, is unknown. respiratory infection or no known antecedent illness.

SECTION III Diseases of the Central Nervous System450 All forms of ADEM presumably result from a cross- Treatment: reactive immune response to the infectious agent or vac- ACUTE DISSEMINATED cine that then triggers an inflammatory demyelinating ENCEPHALOMYELITIS response. Autoantibodies to MBP and to other myelin antigens have been detected in the CSF from many Initial treatment is with high-dose glucocorticoids as for patients with ADEM. Attempts to demonstrate direct exacerbations of MS (see above); depending on the viral invasion of the CNS have been unsuccessful. response, treatment may need to be continued for 4–8 weeks. Patients who fail to respond within a few CLINICAL MANIFESTATIONS days may benefit from a course of plasma exchange or intravenous immunoglobulin. The prognosis reflects the In severe cases, onset is abrupt and progression rapid severity of the underlying acute illness. Measles (hours to days). In postinfectious ADEM, the neurologic encephalomyelitis is associated with a mortality rate of syndrome generally begins late in the course of the viral 5–20%, and most survivors have permanent neurologic illness as the exanthem is fading. Fever reappears, and sequelae. Children who recover may have persistent headache, meningismus, and lethargy progressing to coma seizures and behavioral and learning disorders. may develop. Seizures are common. Signs of disseminated neurologic disease are consistently present (e.g., hemi- FURTHER READINGS paresis or quadriparesis, extensor plantar responses, lost or hyperactive tendon reflexes, sensory loss and brainstem GOLAN D et al: Impact of exposure to war stress on exacerbations of involvement). In ADEM due to chickenpox, cerebellar multiple sclerosis.Ann Neurol 64:143, 2008 involvement is often conspicuous. CSF protein is mod- estly elevated [0.5–1.5 g/L (50–150 mg/dL)]. Lympho- GOODIN DS et al: Disease modifying therapies in multiple sclerosis: cytic pleocytosis, generally 200 cells/μl, occurs in 80% of Report of the Therapeutics and Technology Assessment Sub- patients. Occasional patients have higher counts or a committee of the American Academy of Neurology. Neurology mixed polymorphonuclear-lymphocytic pattern during 58:169, 2002 the initial days of the illness. Transient CSF oligoclonal banding has been reported. MRI may reveal extensive HAWKER K et al: Rituximab in patients with primary progressive gadolinium enhancement of white matter in brain and multiple sclerosis: Results of a randomized double-blind placebo- spinal cord. controlled multicenter trial.Ann Neurol 66:460, 2009 DIAGNOSIS JACOB A et al: Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol 65:1443, 2008 The diagnosis is easily established when there is a history of recent vaccination or exanthematous illness. In severe KAPPOS L et al: Effect of early vs delayed interferon beta-1b treat- cases with predominantly cerebral involvement, acute ment on disability after a first clinical event suggestive of multi- encephalitis due to infection with herpes simplex or ple sclerosis: A 3-year follow-up analysis of the BENEFIT study. other viruses may be difficult to exclude.The simultane- Lancet 370:389, 2007 ous onset of disseminated symptoms and signs is com- mon in ADEM and rare in MS. Similarly, meningismus, LENNON VA et al: A serum autoantibody marker of neuromyelitis drowsiness, coma, or seizures suggest ADEM rather than optica: Distinction from multiple sclerosis. Lancet 364:2106, 2004 MS. Unlike in MS, in ADEM optic nerve involvement is generally bilateral and transverse myelopathy complete. MILLER DH, Leary SM: Primary-progressive multiple sclerosis. MRI findings that may support a diagnosis of ADEM Lancet Neurol 6:903, 2007 include extensive and relatively symmetric white matter abnormalities and Gd enhancement of all abnormal OKSENBERG JR et al: The genetics of multiple sclerosis: SNPs to areas, indicating active disease and a monophasic course. pathways to pathogenesis. Nat Rev Genet 9:516, 2008 RANSOHOFF RM: Natalizumab for multiple sclerosis. N Engl J Med 356:2622, 2007 THE CAMMS223 TRIAL INVESTIGATORS: Alemtuzumab versus inter- feron beta-1a in early multiple sclerosis. N Engl J Med 359:1786, 2008 THE INTERNATIONAL MULTIPLE SCLEROSIS GENETICS CONSORTIUM: Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851, 2007 TROJANO M et al: Real-life impact of early interferonbeta therapy in relapsing multiple sclerosis.Ann Neurol 66:513, 2009

CHAPTER 35 MENINGITIS, ENCEPHALITIS, BRAIN ABSCESS, AND EMPYEMA Karen L. Roos I Kenneth L. Tyler I Acute Bacterial Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 I Brain Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455 Pathogenesis and Histopathology . . . . . . . . . . . . . . . . . . . . . 476 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 477 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478 I Acute Viral Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 I Nonbacterial Causes of Infectious Focal CNS Lesions . . . . . 478 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478 Laboratory Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 462 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463 I Subdural Empyema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479 Specific Viral Etiologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479 I Viral Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 Laboratory Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 466 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468 I Epidural Abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 Sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 471 Etiology and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . 481 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 I Subacute Meningitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482 Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 Laboratory Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 472 I Suppurative Thrombophlebitis . . . . . . . . . . . . . . . . . . . . . . . 482 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482 I Chronic Encephalitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473 Anatomy and Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . 482 Progressive Multifocal Leukoencephalopathy . . . . . . . . . . . . 473 Clinical Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482 Subacute Sclerosing Panencephalitis (SSPE) . . . . . . . . . . . . 474 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 Progressive Rubella Panencephalitis . . . . . . . . . . . . . . . . . . . 475 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 483 Acute infections of the nervous system are among the prodrome of fever and headache, which in a previously most important problems in medicine because early healthy individual may initially be thought to be recognition, efficient decision-making, and rapid insti- benign, until (with the exception of viral meningitis) tution of therapy can be lifesaving. These distinct clini- altered consciousness, focal neurologic signs, or seizures cal syndromes include acute bacterial meningitis, appear. Key goals of early management are to emer- viral meningitis, encephalitis, focal infections such as gently distinguish between these conditions, identify brain abscess and subdural empyema, and infectious the responsible pathogen, and initiate appropriate thrombophlebitis. Each may present with a nonspecific antimicrobial therapy. 451

452 space (meningitis) or whether there is evidence of either generalized or focal involvement of brain tissue Approach to the Patient: in the cerebral hemispheres, cerebellum, or brainstem. CNS INFECTION When brain tissue is directly injured by a viral infec- tion the disease is referred to as encephalitis, whereas (Fig. 35-1) The first task is to identify whether an infection predominantly involves the subarachnoid Headache, Fever, ±Nuchal Rigidity Altered mental status? SECTION III Diseases of the Central Nervous System Yes No Meningoencephalitis, ADEM, encephalopathy, or mass lesion Meningitis Yes Papilledema and/or focal neurologic deficit? Obtain blood culture and start Immunocompromised? empirical antimicrobial therapy History of recent head trauma, known cancer, sinusitis? No Imaging: Head CT or MRI (preferred) Mass lesion No mass lesion Abscess Focal or White matter or tumor generalized abnormalities gray matter Appropriate medical abnormalities ADEM and/or surgical or normal interventions Immediate blood culture Encephalitis and lumbar puncture Pleocytosis with PMNs Pleocytosis with MNCs Elevated protein Normal or increased protein Decreased glucose Normal or decreased glucose Gram’s stain positive Gram’s stain negative Bacterial process Tier 1 Eval (no unusual historic points or exposures): Viral: CSF PCR for enterovirus, HSV, VZV CSF IgM for WNV Viral culture: CSF, throat, stool If skin lesions DFA for HSV, VZV HIV serology Serology for enteroviruses and arthropod-borne viruses Fungal: CSF cryptococcal Ag, fungal cultures Bacterial: VDRL and bacterial culture Mycobacterial: CSF AFB stain and TB PCR, TB A culture, CXR, PPD FIGURE 35-1 WNV, West Nile virus; DFA, direct fluorescent antibody; Ag, The management of patients with suspected CNS antigen; VDRL, Venereal Disease Research Laboratory; AFB, infection. ADEM, acute disseminated encephalomyelitis; CT, acid-fast bacillus; TB, tuberculosis; CXR, chest x-ray; PPD, computed tomography; MRI, magnetic resonance imaging; purified protein derivative; EBV, Epstein-Barr virus; CTFV, PMNs, polymorphonuclear leukocytes; MNCs, mononuclear Colorado tick fever virus; HHV, human herpesvirus; LCMV, cells; CSF, cerebrospinal fluid; PCR, polymerase chain reac- lymphocytic choriomeningitis virus. tion; HSV, herpes simplex virus; VZV, varicella-zoster virus;

Tier 2 Evaluation (if above negative): 453 EBV: Serum serology, CSF PCR Mycoplasma: Serum serology, CSF PCR Influenza A, B: Serology, respiratory culture, CSF PCR Adenovirus: Serology, throat swab. CSF PCR Fungal: CSF & serum coccidioidal antibody, Histoplasma antigen & antibody Tier 3 Evaluation (based on epidemiology) Mosquito or Recent Diarrhea Hepatitis tick exposure exanthemal (infant/child) Hepatitis C illness CTFV Rotavirus Arbovirus Rickettsial Measles Borrelia Rubella Ehrilichia HHV-6 Raccoon Wild rodent Cat Swimming in CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema exposure or or hamster exposure lakes or ponds Hx of pica exposure or nonchlorinated water Baylisascaris LCMV Bartonella spp. procyonis (cat scratch fever) Bat exposure Pet bird Exposure to Acanthamoeba or Animal bite (Psittacine) cattle or Naegleria fowleri exposure unpasteurized (amebic dairy products meningoencephalitis) Rabies Chlamydia psittaci (Psittacosis) Brucella spp. (Brucellosis) B Coxiella burnetii (Q fever) FIGURE 35-1 (Continued.) focal bacterial, fungal, or parasitic infections involving patients, immunocompromised individuals, or patients brain tissue are classified as either cerebritis or abscess, with a severely depressed mental status. The high depending on the presence or absence of a capsule. prevalence of cervical spine disease in older individu- als may result in false-positive tests for nuchal rigidity. Nuchal rigidity (“stiff neck”) is the pathogno- monic sign of meningeal irritation and is present Initial management can be guided by several con- when the neck resists passive flexion. Kernig’s and siderations: (1) Empirical therapy should be initiated Brudzinski’s signs are also classic signs of meningeal promptly whenever bacterial meningitis is a signifi- irritation. Kernig’s sign is elicited with the patient in cant diagnostic consideration. (2) All patients who the supine position. The thigh is flexed on the have had recent head trauma, are immunocompro- abdomen, with the knee flexed; attempts to passively mised, have known malignant lesions or central nervous extend the knee elicit pain when meningeal irritation system (CNS) neoplasms, or have focal neurologic is present. Brudzinski’s sign is elicited with the patient findings that include papilledema or a depressed level in the supine position and is positive when passive of consciousness should undergo CT or MRI of the flexion of the neck results in spontaneous flexion of brain prior to lumbar puncture (LP). In these cases the hips and knees. Although commonly tested on empirical antibiotic therapy should not be delayed physical examinations, the sensitivity and specificity pending test results but should be administered prior of Kernig’s and Brudzinski’s signs are uncertain. Both to neuroimaging and LP. (3) A significantly depressed may be absent or reduced in very young or elderly level of consciousness (e.g., somnolence, coma),

SECTION III Diseases of the Central Nervous System454 seizures, or focal neurologic deficits do not occur in factors include coexisting acute or chronic pneumococ- viral (aseptic) meningitis; patients with these symp- cal sinusitis or otitis media, alcoholism, diabetes, splenec- toms should be hospitalized for further evaluation tomy, hypogammaglobulinemia, complement deficiency, and treated empirically for bacterial and viral menin- and head trauma with basilar skull fracture and CSF rhi- goencephalitis. (4) Immunocompetent patients with a norrhea. Mortality remains ~20% despite antibiotic normal level of consciousness, no prior antimicrobial therapy. Recently, pneumococcal vaccination has been treatment, and a cerebrospinal fluid (CSF) profile shown to decrease rates of meningitis. consistent with viral meningitis (lymphocytic pleocy- tosis and a normal glucose concentration) can often N. meningitidis accounts for 25% of all cases of bacterial be treated as outpatients if appropriate contact and meningitis (0.6 cases per 100,000 persons per year) and for monitoring can be ensured. Failure of a patient with up to 60% of cases in children and young adults between 2 suspected viral meningitis to improve within 48 h and 20 years of age.The presence of petechial or purpuric should prompt a reevaluation including follow-up skin lesions can provide an important clue to the diagnosis neurologic and general medical examination and of meningococcal infection. In some patients the disease is repeat imaging and laboratory studies, often including fulminant, progressing to death within hours of symptom a second LP. onset. Infection may be initiated by nasopharyngeal colo- nization, which can result in either an asymptomatic carrier ACUTE BACTERIAL MENINGITIS state or invasive meningococcal disease.The risk of invasive disease following nasopharyngeal colonization depends on DEFINITION both bacterial virulence factors and host immune defense mechanisms, including the host’s capacity to produce anti- Bacterial meningitis is an acute purulent infection within meningococcal antibodies and to lyse meningococci by the subarachnoid space. It is associated with a CNS both classic and alternative complement pathways. Individ- inflammatory reaction that may result in decreased con- uals with deficiencies of any of the complement components, sciousness, seizures, raised intracranial pressure (ICP), including properdin, are highly susceptible to meningococcal and stroke. The meninges, the subarachnoid space, and infections. the brain parenchyma are all frequently involved in the inflammatory reaction (meningoencephalitis). Enteric gram-negative bacilli are an increasingly common cause of meningitis in individuals with chronic EPIDEMIOLOGY and debilitating diseases such as diabetes, cirrhosis, or alcoholism and in those with chronic urinary tract Bacterial meningitis is the most common form of sup- infections. Gram-negative meningitis can also compli- purative CNS infection, with an annual incidence in the cate neurosurgical procedures, particularly craniotomy. United States of >2.5 cases/100,000 population. The epidemiology of bacterial meningitis has changed signif- Group B streptococcus, or S. agalactiae, was previously icantly in recent years, reflecting a dramatic decline in responsible for meningitis predominantly in neonates, but the incidence of meningitis due to Haemophilus influenzae, it has been reported with increasing frequency in individ- and a smaller decline in that due to Neisseria meningitidis, uals >50 years, particularly those with underlying diseases. following the introduction and increasingly widespread use of vaccines for both these organisms. Currently, the L. monocytogenes has become an increasingly important organisms most commonly responsible for community- cause of meningitis in neonates (<1 month), pregnant acquired bacterial meningitis are Streptococcus pneumoniae women, individuals >60 years, and immunocompro- (~50%), N. meningitidis (~25%), group B streptococci mised individuals of all ages. Infection is acquired by (~15%), and Listeria monocytogenes (~10%). H. influenzae ingesting foods contaminated by Listeria. Foodborne now accounts for <10% of cases of bacterial meningitis human listerial infection has been reported from conta- in most series. minated coleslaw, milk, soft cheeses, and several types of “ready-to-eat” foods, including delicatessen meat and ETIOLOGY uncooked hotdogs. S. pneumoniae is the most common cause of meningitis The frequency of H. influenzae type b meningitis in in adults >20 years of age, accounting for nearly half the children has declined dramatically since the introduction reported cases (1.1 per 100,000 persons per year).There of the Hib conjugate vaccine, although rare cases of Hib are a number of predisposing conditions that increase meningitis in vaccinated children have been reported. the risk of pneumococcal meningitis, the most important More frequently, H. influenzae causes meningitis in of which is pneumococcal pneumonia. Additional risk unvaccinated children and adults. Staphylococcus aureus and coagulase-negative staphylococci are important causes of meningitis that occurs following invasive neurosurgical procedures, particularly shunting pro- cedures for hydrocephalus, or as a complication of the use of subcutaneous Ommaya reservoirs for administration of intrathecal chemotherapy.

PATHOPHYSIOLOGY (WBCs) and relatively small amounts of complement 455 CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema proteins and immunoglobulins. The paucity of the latter The most common bacteria that cause meningitis, S. two prevents effective opsonization of bacteria, an essen- pneumoniae and N. meningitidis, initially colonize the tial prerequisite for bacterial phagocytosis by neu- nasopharynx by attaching to nasopharyngeal epithelial trophils. Phagocytosis of bacteria is further impaired by cells. Bacteria are transported across epithelial cells in the fluid nature of CSF, which is less conducive to membrane-bound vacuoles to the intravascular space or phagocytosis than a solid tissue substrate. invade the intravascular space by creating separations in the apical tight junctions of columnar epithelial cells. A critical event in the pathogenesis of bacterial Once in the bloodstream, bacteria are able to avoid meningitis is the inflammatory reaction induced by the phagocytosis by neutrophils and classic complement– invading bacteria. Many of the neurologic manifesta- mediated bactericidal activity because of the presence of tions and complications of bacterial meningitis result a polysaccharide capsule. Bloodborne bacteria can reach from the immune response to the invading pathogen the intraventricular choroid plexus, directly infect rather than from direct bacteria-induced tissue injury. As choroid plexus epithelial cells, and gain access to the a result, neurologic injury can progress even after the CSF. Some bacteria, such as S. pneumoniae, can adhere to CSF has been sterilized by antibiotic therapy. cerebral capillary endothelial cells and subsequently migrate through or between these cells to reach the The lysis of bacteria with the subsequent release of CSF. Bacteria are able to multiply rapidly within CSF cell-wall components into the subarachnoid space is the because of the absence of effective host immune initial step in the induction of the inflammatory response defenses. Normal CSF contains few white blood cells and the formation of a purulent exudate in the subarach- noid space (Fig. 35-2). Bacterial cell-wall components, Invasion of SAS by meningeal pathogens Multiplication of organisms and lysis of organisms by bactericidal antibiotics Release of bacterial cell wall components (endotoxin, teichoic acid) Production of inflammatory cytokines Altered blood-brain Adherence of leukocytes Alterations Production of barrier permeability to cerebral capillary in cerebral excitatory amino endothelial cells blood flow acids and reactive oxygen and Permeability of Leukocytes migrate into nitrogen species blood vessels with CSF, degranulate, and leakage of plasma release toxic metabolites Cell injury proteins into CSF and death Exudate in SAS obstructs Cerebral blood flow blood flow outflow and resorption of ischemia CSF and surrounds and infiltrates cerebral vasculature Vasogenic Obstructive Cytotoxic edema, edema and communicating stroke, seizures hydrocephalus and interstitial edema Intracranial pressure Coma FIGURE 35-2 The pathophysiology of the neurologic complications of bacterial meningitis. SAS, subarachnoid space; CSF, cerebrospinal fluid.

SECTION III Diseases of the Central Nervous System456 such as the lipopolysaccharide (LPS) molecules of gram- vasogenic, and cytotoxic edema leads to raised ICP and negative bacteria and teichoic acid and peptidoglycans of coma. Cerebral herniation usually results from the S. pneumoniae, induce meningeal inflammation by stimu- effects of cerebral edema, either focal or generalized; lating the production of inflammatory cytokines and hydrocephalus and dural sinus or cortical vein thrombo- chemokines by microglia, astrocytes, monocytes, microvas- sis may also play a role. cular endothelial cells, and CSF leukocytes. In experi- mental models of meningitis, cytokines including tumor CLINICAL PRESENTATION necrosis factor (TNF) and interleukin 1 (IL-1) are pre- sent in CSF within 1–2 h of intracisternal inoculation of Meningitis can present as either an acute fulminant illness LPS. This cytokine response is quickly followed by an that progresses rapidly in a few hours or as a subacute increase in CSF protein concentration and leukocytosis. infection that progressively worsens over several days.The Chemokines (cytokines that induce chemotactic migration classic clinical triad of meningitis is fever, headache, and in leukocytes) and a variety of other proinflammatory nuchal rigidity. A decreased level of consciousness occurs cytokines are also produced and secreted by leukocytes in >75% of patients and can vary from lethargy to coma. and tissue cells that are stimulated by IL-1 and TNF. Nausea, vomiting, and photophobia are also common In addition, bacteremia and the inflammatory cytokines complaints. induce the production of excitatory amino acids, reactive oxygen and nitrogen species (free oxygen radicals, nitric Seizures occur as part of the initial presentation of oxide, and peroxynitrite), and other mediators that can bacterial meningitis or during the course of the illness induce death of brain cells. in 20–40% of patients. Focal seizures are usually due to Much of the pathophysiology of bacterial meningitis focal arterial ischemia or infarction, cortical venous is a direct consequence of elevated levels of CSF thrombosis with hemorrhage, or focal edema. General- cytokines and chemokines.TNF and IL-1 act synergisti- ized seizure activity and status epilepticus may be due to cally to increase the permeability of the blood-brain hyponatremia, cerebral anoxia, or, less commonly, the barrier, resulting in induction of vasogenic edema and toxic effects of antimicrobial agents such as high-dose the leakage of serum proteins into the subarachnoid penicillin. space (Fig. 35-2).The subarachnoid exudate of proteina- ceous material and leukocytes obstructs the flow of CSF Raised ICP is an expected complication of bacterial through the ventricular system and diminishes the meningitis and the major cause of obtundation and coma resorptive capacity of the arachnoid granulations in the in this disease. More than 90% of patients will have a dural sinuses, leading to obstructive and communicating CSF opening pressure >180 mm H2O, and 20% have hydrocephalus and concomitant interstitial edema. opening pressures >400 mm H2O. Signs of increased Inflammatory cytokines upregulate the expression of ICP include a deteriorating or reduced level of con- selectins on cerebral capillary endothelial cells and leuko- sciousness, papilledema, dilated poorly reactive pupils, cytes, promoting leukocyte adherence to vascular sixth nerve palsies, decerebrate posturing, and the Cush- endothelial cells and subsequent migration into the CSF. ing reflex (bradycardia, hypertension, and irregular respi- The adherence of leukocytes to capillary endothelial cells rations). The most disastrous complication of increased increases the permeability of blood vessels, allowing for ICP is cerebral herniation. The incidence of herniation the leakage of plasma proteins into the CSF, which adds in patients with bacterial meningitis has been reported to to the inflammatory exudate. Neutrophil degranulation occur in as few as 1% to as many as 8% of cases. results in the release of toxic metabolites that contribute to cytotoxic edema, cell injury, and death. Contrary to Specific clinical features may provide clues to the previous beliefs, CSF leukocytes probably do little to diagnosis of individual organisms and are discussed in contribute to the clearance of CSF bacterial infection. more detail in specific chapters devoted to individual During the very early stages of meningitis, there is an pathogens.The most important of these clues is the rash increase in cerebral blood flow, soon followed by a of meningococcemia, which begins as a diffuse erythe- decrease in cerebral blood flow and a loss of cerebrovas- matous maculopapular rash resembling a viral exanthem; cular autoregulation (Chap. 22). Narrowing of the large however, the skin lesions of meningococcemia rapidly arteries at the base of the brain due to encroachment by become petechial. Petechiae are found on the trunk and the purulent exudate in the subarachnoid space and infil- lower extremities, in the mucous membranes and con- tration of the arterial wall by inflammatory cells with junctiva, and occasionally on the palms and soles. intimal thickening (vasculitis) also occur and may result in ischemia and infarction, obstruction of branches of the DIAGNOSIS middle cerebral artery by thrombosis, thrombosis of the major cerebral venous sinuses, and thrombophlebitis of When bacterial meningitis is suspected, blood cultures the cerebral cortical veins.The combination of interstitial, should be immediately obtained and empirical antimi- crobial therapy is initiated without delay (Table 35-1). The diagnosis of bacterial meningitis is made by exami- nation of the CSF (Table 35-2). The need to obtain

TABLE 35-1 TABLE 35-2 457 ANTIBIOTICS USED IN EMPIRICAL THERAPY OF CEREBROSPINAL FLUID (CSF) ABNORMALITIES BACTERIAL MENINGITIS AND FOCAL CNS IN BACTERIAL MENINGITIS INFECTIONSa Opening pressure >180 mm H2O INDICATION ANTIBIOTIC White blood cells 10/μL to 10,000/μL; neutrophils predominate Preterm infants to Ampicillin + Red blood cells Absent in nontraumatic tap CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema infants <1 month cefotaxime Glucose <2.2 mmol/L (<40 mg/dL) Infants 1–3 months Ampicillin + CSF/serum glucose <0.4 cefotaxime or Protein >0.45 g/L (>45 mg/dL) Immunocompetent children ceftriaxone Gram’s stain Positive in >60% >3 months and adults <55 years Cefotaxime or Culture Positive in >80% ceftriaxone + Latex agglutination May be positive in patients Adults >55 years and adults vancomycin with meningitis due to of any age with alcoholism Ampicillin + Limulus lysate S. pneumoniae, N. meningitidis, or other debilitating illnesses cefotaxime or H. influenzae type b, E. coli, ceftriaxone + PCR group B streptococci Hospital-acquired meningitis, vancomycin Positive in cases of gram- posttraumatic or postneurosurgery Ampicillin + negative meningitis meningitis, neutropenic patients, ceftazidime + Detects bacterial DNA or patients with impaired vancomycin cell-mediated immunity Note: PCR, polymerase chain reaction. ANTIMICROBIAL TOTAL DAILY DOSE AND AGENT DOSING INTERVAL Ampicillin CHILD (>1 MONTH) ADULT WBC count or glucose concentration, nor is it likely to Cefepime prevent visualization of organisms by Gram’s stain or Cefotaxime 200 (mg/kg)/d, q4h 12 g/d, q4h detection of bacterial nucleic acid by polymerase chain Ceftriaxone 150 (mg/kg)/d, q8h 6 g/d, q8h reaction (PCR) assay. Ceftazidime 200 (mg/kg)/d, q6h 12 g/d, q4h Gentamicin 100 (mg/kg)/d, q12h 4 g/d, q12h The classic CSF abnormalities in bacterial meningitis 150 (mg/kg)/d, q8h 6 g/d, q8h (Table 35-2) are (1) polymorphonuclear (PMN) leukocytosis Meropenem 7.5 (mg/kg)/d, q8hb 7.5 (mg/kg)/d, (>100 cells/μL in 90%), (2) decreased glucose concentration Metronidazole q8h [<2.2 mmol/L (<40 mg/dL) and/or CSF/serum glucose 120 (mg/kg)/d, q8h 3 g/d, q8h ratio of <0.4 in ~60%], (3) increased protein concentration Nafcillin 30 (mg/kg)/d, q6h 1500–2000 [>0.45 g/L (>45 mg/dL) in 90%], and (4) increased open- mg/d, q6h ing pressure (>180 mm H2O in 90%). CSF bacterial cul- Penicillin G 100–200 (mg/kg)/d, 9–12 g/d, tures are positive in >80% of patients, and CSF Gram’s stain q6h q4h demonstrates organisms in >60%. Vancomycin 400,000 (U/kg)/d, 20–24 million q4h U/d, q4h CSF glucose concentrations <2.2 mmol/L (<40 mg/dL) 60 (mg/kg)/d, q6h 2 g/d, q12hb are abnormal, and a CSF glucose concentration of zero can be seen in bacterial meningitis. Use of the CSF/ aAll antibiotics are administered intravenously; doses indicated serum glucose ratio corrects for hyperglycemia that may assume normal renal and hepatic function. mask a relative decrease in the CSF glucose concentra- bDoses should be adjusted based on serum peak and trough levels: tion. The CSF glucose concentration is low when the gentamicin therapeutic level: peak: 5–8 μg/mL; trough: <2 μg/mL; van- CSF/serum glucose ratio is <0.6. A CSF/ serum glucose comycin therapeutic level: peak: 25–40 μg/mL; trough: 5–15 μg/mL. ratio <0.4 is highly suggestive of bacterial meningitis but may also be seen in other conditions, including fun- neuroimaging studies (CT or MRI) prior to LP requires gal, tuberculous, and carcinomatous meningitis. It takes clinical judgment. In an immunocompetent patient with from 30 min to several hours for the concentration of no known history of recent head trauma, a normal level CSF glucose to reach equilibrium with blood glucose of consciousness, and no evidence of papilledema or levels; therefore, administration of 50 mL of 50% glucose focal neurologic deficits, it is considered safe to perform (D50) prior to LP, as commonly occurs in emergency LP without prior neuroimaging studies. If LP is delayed department settings, is unlikely to alter CSF glucose in order to obtain neuroimaging studies, empirical concentration significantly unless more than a few hours antibiotic therapy should be initiated after blood cul- have elapsed between glucose administration and LP. tures are obtained. Antibiotic therapy initiated a few hours prior to LP will not significantly alter the CSF A broad-range PCR can detect small numbers of viable and nonviable organisms in CSF and is expected

SECTION III Diseases of the Central Nervous System458 to be useful for making a diagnosis of bacterial meningi- pleocytosis with a normal glucose concentration, in tis in patients who have been pretreated with oral or contrast to PMN pleocytosis and hypoglycorrhachia parenteral antibiotics and in whom Gram’s stain and characteristic of bacterial meningitis. MRI abnormalities CSF culture are negative.When the broad-range PCR is (other than meningeal enhancement) are not seen in positive, a PCR that uses specific bacterial primers to uncomplicated bacterial meningitis. By contrast, in HSV detect the nucleic acid of S. pneumoniae, N. meningitidis, encephalitis, on T2-weighted and fluid-attenuated inver- Escherichia coli, L. monocytogenes, H. influenzae, and sion recovery (FLAIR) MRI images, high signal inten- S. agalactiae can be obtained based on the clinical suspi- sity lesions are seen in the orbitofrontal, anterior, and cion of the meningeal pathogen.The latex agglutination medial temporal lobes in the majority of patients within (LA) test for the detection of bacterial antigens of 48 h of symptom onset. Some patients with HSV S. pneumoniae, N. meningitidis, H. influenzae type b, group encephalitis have a distinctive periodic pattern on EEG B streptococcus, and E. coli K1 strains in the CSF has (see later). been useful for making a diagnosis of bacterial meningi- tis but is being replaced by the CSF bacterial PCR assay. Rickettsial disease can resemble bacterial meningitis. The CSF LA test has a specificity of 95–100% for S. pneu- Rocky Mountain spotted fever (RMSF) is transmitted moniae and N. meningitidis, so a positive test is virtually by a tick bite and caused by the bacteria Rickettsia diagnostic of bacterial meningitis caused by these organ- rickettsii. The disease may present acutely with high isms. However, the sensitivity of the CSF <LA test is fever, prostration, myalgia, headache, nausea, and vomit- only 70–100% for detection of S. pneumoniae and ing. Most patients develop a characteristic rash within 33–70% for detection of N. meningitidis antigens, so a 96 h of the onset of symptoms.The rash is initially a dif- negative test does not exclude infection by these organ- fuse erythematous maculopapular rash that may be diffi- isms.The Limulus amebocyte lysate assay is a rapid diag- cult to distinguish from that of meningococcemia. It nostic test for the detection of gram-negative endotoxin progresses to a petechial rash, then to a purpuric rash in CSF and thus for making a diagnosis of gram-nega- and, if untreated, to skin necrosis or gangrene.The color tive bacterial meningitis. The test has a specificity of of the lesions changes from bright red to very dark red, 85–100% and a sensitivity approaching 100%. Thus, a then yellowish-green to black. The rash typically begins positive Limulus amebocyte lysate assay occurs in virtu- in the wrist and ankles and then spreads distally and ally all patients with gram-negative bacterial meningitis, proximally within a matter of a few hours, involving the but false positives may occur. palms and soles. Diagnosis is made by immunofluores- Almost all patients with bacterial meningitis will have cent staining of skin biopsy specimens. Ehrlichioses are neuroimaging studies performed during the course of also transmitted by a tick bite. These are small gram- their illness. MRI is preferred over CT because of its negative coccobacilli of which two species cause human superiority in demonstrating areas of cerebral edema disease. Anaplasma phagocytophilum causes human granu- and ischemia. In patients with bacterial meningitis, dif- locytic ehrlichiosis (anaplasmosis), and Ehrlichia chaffeensis fuse meningeal enhancement is often seen after the causes human monocytic ehrlichiosis. The clinical and administration of gadolinium. Meningeal enhancement laboratory manifestations of the infections are similar. is not diagnostic of meningitis but occurs in any CNS Patients present with fever, headache, nausea, and vomit- disease associated with increased blood-brain barrier ing. Twenty percent of patients have a maculopapular or permeability. petechial rash. There is laboratory evidence of leukope- Petechial skin lesions, if present, should be biopsied. nia, thrombocytopenia and anemia, and mild to moder- The rash of meningococcemia results from the dermal ate elevations in alanine aminotransferases, alkaline seeding of organisms with vascular endothelial damage, phosphatase, and lactate dehydrogenase. Patients with and biopsy may reveal the organism on Gram’s stain. RMSF and those with ehrlichial infections may have an altered level of consciousness ranging from mild lethargy DIFFERENTIAL DIAGNOSIS to coma, confusion, focal neurologic signs, cranial nerve palsies, hyperreflexia, and seizures. Viral meningoencephalitis, and particularly herpes sim- plex virus (HSV) encephalitis, can mimic the clinical Focal suppurative CNS infections (see later), includ- presentation of bacterial meningitis (see Encephalitis, ing subdural and epidural empyema and brain abscess, below). HSV encephalitis typically presents with should also be considered, especially when focal neuro- headache, fever, altered consciousness, focal neurologic logic findings are present. MRI should be performed deficits (e.g., dysphasia, hemiparesis), and focal or gener- promptly in all patients with suspected meningitis who alized seizures.The findings on CSF studies, neuroimag- have focal features, both to detect the intracranial infec- ing, and electroencephalogram (EEG) distinguish HSV tion and to search for associated areas of infection in the encephalitis from bacterial meningitis. The typical CSF sinuses or mastoid bones. profile with viral CNS infections is a lymphocytic A number of noninfectious CNS disorders can mimic bacterial meningitis. Subarachnoid hemorrhage (SAH; Chap. 22) is generally the major consideration. Other

possibilities include chemical meningitis due to rupture meningitis, and particularly meningitis following neuro- 459 of tumor contents into the CSF (e.g., from a cystic surgical procedures, staphylococci and gram-negative glioma or craniopharyngioma epidermoid or dermoid organisms including P. aeruginosa are the most common CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema cyst); drug-induced hypersensitivity meningitis; carcino- etiologic organisms. In these patients, empirical therapy matous or lymphomatous meningitis; meningitis associ- should include a combination of vancomycin and ated with inflammatory disorders such as sarcoid, systemic ceftazidime, cefepime, or meropenem. Ceftazidime, lupus erythematosus (SLE), and Behçet’s syndrome; cefepime, or meropenem should be substituted for ceftri- pituitary apoplexy; and uveomeningitic syndromes axone or cefotaxime in neurosurgical patients and in neu- (Vogt-Koyanagi-Harada syndrome). tropenic patients, as ceftriaxone and cefotaxime do not provide adequate activity against CNS infection with On occasion, subacutely evolving meningitis may be P. aeruginosa. Meropenem is a carbapenem antibiotic that considered in the differential diagnosis of acute meningi- is highly active in vitro against L. monocytogenes, has tis.The principal causes include Mycobacterium tuberculosis, been demonstrated to be effective in cases of meningitis Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides caused by P. aeruginosa, and shows good activity against immitis, and Treponema pallidum. penicillin-resistant pneumococci. In experimental pneu- mococcal meningitis, meropenem was comparable to Treatment: ceftriaxone and inferior to vancomycin in sterilizing CSF ACUTE BACTERIAL MENINGITIS cultures.The number of patients with bacterial meningitis enrolled in clinical trials of meropenem has not been suf- EMPIRICAL ANTIMICROBIAL THERAPY ficient to definitively assess the efficacy of this antibiotic. (Table 35-1) Bacterial meningitis is a medical emergency. SPECIFIC ANTIMICROBIAL THERAPY The goal is to begin antibiotic therapy within 60 min of a Meningococcal Meningitis (Table 35-3) patient’s arrival in the emergency department. Empirical Although ceftriaxone and cefotaxime provide adequate antimicrobial therapy is initiated in patients with sus- pected bacterial meningitis before the results of CSF empirical coverage for N. meningitidis, penicillin G remains Gram’s stain and culture are known. S. pneumoniae and the antibiotic of choice for meningococcal meningitis N. meningitidis are the most common etiologic organ- caused by susceptible strains. Isolates of N. meningitidis isms of community-acquired bacterial meningitis. Due with moderate resistance to penicillin have been identi- to the emergence of penicillin- and cephalosporin-resis- fied, but patients infected with these strains have still tant S. pneumoniae, empirical therapy of community- acquired suspected bacterial meningitis in children and TABLE 35-3 adults should include a combination of dexamethasone, a third-generation cephalosporin (e.g., ceftriaxone or ANTIMICROBIAL THERAPY OF CNS BACTERIAL cefotaxime) and vancomycin, plus acyclovir, as HSV INFECTIONS BASED ON PATHOGENa encephalitis is the leading disease in the differential diagnosis, and doxycycline during tick season to treat ORGANISM ANTIBIOTIC tick-borne bacterial infections. Ceftriaxone or cefotaxime provide good coverage for susceptible S. pneumoniae, Neisseria meningitides Penicillin G or ampicillin group B streptococci, and H. influenzae and adequate Penicillin-sensitive Ceftriaxone or cefotaxime coverage for N. meningitidis. Cefepime is a broad-spec- Penicillin-resistant trum fourth-generation cephalosporin with in vitro Penicillin G activity similar to that of cefotaxime or ceftriaxone Streptococcus pneumoniae Ceftriaxone or cefotaxime against S. pneumoniae and N. meningitidis and greater Penicillin-sensitive (Ceftriaxone or activity against Enterobacter species and Pseudomonas Penicillin-intermediate cefotaxime) + aeruginosa. In clinical trials, cefepime has been demon- Penicillin-resistant vancomycin strated to be equivalent to cefotaxime in the treatment Ceftriaxone or cefotaxime of penicillin-sensitive pneumococcal and meningococ- Gram-negative bacilli cal meningitis, and it has been used successfully in some (except Pseudomonas spp.) Ceftazidime or cefepime patients with meningitis due to Enterobacter species and or meropenem P. aeruginosa. Ampicillin should be added to the empirical Pseudomonas aeruginosa regimen for coverage of L. monocytogenes in individuals Nafcillin <3 months, those >55 years, or those with suspected Staphylococci spp. Vancomycin impaired cell-mediated immunity because of chronic Methicillin-sensitive Ampicillin + gentamicin illness, organ transplantation, pregnancy, malignancy, or Methicillin-resistant Ceftriaxone or cefotaxime immunosuppressive therapy. In hospital-acquired Penicillin G or ampicillin Listeria monocytogenes Metronidazole Haemophilus influenzae Metronidazole Streptococcus agalactiae Bacteroides fragilis Fusobacterium spp. aDoses are as indicated in Table 35-1.

SECTION III Diseases of the Central Nervous System460 been successfully treated with penicillin. CSF isolates of preferred over the intrathecal route because adequate concentrations of vancomycin in the cerebral ventricles N. meningitidis should be tested for penicillin and ampi- are not always achieved with intrathecal administration. cillin susceptibility, and if resistance is found, cefotaxime or ceftriaxone should be substituted for penicillin. Listeria Meningitis Meningitis due to L. monocy- A 7-day course of intravenous antibiotic therapy is ade- togenes is treated with ampicillin for at least 3 weeks quate for uncomplicated meningococcal meningitis. The (Table 35-3). Gentamicin is often added (2 mg/kg load- index case and all close contacts should receive chemo- ing dose, then 7.5 mg/kg per day given every 8 h and prophylaxis with a 2-day regimen of rifampin (600 mg adjusted for serum levels and renal function). The com- every 12 h for 2 days in adults and 10 mg/kg every 12 h bination of trimethoprim [10–20 (mg/kg)/d] and sul- for 2 days in children >1 year). Rifampin is not recom- famethoxazole [50–100 (mg/kg)/d] given every 6 h may mended in pregnant women. Alternatively, adults can be provide an alternative in penicillin-allergic patients. treated with one dose of ciprofloxacin (750 mg), one dose of azithromycin (500 mg), or one intramuscular Staphylococcal Meningitis Meningitis due to dose of ceftriaxone (250 mg). Close contacts are defined susceptible strains of S. aureus or coagulase-negative as those individuals who have had contact with oropha- staphylococci is treated with nafcillin (Table 35-3). Van- ryngeal secretions, either through kissing or by sharing comycin is the drug of choice for methicillin-resistant toys, beverages, or cigarettes. staphylococci and for patients allergic to penicillin. In these patients, the CSF should be monitored during Pneumococcal Meningitis Antimicrobial ther- therapy. If the CSF is not sterilized after 48 h of intra- apy of pneumococcal meningitis is initiated with a venous vancomycin therapy, then either intraventricular cephalosporin (ceftriaxone, cefotaxime, or cefepime) or intrathecal vancomycin, 20 mg once daily, can be and vancomycin. All CSF isolates of S. pneumoniae added. should be tested for sensitivity to penicillin and the cephalosporins. Once the results of antimicrobial sus- Gram-Negative Bacillary Meningitis The ceptibility tests are known, therapy can be modified third-generation cephalosporins (cefotaxime, ceftriaxone, accordingly (Table 35-3). For S. pneumoniae meningitis, an and ceftazidime) are equally efficacious for the treatment isolate of S.pneumoniae is considered to be susceptible to of gram-negative bacillary meningitis, with the exception penicillin with a minimal inhibitory concentration (MIC) of meningitis due to P. aeruginosa, which should be <0.06 μg/mL, to have intermediate resistance when the treated with ceftazidime, cefepime, or meropenem MIC is 0.1–1.0 μg/mL, and to be highly resistant when (Table 35-3). A 3-week course of intravenous antibiotic the MIC >1.0 μg/mL. Isolates of S. pneumoniae that therapy is recommended for meningitis due to gram- have cephalosporin MICs ≤0.5 μg/mL are considered negative bacilli. sensitive to the cephalosporins (cefotaxime, ceftriaxone, cefepime). Those with MICs of 1 μg/mL are considered Adjunctive Therapy The release of bacterial cell- to have intermediate resistance, and those with MICs wall components by bactericidal antibiotics leads to the ≥2 μg/mL are considered resistant. For meningitis due production of the inflammatory cytokines IL-1 and TNF to pneumococci with cefotaxime or ceftriaxone MICs in the subarachnoid space. Dexamethasone exerts its ≤0.5 μg/mL, treatment with cefotaxime or ceftriaxone is beneficial effect by inhibiting the synthesis of IL-1 and usually adequate. If the MIC >1 μg/mL, vancomycin is TNF at the level of mRNA, decreasing CSF outflow resis- the antibiotic of choice. Rifampin can be added to van- tance, and stabilizing the blood-brain barrier. The ratio- comycin for its synergistic effect but is inadequate as nale for giving dexamethasone 20 min before antibiotic monotherapy because resistance develops rapidly when therapy is that dexamethasone inhibits the production it is used alone. A 2-week course of intravenous antimi- of TNF by macrophages and microglia only if it is admin- crobial therapy is recommended for pneumococcal istered before these cells are activated by endotoxin. meningitis. Dexamethasone does not alter TNF production once it has been induced. The results of clinical trials of dexam- Patients with S. pneumoniae meningitis should have ethasone therapy in children, predominantly with a repeat LP performed 24–36 h after the initiation of meningitis due to H. influenzae and S. pneumoniae, have antimicrobial therapy to document sterilization of the demonstrated its efficacy in decreasing meningeal CSF. Failure to sterilize the CSF after 24–36 h of antibi- inflammation and neurologic sequelae such as the inci- otic therapy should be considered presumptive evi- dence of sensorineural hearing loss. dence of antibiotic resistance. Patients with penicillin- and cephalosporin-resistant strains of S. pneumoniae A prospective European trial of adjunctive therapy for who do not respond to intravenous vancomycin alone acute bacterial meningitis in 301 adults found that dex- may benefit from the addition of intraventricular van- amethasone reduced the number of unfavorable out- comycin. The intraventricular route of administration is comes (15% vs. 25%, p = .03) including death (7% vs. 15%, p = .04). The benefits were most striking in patients with

pneumococcal meningitis. Dexamethasone (10 mg intra- headache of viral meningitis is usually frontal or retroor- 461 CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema venously) was administered 15–20 min before the first bital and is often associated with photophobia and pain dose of an antimicrobial agent, and the same dose was on moving the eyes. Nuchal rigidity is present in most repeated every 6 h for 4 days. These results were con- cases but may be mild and present only near the limit of firmed in a second trial of dexamethasone in adults with neck anteflexion. Constitutional signs can include malaise, pneumococcal meningitis. Therapy with dexamethasone myalgia, anorexia, nausea and vomiting, abdominal pain, should ideally be started 20 min before, or not later than and/or diarrhea. Patients often have mild lethargy or concurrent with, the first dose of antibiotics. It is unlikely drowsiness; however, profound alterations in conscious- to be of significant benefit if started >6 h after antimicro- ness, such as stupor, coma, or marked confusion, are bial therapy has been initiated. Dexamethasone may unusual in viral meningitis and suggest the presence of decrease the penetration of vancomycin into CSF, and it encephalitis or other alternative diagnoses. Similarly, seizures delays the sterilization of CSF in experimental models of or focal neurologic signs or symptoms or neuroimaging S. pneumoniae meningitis. As a result, its potential benefit abnormalities indicative of brain parenchymal involve- should be carefully weighed when vancomycin is the ment are not typical of viral meningitis and suggest the antibiotic of choice. Alternatively, vancomycin can be presence of encephalitis or another CNS infectious or administered by the intraventricular route. inflammatory process. INCREASED INTRACRANIAL PRESSURE ETIOLOGY Emergency treatment of increased ICP includes eleva- tion of the patient’s head to 30°–45°, intubation and Using a variety of diagnostic techniques, including hyperventilation (PaCO2 25–30 mm Hg), and mannitol. CSF PCR, culture, and serology, a specific viral cause Patients with increased ICP should be managed in an can be found in 75–90% of cases of viral meningitis. intensive care unit; accurate ICP measurements are best The most important agents are enteroviruses, HSV obtained with an ICP monitoring device. Treatment of type 2 (HSV-2), and arboviruses (Table 35-4). CSF increased intracranial pressure is discussed in detail in cultures are positive in 30–70% of patients, the fre- Chap. 22. quency of isolation depending on the specific viral agent. Approximately two-thirds of culture-negative PROGNOSIS TABLE 35-4 Mortality is 3–7% for meningitis caused by H. influenzae, N. meningitidis, or group B streptococci; 15% for that due VIRUSES CAUSING ACUTE MENINGITIS to L. monocytogenes; and 20% for S. pneumoniae. In gen- AND ENCEPHALITIS IN NORTH AMERICAa eral, the risk of death from bacterial meningitis increases with (1) decreased level of consciousness on admission, ACUTE MENINGITIS (2) onset of seizures within 24 h of admission, (3) signs of increased ICP, (4) young age (infancy) and >50 years, COMMON LESS COMMON (5) the presence of comorbid conditions including shock and/or the need for mechanical ventilation, and Enteroviruses Varicella zoster virus (6) delay in the initiation of treatment. Decreased CSF (coxsackieviruses, Epstein-Barr virus glucose concentration [<2.2 mmol/L (<40 mg/dL)] and echoviruses, and human Lymphocytic markedly increased CSF protein concentration [>3 g/L enteroviruses 68–71) choriomeningitis virus (>300 mg/dL)] have been predictive of increased mor- tality and poorer outcomes in some series. Moderate or Herpes simplex virus 2 severe sequelae occur in ~25% of survivors, although the Arthropod-borne viruses exact incidence varies with the infecting organism. HIV Common sequelae include decreased intellectual func- tion, memory impairment, seizures, hearing loss and ACUTE ENCEPHALITIS dizziness, and gait disturbances. COMMON LESS COMMON ACUTE VIRAL MENINGITIS Herpesviruses Rabies CLINICAL MANIFESTATIONS Herpes simplex virus 1 Eastern equine encephalitis virus Patients with viral meningitis usually present with Varicella zoster virus Western equine headache, fever, and signs of meningeal irritation cou- encephalitis virus pled with an inflammatory CSF profile (see later). The Epstein-Barr virus Powassan virus Arthropod-borne viruses Cytomegalovirusa La Crosse virus Enterovirusesa West Nile virus Colorado tick fever St. Louis encephalitis virus Mumps aImmunocompromised host.

SECTION III Diseases of the Central Nervous System462 cases of aseptic meningitis have a specific viral etiology potential discriminators between viral and bacterial identified by CSF PCR testing (see later). meningitis or as markers of specific types of viral infec- tion (e.g., infection with HIV), but they remain of EPIDEMIOLOGY uncertain sensitivity and specificity and are not widely used for diagnostic purposes. Viral meningitis is not a nationally reportable disease; however, it has been estimated that the incidence is Polymerase Chain Reaction Amplification ~75,000 cases per year. In temperate climates, there is a of Viral Nucleic Acid substantial increase in cases during the summer and early fall months, reflecting the seasonal predominance of Amplification of viral-specific DNA or RNA from CSF enterovirus and arthropod-borne virus (arbovirus) infec- using PCR amplification has become the single most tions, with a peak monthly incidence of about 1 reported important method for diagnosing CNS viral infections. case per 100,000 population. In both enteroviral and HSV infections of the CNS, PCR has become the diagnostic procedure of choice LABORATORY DIAGNOSIS and is substantially more sensitive than viral cultures. HSV PCR is also an important diagnostic test in CSF Examination patients with recurrent episodes of “aseptic” meningitis, many of whom have amplifiable HSV DNA in CSF The most important laboratory test in the diagnosis of despite negative viral cultures. CSF PCR is also used viral meningitis is examination of the CSF. The typical routinely to diagnose CNS viral infections caused by profile is a lymphocytic pleocytosis (25–500 cells/μL), cytomegalovirus (CMV), Epstein-Barr virus (EBV), a normal or slightly elevated protein concentration VZV, and human herpesvirus 6 (HHV-6). CSF PCR [0.2–0.8 g/L (20–80 mg/dL)], a normal glucose tests are available for WNV but are not as sensitive as concentration, and a normal or mildly elevated opening CSF IgM. PCR is also useful in the diagnosis of CNS pressure (100–350 mm H2O). Organisms are not seen infection caused by Mycoplasma pneumoniae, which can on Gram’s or acid-fast stained smears or India ink mimic viral meningitis and encephalitis. preparations of CSF. Rarely, PMNs may predominate in the first 48 h of illness, especially with infections due to Viral Culture echovirus 9, eastern equine encephalitis (EEE) virus, or mumps. A pleocytosis of polymorphonuclear neutrophils The sensitivity of CSF cultures for the diagnosis of viral also occurs in 45% of patients with West Nile virus meningitis and encephalitis, in contrast to its utility in (WNV) meningitis and can persist for a week or longer bacterial infections, is generally poor. In addition to before shifting to a lymphocytic pleocytosis. Despite CSF, specific viruses may also be isolated from throat these exceptions, the presence of a CSF PMN pleocy- swabs, stool, blood, and urine. Enteroviruses and aden- tosis in a patient with suspected viral meningitis should oviruses may be found in feces; arboviruses, some always prompt consideration of alternative diagnoses, enteroviruses, and LCMV in blood; mumps and CMV including bacterial meningitis or parameningeal infec- in urine; and enteroviruses, mumps, and adenoviruses in tions. The total CSF cell count in viral meningitis is throat washings. During enteroviral infections, viral typically 25–500/μL, although cell counts of several shedding in stool may persist for several weeks. The thousand/μL are occasionally seen, especially with presence of enterovirus in stool is not diagnostic and infections due to lymphocytic choriomeningitis virus may result from residual shedding from a previous (LCMV) and mumps virus. The CSF glucose concen- enteroviral infection; it also occurs in some asympto- tration is typically normal in viral infections, although it matic individuals during enteroviral epidemics. may be decreased in 10–30% of cases due to mumps or LCMV. Rare instances of decreased CSF glucose con- Serologic Studies centration occur in cases of meningitis due to echoviruses and other enteroviruses, HSV-2, and For some viruses, including many arboviruses such as varicella-zoster virus (VZV). As a rule, a lymphocytic WNV, serologic studies remain a crucial diagnostic tool. pleocytosis with a low glucose concentration should Serum antibody determination is less useful for viruses suggest fungal or tuberculous meningitis, Listeria with high seroprevalence rates in the general population meningoencephalitis, or noninfectious disorders (e.g., such as HSV,VZV, CMV, and EBV. For viruses with low sarcoid, neoplastic meningitis). seroprevalence rates, diagnosis of acute viral infection can be made by documenting seroconversion between A number of tests measuring levels of various CSF acute-phase and convalescent sera (typically obtained proteins, enzymes, and mediators—including C-reactive after 2–4 weeks) or by demonstrating the presence of protein, lactic acid, lactate dehydrogenase, neopterin, virus-specific IgM antibodies. Documentation of synthesis quinolinate, IL-1β, IL-6, soluble IL-2 receptor, of virus-specific antibodies in CSF, as shown by an β2-microglobulin, and TNF—have been proposed as

increased IgG index or the presence of CSF IgM anti- PCR (RT-PCR) is the diagnostic procedure of choice 463 CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema bodies, is more useful than serum serology alone and can and is both sensitive (>95%) and specific (>100%). provide presumptive evidence of CNS infection. Enteroviruses are the most likely cause of viral meningi- Although serum and CSF IgM antibodies generally per- tis in the summer months, especially in children sist for only a few months after acute infection, there are (<15 years), although cases occur at reduced frequency exceptions to this rule. For example, WNV IgM has year round. Although the incidence of enteroviral been shown to persist in some patients for >1 year fol- meningitis declines with increasing age, some outbreaks lowing acute infection. Unfortunately, the delay have preferentially affected older children and adults. between onset of infection and the host’s generation of a Meningitis outside the neonatal period is usually virus-specific antibody response often means that sero- benign. Patients present with sudden onset of fever; logic data are useful mainly for the retrospective estab- headache; nuchal rigidity; and often constitutional signs, lishment of a specific diagnosis, rather than in aiding including vomiting, anorexia, diarrhea, cough, pharyngi- acute diagnosis or management. tis, and myalgias. The physical examination should include a careful search for stigmata of enterovirus infec- CSF oligoclonal gamma globulin bands occur in tion, including exanthemata, hand-foot-mouth disease, association with a number of viral infections.The associ- herpangina, pleurodynia, myopericarditis, and hemor- ated antibodies are often directed against viral proteins. rhagic conjunctivitis.The CSF profile is typically a lym- Oligoclonal bands occur commonly in certain nonin- phocytic pleocytosis (100–1000 cells/μL) with normal fectious neurologic diseases (e.g., multiple sclerosis) and glucose and normal or mildly elevated protein concen- may be found in nonviral infections (e.g., neurosyphilis, tration. In rare cases, PMNs may predominate during Lyme neuroborreliosis). the first 48 h of illness. Treatment is supportive, and patients usually recover without sequelae. Chronic and Other Laboratory Studies severe infections can occur in neonates and in individu- als with hypo- or agammaglobulinemia. All patients with suspected viral meningitis should have a complete blood count and differential, liver and renal Arbovirus infections occur predominantly in the sum- function tests, erythrocyte sedimentation rate (ESR) and mer and early fall.Arboviral meningitis should be consid- C-reactive protein, electrolytes, glucose, creatine kinase, ered when clusters of meningitis and encephalitis cases aldolase, amylase, and lipase. Neuroimaging studies occur in a restricted geographic region during the sum- (MRI, CT) are not necessary in patients with uncompli- mer or early fall. In WNV epidemics, avian deaths may cated viral meningitis but should be performed in serve as sentinel infections for subsequent human disease. patients with altered consciousness, seizures, focal neuro- A history of tick exposure or travel or residence in the logic signs or symptoms, or atypical CSF profiles. appropriate geographic area should suggest the possibility of Colorado tick fever virus or Powassan virus infection, DIFFERENTIAL DIAGNOSIS although nonviral tick-borne diseases, including RMSF and Lyme neuroborreliosis, may present similarly. The most important issue in the differential diagnosis of Arbovirus meningoencephalitis is typically associated viral meningitis is to consider diseases that can mimic with a CSF lymphocytic pleocytosis, normal glucose viral meningitis, including (1) untreated or partially concentration, and normal or mildly elevated protein treated bacterial meningitis; (2) early stages of meningitis concentration. However, 40–45% of patients with WNV caused by fungi, mycobacteria, or Treponema pallidum meningoencephalitis have CSF neutrophilia, which can (neurosyphilis), in which a lymphocytic pleocytosis is persist for a week or more. The rarity of hypoglycor- common, cultures may be slow growing or negative, and rhachia in WNV infection as well as the absence of hypoglycorrhachia may not be present early; (3) meningitis positive Gram’s stains and the negative cultures helps dis- caused by agents such as Mycoplasma, Listeria spp., tinguish these patients from those with bacterial menin- Brucella spp., Coxiella spp., Leptospira spp., and Rickettsia gitis.The presence of increased numbers of plasmacytoid spp.; (4) parameningeal infections; (5) neoplastic meningi- cells or Mollaret-like large mononuclear cells in the CSF tis; and (6) meningitis secondary to noninfectious inflam- may be a clue to the diagnosis of WNV infection. Defin- matory diseases, including hypersensitivity meningitis, itive diagnosis of arboviral meningoencephalitis is based SLE and other rheumatologic diseases, sarcoidosis, on demonstration of viral-specific IgM in CSF or sero- Behçet’s syndrome, and the uveomeningitic syndromes. conversion. CSF PCR tests are available for some viruses in selected diagnostic laboratories and at the Centers for SPECIFIC VIRAL ETIOLOGIES Disease Control and Prevention (CDC), but in the case of WNV, sensitivity (~70%) of CSF PCR is less than that Enteroviruses are the most common cause of viral menin- of CSF serology. gitis, accounting for >75% of cases in which a specific etiology can be identified. CSF reverse transcriptase HSV-2 meningitis occurs in ~25% of women and 11% of men at the time of an initial (primary) episode of

SECTION III Diseases of the Central Nervous System464 genital herpes. Of these patients, 20% go on to have VIII, are more common in HIV meningitis than in other recurrent attacks of meningitis. HSV-2 has been increas- viral infections. Diagnosis can be confirmed by detection ingly recognized as a major cause of viral meningitis in of HIV genome in blood or CSF. Seroconversion may be adults, and overall it is probably second in importance to delayed, and patients with negative HIV serologies who enteroviruses as a cause of viral meningitis. Diagnosis of are suspected of having HIV meningitis should be moni- HSV meningitis is usually by HSV CSF PCR as cul- tored for delayed seroconversion. For further discussion tures may be negative, especially in patients with recur- of HIV infection, see Chap. 37. rent meningitis. Demonstration of intrathecal synthesis of HSV-specific antibody may also be useful in diagno- Mumps should be considered when meningitis occurs sis, although antibody tests are less sensitive and less spe- in the late winter or early spring, especially in males cific than PCR and may not become positive until after (male:female ratio 3:1). With the widespread use of the the first week of infection. In contrast to HSV live attenuated mumps vaccine in the United States since encephalitis in adults in which >90% of cases are due to 1967, the incidence of mumps meningitis has fallen by HSV-1, the overwhelming majority of HSV meningitis >95%.The presence of parotitis, orchitis, oophoritis, pan- is due to HSV-2. Although a history of or the presence creatitis, or elevations in serum lipase and amylase are of HSV genital lesions is an important diagnostic clue, suggestive of mumps meningitis; however, their absence many patients with HSV meningitis give no history and does not exclude the diagnosis. Clinical meningitis have no evidence of active genital herpes at the time of occurs in up to 30% of patients with mumps parotitis, presentation. Most cases of recurrent viral or “aseptic” and CSF pleocytosis occurs in >50%. Mumps infection meningitis, including cases previously diagnosed as Mol- confers lifelong immunity, so a documented history of laret’s meningitis, are likely due to HSV. previous infection excludes this diagnosis. Patients with VZV meningitis should be suspected in the presence meningitis have a CSF pleocytosis that can exceed 1000 of concurrent chickenpox or shingles. However, it is cells/μL in 25%. Lymphocytes predominate in 75%, important to recognize that in some series, up to 40% of although CSF neutrophilia occurs in 25%. Hypoglycor- VZV meningitis cases have been reported to occur in rhachia, occurs in 10–30% of patients and may be a clue the absence of rash.The frequency of VZV as a cause of to the diagnosis when present. Diagnosis is typically meningitis is extremely variable, ranging from as low as made by culture of virus from CSF or by detecting IgM 3% to as high as 20% in different series. Diagnosis is antibodies or seroconversion. CSF PCR is available in usually based on CSF PCR, although the sensitivity of some diagnostic and research laboratories.The frequency this test may not be as high as for the other her- of mumps meningitis has declined dramatically with the pesviruses. In patients with negative CSF PCR results, widespread use of the live-attenuated mumps vaccine. the diagnosis of VZV CNS infection can be made by Rare cases of vaccine-associated meningitis occur, with a the demonstration of VZV-specific intrathecal antibody frequency of 10–100/100,000 doses typically 2–4 weeks synthesis and/or the presence of VZV CSF IgM anti- after vaccination. bodies, or by positive CSF cultures. EBV infections may also produce aseptic meningitis, LCMV infection should be considered when aseptic with or without associated infectious mononucleosis. meningitis occurs in the late fall or winter and in indi- The presence of atypical lymphocytes in the CSF or viduals with a history of exposure to house mice (Mus peripheral blood is suggestive of EBV infection but may musculus), pet or laboratory rodents (e.g., hamsters, rats, occasionally be seen with other viral infections. EBV is mice), or their excreta. Some patients have an associated almost never cultured from CSF. Serum and CSF serol- rash, pulmonary infiltrates, alopecia, parotitis, orchitis, or ogy can help establish the presence of acute infection, myopericarditis. Laboratory clues to the diagnosis of which is characterized by IgM viral capsid antibodies LCMV, in addition to the clinical findings noted above, (VCAs), antibodies to early antigens (EA), and the may include the presence of leukopenia, thrombocytope- absence of antibodies to EBV-associated nuclear antigen nia, or abnormal liver function tests. Some cases present (EBNA). CSF PCR is another important diagnostic test, with a marked CSF pleocytosis (>1000 cells/μL) and although positive results may reflect viral reactivation hypoglycorrachia (<30%). Diagnosis is based on serology associated with other infectious or inflammatory and/or culture of virus from CSF. processes. HIV meningitis should be suspected in any patient pre- Treatment: senting with a viral meningitis with known or suspected ACUTE VIRAL MENINGITIS risk factors for HIV infection. Meningitis may occur fol- lowing primary infection with HIV in 5–10% of patients Treatment of almost all cases of viral meningitis is pri- and less commonly at later stages of illness. Cranial nerve marily symptomatic and includes use of analgesics, palsies, most commonly involving cranial nerves V,VII, or antipyretics, and antiemetics. Fluid and electrolyte status

should be monitored. Patients with suspected bacterial measles infection. A live attenuated VZV vaccine (Vari- 465 meningitis should receive appropriate empirical therapy vax) is available in the United States. Clinical studies pending culture results (see earlier). Hospitalization may indicate an effectiveness rate of 70–90% for this vaccine, not be required in immunocompetent patients with but a booster may be required to maintain immunity. presumed viral meningitis and no focal signs or symp- An inactivated varicella vaccine is available for trans- toms, no significant alteration in consciousness, and a plant recipients. classic CSF profile (lymphocytic pleocytosis, normal glu- cose, negative Gram’s stain) if adequate provision for PROGNOSIS CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema monitoring at home and medical follow-up can be ensured. Immunocompromised patients; patients with In adults, the prognosis for full recovery from viral significant alteration in consciousness, seizures, or the meningitis is excellent. Rare patients complain of per- presence of focal signs and symptoms suggesting the sisting headache, mild mental impairment, incoordina- possibility of encephalitis or parenchymal brain involve- tion, or generalized asthenia for weeks to months. The ment; and those patients who have an atypical CSF pro- outcome in infants and neonates (<1 year) is less cer- file should be hospitalized. Oral or intravenous acyclovir tain; intellectual impairment, learning disabilities, hear- may be of benefit in patients with meningitis caused by ing loss, and other lasting sequelae have been reported in HSV-1 or -2 and in cases of severe EBV or VZV infection. some studies. Data concerning treatment of HSV, EBV, and VZV menin- gitis are extremely limited. Seriously ill patients should VIRAL ENCEPHALITIS probably receive intravenous acyclovir (15–30 mg/kg per day in three divided doses), which can be followed DEFINITION by an oral drug such as acyclovir (800 mg, five times daily), famciclovir (500 mg tid), or valacyclovir (1000 mg In contrast to viral meningitis, where the infectious process tid) for a total course of 7–14 days. Patients who are less and associated inflammatory response are limited largely to ill can be treated with oral drugs alone. Patients with HIV the meninges, in encephalitis the brain parenchyma is also meningitis should receive highly active antiretroviral involved. Many patients with encephalitis also have evidence therapy (Chap. 37). of associated meningitis (meningoencephalitis) and, in some cases, involvement of the spinal cord or nerve Patients with viral meningitis who are known to roots (encephalomyelitis, encephalomyeloradiculitis). have deficient humoral immunity (e.g., X-linked agam- maglobulinemia) and who are not already receiving CLINICAL MANIFESTATIONS either intramuscular gamma globulin or intravenous immunoglobulin (IVIg), should be treated with these In addition to the acute febrile illness with evidence of agents. Intraventricular administration of immunoglob- meningeal involvement characteristic of meningitis, the ulin through an Ommaya reservoir has been tried in patient with encephalitis commonly has an altered level some patients with chronic enteroviral meningitis who of consciousness (confusion, behavioral abnormalities), have not responded to intramuscular or intravenous or a depressed level of consciousness, ranging from mild immunoglobulin. lethargy to coma, and evidence of either focal or diffuse neurologic signs and symptoms. Patients with encephali- An investigational drug, pleconaril, has shown efficacy tis may have hallucinations, agitation, personality against a variety of enteroviral infections and has good change, behavioral disorders, and, at times, a frankly psy- oral bioavailability and excellent CNS penetration. Clini- chotic state. Focal or generalized seizures occur in many cal trials in patients with enteroviral meningitis indicated patients with encephalitis. Virtually every possible type that pleconaril decreased the duration of symptoms of focal neurologic disturbance has been reported in compared to placebo. Most cases of enteroviral CNS viral encephalitis; the signs and symptoms reflect the infection are benign and self-limited and do not require sites of infection and inflammation. The most com- specific antiviral therapy. However, pleconaril treatment monly encountered focal findings are aphasia, ataxia, might benefit patients with chronic CNS enteroviral upper or lower motor neuron patterns of weakness, infections in the setting of agammaglobulinemia or involuntary movements (e.g., myoclonic jerks, tremor), those who develop poliomyelitis as a complication of and cranial nerve deficits (e.g., ocular palsies, facial polio vaccine administration. Unfortunately, the availabil- weakness). Involvement of the hypothalamic-pituitary ity of pleconaril for compassionate-use purposes is cur- axis may result in temperature dysregulation, diabetes rently uncertain. insipidus, or the development of the syndrome of inap- propriate secretion of antidiuretic hormone (SIADH). Vaccination is an effective method of preventing the development of meningitis and other neurologic com- plications associated with poliovirus, mumps, and

SECTION III Diseases of the Central Nervous System466 Despite the clear neuropathologic evidence that viruses occurs in >95% of patients with documented viral differ in the regions of the CNS they injure, it is often encephalitis. In rare cases, a pleocytosis may be absent on impossible to distinguish reliably on clinical grounds the initial LP but present on subsequent LPs. Patients alone one type of viral encephalitis (e.g., that caused by who are severely immunocompromised by HIV infec- HSV) from others (see Differential Diagnosis, below). tion, glucocorticoid or other immunosuppressant drugs, chemotherapy, or lymphoreticular malignancies may fail ETIOLOGY to mount a CSF inflammatory response. CSF cell counts exceed 500/μL in only about 10% of patients with In the United States, there are ~20,000 reported cases encephalitis. Infections with certain arboviruses (e.g., of encephalitis per year, although the actual number of EEE virus or California encephalitis virus), mumps, and cases is likely to be significantly larger. Hundreds of LCMV may occasionally result in cell counts >1000/μL, viruses are capable of causing encephalitis, although but this degree of pleocytosis should suggest the possibil- only a limited subset is responsible for most cases in ity of nonviral infections or other inflammatory which a specific cause is identified (Table 35-4). The processes. Atypical lymphocytes in the CSF may be seen same organisms responsible for aseptic meningitis are in EBV infection and less commonly with other viruses, also responsible for encephalitis, although the relative including CMV, HSV, and enteroviruses. Increased num- frequencies with which specific organisms cause these bers of plasmacytoid or Mollaret-like large mononuclear two patterns of infection often differ. The most impor- cells have been reported in WNV encephalitis. Polymor- tant viruses causing sporadic cases of encephalitis in phonuclear pleocytosis occurs in ~40% of patients with immunocompetent adults are herpesviruses (HSV,VZV, WNV encephalitis. Large numbers of CSF PMNs may EBV). Epidemics of encephalitis are caused by be present in patients with encephalitis due to EEE arboviruses, which belong to several different viral tax- virus, echovirus 9, and, more rarely, other enteroviruses. onomic groups including Alphaviruses (e.g., EEE virus, However, persisting CSF neutrophilia should prompt western equine encephalitis virus), Flaviviruses (e.g., consideration of bacterial infection, leptospirosis, amebic WNV, St. Louis encephalitis virus, Japanese encephalitis infection, and noninfectious processes such as acute hem- virus, Powassan virus), and Bunyaviruses (e.g., California orrhagic leukoencephalitis. About 20% of patients with encephalitis virus serogroup, LaCrosse virus). Histori- encephalitis will have a significant number of red blood cally, the largest number of cases of arbovirus encephali- cells (>500/μL) in the CSF in a nontraumatic tap. The tis in the United States has been due to St. Louis pathologic correlate of this finding may be a hemor- encephalitis virus and the California encephalitis virus rhagic encephalitis of the type seen with HSV; however, serogroup. However, since 2002, WNV has been CSF red blood cells occur with similar frequency and in responsible for the majority of arbovirus meningitis and similar numbers in patients with nonherpetic focal encephalitis cases in the United States. The 2003 epi- encephalitides. A decreased CSF glucose concentration is demic was the largest epidemic of arboviral neuroinva- distinctly unusual in viral encephalitis and should suggest sive disease (encephalitis + meningitis) ever recorded in the possibility of bacterial, fungal, tuberculous, parasitic, the United States, with 2860 cases and 264 deaths. leptospiral, syphilitic, sarcoid, or neoplastic meningitis. Since 2003, WNV has accounted for ~1100–1300 cases Rare patients with mumps, LCMV, or advanced HSV of neuroinvasive disease per year and 100–120 deaths in encephalitis may have low CSF glucose concentrations. the United States. New causes of viral CNS infections are constantly appearing, as evidenced by the recent CSF PCR outbreak of cases of encephalitis in Southeast Asia caused by Nipah virus, a newly identified member of CSF PCR has become the primary diagnostic test for the Paramyxovirus family, and of meningitis in Europe CNS infections caused by CMV, EBV,VZV, HHV-6, and caused by Toscana virus, an arbovirus belonging to the enteroviruses (see Viral Meningitis, above). The sensitiv- Bunyavirus family. ity and specificity of CSF PCRs varies with the virus being tested. The sensitivity (~96%) and specificity LABORATORY DIAGNOSIS (~99%) of HSV CSF PCR is equivalent to or exceeds that of brain biopsy. It is important to recognize that CSF Examination HSV CSF PCR results need to be interpreted after considering the likelihood of disease in the patient CSF examination should be performed in all patients being tested, the timing of the test in relationship to with suspected viral encephalitis unless contraindicated by onset of symptoms, and the prior use of antiviral therapy. the presence of severely increased ICP. The characteristic A negative HSV CSF PCR test performed by a qualified CSF profile is indistinguishable from that of viral menin- laboratory at the appropriate time during illness in a gitis and typically consists of a lymphocytic pleocytosis, a patient with a high likelihood of HSV encephalitis based mildly elevated protein concentration, and a normal glu- on clinical and laboratory abnormalities significantly cose concentration. A CSF pleocytosis (>5 cells/μL)

reduces the likelihood of HSV encephalitis but does not >1 week in duration and who are CSF PCR–negative 467 CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema exclude it. For example, in a patient with a pretest prob- for HSV. Demonstration of WNV IgM antibodies is ability of 35% of having HSV encephalitis, a negative diagnostic of WNV encephalitis as IgM antibodies do HSV CSF PCR reduces the posttest probability to ~2%, not cross the blood-brain barrier, and their presence in and for a patient with a pretest probability of 60%, a CSF is therefore indicative of intrathecal synthesis.Tim- negative test reduces the posttest probability to ~6%. In ing of antibody collection may be important as the rate both situations a positive test makes the diagnosis almost of CSF WNV IgM seropositivity increases by ~10% per certain (98–99%).There have been several recent reports day during the first week after illness onset. of initially negative HSV CSF PCR tests that were obtained early (≤72 h) following symptom onset, and MRI, CT, EEG that became positive when repeated 1–3 days later. The frequency of positive HSV CSF PCRs in patients with Patients with suspected encephalitis almost invariably herpes encephalitis also decreases as a function of the undergo neuroimaging studies and often EEG. These duration of illness, with only ~20% of cases remaining tests help identify or exclude alternative diagnoses and positive after ≥14 days. PCR results are generally not assist in the differentiation between a focal, as opposed affected by ≤1 week of antiviral therapy. In one study, 98% to a diffuse, encephalitic process. Focal findings in a of CSF specimens remained PCR-positive during the first patient with encephalitis should always raise the possi- week of initiation of antiviral therapy, but the numbers fell bility of HSV encephalitis. Examples of focal findings to ~50% by 8–14 days and to ~21% by >15 days after ini- include: (1) areas of increased signal intensity in the tiation of antiviral therapy. frontotemporal, cingulate, or insular regions of the brain on T2-weighted, FLAIR, or diffusion-weighted The sensitivity and specificity of CSF PCR tests for MRI images (Fig. 35-3); (2) focal areas of low absorp- viruses other than herpes simplex have not been defini- tion, mass effect, and contrast enhancement on CT; or tively characterized. Enteroviral CSF PCR appears to (3) periodic focal temporal lobe spikes on a back- have a sensitivity and specificity of >95%.The specificity ground of slow or low-amplitude (“flattened”) activity of EBV CSF PCR has not been established. Positive on EEG. Approximately 10% of patients with PCR- EBV CSF PCRs associated with positive tests for other documented HSV encephalitis will have a normal pathogens have been reported and may reflect reactiva- MRI, although nearly 80% will have abnormalities in tion of EBV latent in lymphocytes that enter the CNS as a result of an unrelated infectious or inflammatory process. In patients with CNS infection due to VZV, CSF antibody and PCR studies should be considered comple- mentary, as patients may have evidence of intrathecal synthesis of VZV-specific antibodies and negative CSF PCRs. In the case of WNV infection, CSF PCR appears to be less sensitive (~70% sensitivity) than detection of WNV-specific CSF IgM, although PCR testing remains useful in immunocompromised patients who may not mount an effective anti-WNV antibody response. CSF Culture Attempts to culture viruses from the CSF in cases of encephalitis are often disappointing. Cultures are nega- tive in >95% of cases of HSV-1 encephalitis. Serologic Studies and Antigen Detection FIGURE 35-3 Coronal FLAIR magnetic resonance image from a patient The basic approach to the serodiagnosis of viral with herpes simplex encephalitis. Note the area of encephalitis is identical to that discussed earlier for viral increased signal in the right temporal lobe (left side of image) meningitis. In patients with HSV encephalitis, both anti- confined predominantly to the gray matter. This patient had bodies to HSV-1 glycoproteins and glycoprotein anti- predominantly unilateral disease; bilateral lesions are more gens have been detected in the CSF. Optimal detection common but may be quite asymmetric in their intensity. of both HSV antibodies and antigen typically occurs after the first week of illness, limiting the utility of these tests in acute diagnosis. Nonetheless, HSV CSF antibody testing is of value in selected patients whose illness is

SECTION III Diseases of the Central Nervous System468 the temporal lobe, and an additional 10% in extratem- this virus to produce a CNS vasculopathy rather than a poral regions. The lesions are typically hyperintense on true encephalitis. Immunocompromised adult patients T2-weighted images. CT is less sensitive than MRI with CMV often have enlarged ventricles with areas of and is normal in up to 33% of patients.The addition of increased T2 signal on MRI outlining the ventricles FLAIR and diffusion-weighted images to the standard and sub-ependymal enhancement on T1-weighted post- MRI sequences enhances sensitivity. EEG abnormali- contrast images. Table 35-5 highlights specific diagnos- ties occur in >90% of PCR-documented cases of HSV tic test results in encephalitis that can be useful in clinical encephalitis; they typically involve the temporal lobes decision-making. but are often nonspecific. Some patients with HSV encephalitis have a distinctive EEG pattern consisting Brain Biopsy of periodic, stereotyped, sharp-and-slow complexes originating in one or both temporal lobes and repeat- Brain biopsy is now generally reserved for patients in ing at regular intervals of 2–3 s.The periodic complexes whom CSF PCR studies fail to lead to a specific diag- are typically noted between the 2nd and 15th day of the nosis, who have focal abnormalities on MRI, and who illness and are present in two-thirds of pathologically continue to show progressive clinical deterioration proven cases of HSV encephalitis. despite treatment with acyclovir and supportive therapy. Significant MRI abnormalities are found in only ~50% of patients with WNV encephalitis, a frequency DIFFERENTIAL DIAGNOSIS less than that with HSV encephalitis. When present, abnormalities often involve deep brain structures, includ- Infection by a variety of other organisms can mimic ing the thalamus, basal ganglia, and brainstem, rather than viral encephalitis. In studies of biopsy-proven HSV the cortex and may only be apparent on FLAIR images. encephalitis, common infectious mimics of focal viral EEGs typically show generalized slowing that may be encephalitis included mycobacteria, fungi, rickettsia, more anteriorly prominent rather than the temporally Listeria and other bacteria (including Bartonella sp.), and predominant pattern of sharp or periodic discharges Mycoplasma. more characteristic of HSV encephalitis. Patients with VZV encephalitis may show multifocal areas of hemor- Infection caused by the ameba Naegleria fowleri can rhagic and ischemic infarction reflecting the tendency of also cause acute meningoencephalitis (primary amebic TABLE 35-5 USE OF DIAGNOSTIC TESTS IN ENCEPHALITIS The best test for WNV encephalitis is the CSF IgM antibody test. The prevalence of positive CSF IgM tests increases by about 10%/day after illness onset and reaches 70–80% by the end of the first week. Serum WNV IgM can provide evidence for recent WNV infection, but in the absence of other findings does not establish the diagnosis of neuroinvasive disease (meningitis, encephalitis, acute flaccid paralysis). Approximately 80% of patients with proven HSV encephalitis have MRI abnormalities involving the temporal lobes. This percentage likely increases to >90% when FLAIR and DWI MR sequences are also utilized. The absence of temporal lobe lesions on MR reduces the likelihood of HSV encephalitis and should prompt consideration of other diagnostic possibilities. The CSF HSV PCR test may be negative in the first 72 h of symptoms of HSV encephalitis. A repeat study should be considered in patients with an initial early negative PCR in whom diagnostic suspicion of HSV encephalitis remains high and no alternative diagnosis has yet been established. Detection of intrathecal synthesis (increased CSF/serum HSV antibody ratio corrected for breakdown of the blood-brain barrier) of HSV-specific antibody may be useful in diagnosis of HSV encephalitis in patients in whom only late (>1 week post-onset) CSF specimens are available and PCR studies are negative. Serum serology alone is of no value in diagnosis of HSV encephalitis due to the high seroprevalence rate in the general population. Negative CSF viral cultures are of no value in excluding the diagnosis of HSV or EBV encephalitis. VZV CSF IgM antibodies may be present in patients with a negative VZV CSF PCR. Both tests should be performed in patients with suspected VZV CNS disease. The specificity of EBV CSF PCR for diagnosis of CNS infection is unknown. Positive tests may occur in patients with a CSF pleocytosis due to other causes. Detection of EBV CSF IgM or intrathecal synthesis of antibody to VCA supports the diagnosis of EBV encephalitis. Serological studies consistent with acute EBV infection (e.g., IgM VCA, presence of antibodies against EA but not against EBNA) can help support the diagnosis. Note: CSF, cerebrospinal fluid; IgM, immunoglobulin M; WNV, West Nile virus; HSV, herpes simplex virus; MRI, magnetic resonance imaging; FLAIR, fluid attenuated inversion recovery; DWI, diffusion-weighted imaging; PCR, polymerase chain reaction; EBV, Epstein-Barr virus; VZV, varicella-zoster virus; CNS, central nervous system; VCA, viral capsid antibody; EA, early antigen; EBNA, EBV-associated nuclear antigen.

meningoencephalitis), whereas that caused by Acanthamoeba weakness with flaccid tone, reduced or absent reflexes, 469 CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema and Balamuthia more typically produces subacute or and relatively preserved sensation. Despite an aggressive chronic granulomatous amebic meningoencephalitis. World Health Organization poliovirus eradication initia- Naegleria thrive in warm, iron-rich pools of water, tive, >1200 cases of wild-type poliovirus-induced including those found in drains, canals, and both natural poliomyelitis have been reported worldwide in 2006, and human-made outdoor pools. Infection has typically with 88% occurring in Nigeria and India and >20 cases occurred in immunocompetent children with a history each from Somalia,Afghanistan, and Namibia.There have of swimming in potentially infected water. The CSF, in been recent small outbreaks of poliomyelitis associated contrast to the typical profile seen in viral encephalitis, with vaccine strains of virus that have reverted to viru- often resembles that of bacterial meningitis with a neu- lence through mutation or recombination with circulating trophilic pleocytosis and hypoglycorrhachia. Motile wild-type enteroviruses in Hispaniola, China, the Philip- trophozoites can be seen in a wet mount of warm, fresh pines, and Madagascar. CSF. No effective treatment has been identified, and mortality approaches 100%. Epidemiologic factors may provide important clues to the diagnosis of viral meningitis or encephalitis. Par- Encephalitis can be caused by the raccoon pinworm ticular attention should be paid to the season of the Baylisascaris procyonis. Clues to the diagnosis include a year; the geographic location and travel history; and pos- history of raccoon exposure, and especially of playing in sible exposure to animal bites or scratches, rodents, and or eating dirt potentially contaminated with raccoon ticks. Although transmission from the bite of an infected feces. Most patients are children, and many have an asso- dog remains the most common cause of rabies world- ciated eosinophilia. wide, in the United States very few cases of dog rabies occur, and the most common risk factor is exposure to Once nonviral causes of encephalitis have been bats—although a clear history of a bite or scratch is excluded, the major diagnostic challenge is to distinguish often lacking. The classic clinical presentation of HSV from other viruses that cause encephalitis.This dis- encephalitic (furious) rabies is of fever, fluctuating con- tinction is particularly important because in virtually sciousness, and autonomic hyperactivity. Phobic spasms every other instance the therapy is supportive, whereas of the larynx, pharynx, neck muscles, and diaphragm can specific and effective antiviral therapy is available for be triggered by attempts to swallow water (hydrophobia) HSV, and its efficacy is enhanced when it is instituted or by inspiration (aerophobia). Patients may also present early in the course of infection. HSV encephalitis should with paralytic (dumb) rabies characterized by acute be considered when clinical features suggesting involve- ascending paralysis. Rabies due to the bite of a bat has a ment of the inferomedial frontotemporal regions of the different clinical presentation than classic rabies. Patients brain are present, including prominent olfactory or gus- present with focal neurologic deficits, myoclonus, tatory hallucinations, anosmia, unusual or bizarre behav- seizures, and hallucinations; phobic spasms are not a typ- ior or personality alterations, or memory disturbance. ical feature. Patients with rabies have a CSF lymphocytic HSV encephalitis should always be suspected in patients pleocytosis and may show areas of increased T2 signal with focal findings on clinical examination, neuroimag- abnormality in the brainstem, hippocampus, and hypo- ing studies, or EEG. The diagnostic procedure of choice thalamus. Diagnosis can be made by finding rabies virus in these patients is CSF PCR analysis for HSV. A positive antigen in brain tissue or in the neural innervation of CSF PCR establishes the diagnosis, and a negative test hair follicles at the nape of the neck. PCR amplification dramatically reduces the likelihood of HSV encephalitis of viral nucleic acid from CSF and saliva or tears may (see earlier). also enable diagnosis. Serology is frequently negative in both serum and CSF in the first week after onset of The anatomic distribution of lesions may provide infection, which limits its acute diagnostic utility. No an additional clue to diagnosis. Patients with specific therapy is available, and cases are almost invari- rapidly progressive encephalitis and prominent ably fatal, with isolated survivors having devastating brainstem signs, symptoms, or neuroimaging abnormalities neurologic sequelae. may be infected by flaviviruses (WNV, St. Louis encephali- tis virus, Japanese encephalitis virus), HSV, rabies, or L. State public health authorities provide a valuable resource monocytogenes. Significant involvement of deep gray mat- concerning isolation of particular agents in individual ter structures, including the basal ganglia and thalamus, regions. Regular updates concerning the number, type and should also suggest possible flavivirus infection. These distribution of cases of arboviral encephalitis can be found patients may present clinically with prominent movement on the CDC and U.S. Geological Survey (USGS) web disorders (tremor, myoclonus) or parkinsonian features. sites (http://www.cdc.gov and http://diseasemaps.usgs. gov). Patients with WNV infection can also present with a poliomyelitis-like acute flaccid paralysis, as can patients The major noninfectious etiologies that should be infected with enterovirus 71 and, less commonly, other included in the differential diagnosis of acute encephali- enteroviruses. Acute flaccid paralysis is characterized by tis are nonvasculitic autoimmune meningoencephalitis, the acute onset of a lower motor neuron type of which may or may not be associated with serum

SECTION III Diseases of the Central Nervous System470 antithyroid microsomal and antithyroglobulin antibod- followed by a repeat CSF PCR test. Neonatal HSV CNS ies; limbic encephalitis associated with antineuronal infection is less responsive to acyclovir therapy than antibodies; limbic encephalopathy not associated with HSV encephalitis in adults; it is recommended that cancer; acute disseminated encephalomyelitis and related neonates with HSV encephalitis receive 20 mg/kg of fulminant demyelinating disorders (Chap. 34); and lym- acyclovir every 8 h (60 mg/kg per day total dose) for a phoma. Finally, Creutzfeldt-Jakob disease (Chap. 38) can minimum of 21 days. rarely present in an explosive fashion mimicking viral encephalitis. Prior to intravenous administration, acyclovir should be diluted to a concentration ≤7 mg/mL. (A 70-kg per- Treatment: son would receive a dose of 700 mg, which would be VIRAL ENCEPHALITIS diluted in a volume of 100 mL.) Each dose should be infused slowly over 1 h rather than by rapid or bolus Specific antiviral therapy should be initiated when infusion, to minimize the risk of renal dysfunction. Care appropriate. Vital functions, including respiration and should be taken to avoid extravasation or intramuscu- blood pressure, should be monitored continuously and lar or subcutaneous administration. The alkaline pH of supported as required. In the initial stages of encephali- acyclovir can cause local inflammation and phlebitis tis, many patients will require care in an intensive care (9%). Dose adjustment is required in patients with unit. Basic management and supportive therapy should impaired renal glomerular filtration. Penetration into include careful monitoring of ICP, fluid restriction, avoid- CSF is excellent, with average drug levels ~50% of ance of hypotonic intravenous solutions, and suppres- serum levels. Complications of therapy include eleva- sion of fever. Seizures should be treated with standard tions in blood urea nitrogen and creatinine levels (5%), anticonvulsant regimens, and prophylactic therapy thrombocytopenia (6%), gastrointestinal toxicity (nau- should be considered in view of the high frequency of sea, vomiting, diarrhea) (7%), and neurotoxicity seizures in severe cases of encephalitis. As with all seri- (lethargy or obtundation, disorientation, confusion, agi- ously ill, immobilized patients with altered levels of con- tation, hallucinations, tremors, seizures) (1%). Acyclovir sciousness, encephalitis patients are at risk for aspiration resistance may be mediated by changes in either the pneumonia, stasis ulcers and decubiti, contractures, viral deoxypyrimidine kinase or DNA polymerase. To deep venous thrombosis and its complications, and date, acyclovir-resistant isolates have not been a signifi- infections of indwelling lines and catheters. cant clinical problem in immunocompetent individuals. However, there have been reports of clinically virulent Acyclovir is of benefit in the treatment of HSV and acyclovir-resistant HSV isolates from sites outside the should be started empirically in patients with suspected CNS in immunocompromised individuals, including viral encephalitis, especially if focal features are present, those with AIDS. while awaiting viral diagnostic studies. Treatment should be discontinued in patients found not to have HSV Oral antiviral drugs with efficacy against HSV, VZV, encephalitis, with the possible exception of patients with and EBV, including acyclovir, famciclovir, and valacy- severe encephalitis due to VZV or EBV. HSV, VZV, and EBV clovir, have not been evaluated in the treatment of all encode an enzyme, deoxypyrimidine (thymidine) encephalitis either as primary therapy or as supplemen- kinase, that phosphorylates acyclovir to produce tal therapy following completion of a course of par- acyclovir-5μ-monophosphate. Host cell enzymes then enteral acyclovir. A National Institute of Allergy and phosphorylate this compound to form a triphosphate Infectious Disease (NIAID)/National Institute of Neuro- derivative. It is the triphosphate that acts as an antiviral logical Disorders and Stroke–sponsored phase III trial of agent by inhibiting viral DNA polymerase and by causing supplemental oral valacyclovir therapy (2 g tid for premature termination of nascent viral DNA chains. The 3 months) following the initial 14- to 21-day course of specificity of action depends on the fact that uninfected therapy with parenteral acyclovir is ongoing in patients cells do not phosphorylate significant amounts of acy- with HSV encephalitis; this may help clarify the role of clovir to acyclovir-5μ-monophosphate. A second level of extended oral antiviral therapy. specificity is provided by the fact that the acyclovir triphosphate is a more potent inhibitor of viral DNA poly- Ganciclovir and foscarnet, either alone or in combi- merase than of the analogous host cell enzymes. nation, are often utilized in the treatment of CMV- related CNS infections, although their efficacy remains Adults should receive a dose of 10 mg/kg of acyclovir unproven. Cidofovir (see later) may provide an alterna- intravenously every 8 h (30 mg/kg per day total dose) tive in patients who fail to respond to ganciclovir and for a minimum of 14 days. CSF PCR can be repeated at foscarnet, although data concerning its use in CMV CNS the completion of the 14-day course, with PCR-positive infections is extremely limited. patients receiving an additional 7 days of treatment, Ganciclovir is a synthetic nucleoside analogue of 2μ-deoxyguanosine. The drug is preferentially phospho- rylated by virus-induced cellular kinases. Ganciclovir

triphosphate acts as a competitive inhibitor of the CMV on clinical response. Patients must be prehydrated with 471 DNA polymerase, and its incorporation into nascent normal saline (e.g., 1 L over 1–2 h) prior to each dose viral DNA results in premature chain termination. Fol- and treated with probenecid (e.g., 1 g 3 h before cido- CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema lowing intravenous administration, CSF concentrations fovir and 1 g 2 and 8 h after cidofovir). Nephrotoxicity is of ganciclovir are 25–70% of coincident plasma levels. common; the dose should be reduced if renal function The usual dose for treatment of severe neurologic ill- deteriorates. nesses is 5 mg/kg every 12 h given intravenously at a constant rate over 1 h. Induction therapy is followed by Intravenous ribavirin (15–25 mg/kg per day in maintenance therapy of 5 mg/kg every day for an indef- divided doses given every 8 h) has been reported to be inite period. Induction therapy should be continued of benefit in isolated cases of severe encephalitis due to until patients show a decline in CSF pleocytosis and a California encephalitis (LaCrosse) virus. Ribavirin might reduction in CSF CMV DNA copy number on quantita- be of benefit for the rare patients, typically infants or tive PCR testing (where available). Doses should be young children, with severe adenovirus or rotavirus adjusted in patients with renal insufficiency. Treatment encephalitis and in patients with encephalitis due to is often limited by the development of granulocytope- LCMV or other arenaviruses. However, clinical trials are nia and thrombocytopenia (20–25%), which may lacking. Hemolysis, with resulting anemia, has been the require reduction in or discontinuation of therapy. Gas- major side effect limiting therapy. trointestinal side effects, including nausea, vomiting, diarrhea, and abdominal pain, occur in ~20% of No specific antiviral therapy of proven efficacy is cur- patients. Some patients treated with ganciclovir for CMV rently available for treatment of WNV encephalitis. retinitis have developed retinal detachment, but the Patients have been treated with μ-interferon, ribavirin, causal relationship to ganciclovir treatment is unclear. WNV-specific antisense oligonucleotides, and an Israeli Valganciclovir is an orally bioavailable prodrug that can IVIg preparation that contains high-titer anti-WNV anti- generate high serum levels of ganciclovir, although body (Omr-IgG-am). WNV chimeric vaccines, in which studies of its efficacy in treating CMV CNS infections are WNV envelope and premembrane proteins are inserted limited. into the background of another flavivirus, are already undergoing human clinical testing for safety and Foscarnet is a pyrophosphate analogue that inhibits immunogenicity. Both chimeric and killed inactivated viral DNA polymerases by binding to the pyrophos- WNV vaccines have been found to be safe and effective phate-binding site. Following intravenous infusion, CSF in preventing equine WNV infection, and several effec- concentrations range from 15 to 100% of coincident tive flavivirus vaccines are already in human use, creat- plasma levels. The usual dose for serious CMV-related ing optimism that a safe and effective human WNV neurologic illness is 60 mg/kg every 8 h administered by vaccine can also be developed. constant infusion over 1 h. Induction therapy for 14–21 days is followed by maintenance therapy (60–120 SEQUELAE mg/kg per day). Induction therapy may need to be extended in patients who fail to show a decline in CSF There is considerable variation in the incidence and pleocytosis and a reduction in CSF CMV DNA copy num- severity of sequelae in patients surviving viral encephali- ber on quantitative PCR tests (where available). Approxi- tis. In the case of EEE virus infection, nearly 80% of sur- mately one-third of patients develop renal impairment vivors have severe neurologic sequelae. At the other during treatment, which is reversible following discon- extreme are infections due to EBV, California tinuation of therapy in most, but not all, cases. This is encephalitis virus, and Venezuelan equine encephalitis often associated with elevations in serum creatinine virus, where severe sequelae are unusual. For example, and proteinuria and is less frequent in patients who approximately 5–15% of children infected with are adequately hydrated. Many patients experience LaCrosse virus have a residual seizure disorder, and 1% fatigue and nausea. Reduction in serum calcium, mag- have persistent hemiparesis. Detailed information about nesium, and potassium occur in ~15% of patients and sequelae in patients with HSV encephalitis treated with may be associated with tetany, cardiac rhythm distur- acyclovir is available from the NIAID-CASG trials. Of bances, or seizures. 32 acyclovir-treated patients, 26 survived (81%). Of the 26 survivors, 12 (46%) had no or only minor sequelae, 3 Cidofovir is a nucleotide analogue that is effective in (12%) were moderately impaired (gainfully employed treating CMV retinitis and equivalent or better than but not functioning at their previous level), and 11 ganciclovir in some experimental models of murine (42%) were severely impaired (requiring continuous CMV encephalitis, although data concerning its efficacy supportive care). The incidence and severity of sequelae in human CMV CNS disease are limited. The usual dose were directly related to the age of the patient and the is 5 mg/kg intravenously once weekly for 2 weeks, then level of consciousness at the time of initiation of ther- biweekly for two or more additional doses, depending apy. Patients with severe neurologic impairment

SECTION III Diseases of the Central Nervous System472 (Glasgow coma score 6) at initiation of therapy either A localized pulmonary fungal infection can then remain died or survived with severe sequelae. Young patients dormant in the lungs until there is an abnormality in (<30 years) with good neurologic function at initiation cell-mediated immunity that allows the fungus to reacti- of therapy did substantially better (100% survival, 62% vate and disseminate to the CNS. The most common with no or mild sequelae) compared with their older pathogen causing fungal meningitis is C. neoformans.This counterparts (>30 years; 64% survival, 57% no or mild fungus is found worldwide in soil and bird excreta. H. sequelae). Some recent studies using quantitative HSV capsulatum is endemic to the Ohio and Mississippi River CSF PCR tests indicate that clinical outcome following valleys of the central United States and to parts of Cen- treatment also correlates with the amount of HSV DNA tral and South America. C. immitis is endemic to the present in CSF at the time of presentation. Many desert areas of the southwest United States, northern patients with WNV infection have acute sequelae, Mexico, and Argentina. including cognitive impairment; weakness; and hyper- or hypokinetic movement disorders, including tremor, Syphilis is a sexually transmitted disease that is mani- myoclonus, and parkinsonism. Improvement in these fest by the appearance of a painless chancre at the site of symptoms may occur over the subsequent 6–12 months, inoculation. T. pallidum invades the CNS early in the although detailed clinical studies of the duration and course of syphilis. Cranial nerves VII and VIII are most severity of WNV sequelae are not yet available. frequently involved. SUBACUTE MENINGITIS LABORATORY DIAGNOSIS CLINICAL MANIFESTATIONS The classic CSF abnormalities in tuberculous meningitis are as follows: (1) elevated opening pressure, (2) lympho- Patients with subacute meningitis typically have an cytic pleocytosis (10–500 cells/μL), (3) elevated protein unrelenting headache, stiff neck, low-grade fever, and concentration in the range of 1–5 g/L (10–500 mg/dL), lethargy for days to several weeks before they present for and (4) decreased glucose concentration in the range of evaluation. Cranial nerve abnormalities and night sweats 1.1–2.2 mmol/L (20–40 mg/dL). The combination of unre- may be present. This syndrome overlaps that of chronic lenting headache, stiff neck, fatigue, night sweats, and fever with meningitis, discussed in detail in Chap. 36. a CSF lymphocytic pleocytosis and a mildly decreased glucose concentration is highly suspicious for tuberculous meningitis. ETIOLOGY The last tube of fluid collected at LP is the best tube to send for a smear for acid-fast bacilli (AFB). If there is a Common causative organisms include M. tuberculosis, C. pellicle in the CSF or a cobweb-like clot on the surface neoformans, H. capsulatum, C. immitis, and T. pallidum. of the fluid, AFB can best be demonstrated in a smear of Initial infection with M. tuberculosis is acquired by inhala- the clot or pellicle. Positive smears are typically reported tion of aerosolized droplet nuclei.Tuberculous meningitis in only 10–40% of cases of tuberculous meningitis in in adults does not develop acutely from hematogenous adults. Cultures of CSF take 4–8 weeks to identify the spread of tubercle bacilli to the meninges. Rather, millet organism and are positive in ~50% of adults. Culture seed–size (miliary) tubercles form in the parenchyma of remains the “gold standard” to make the diagnosis of the brain during hematogenous dissemination of tuber- tuberculous meningitis. PCR for the detection of cle bacilli in the course of primary infection. These M. tuberculosis DNA has a sensitivity of 70–80% but is tubercles enlarge and are usually caseating. The propen- limited at the present time by a high rate of false-posi- sity for a caseous lesion to produce meningitis is deter- tive results. mined by its proximity to the subarachnoid space (SAS) and the rate at which fibrous encapsulation develops. The characteristic CSF abnormalities in fungal Subependymal caseous foci cause meningitis via dis- meningitis are a mononuclear or lymphocytic pleocyto- charge of bacilli and tuberculous antigens into the SAS. sis, an increased protein concentration, and a decreased Mycobacterial antigens produce an intense inflamma- glucose concentration. There may be eosinophils in the tory reaction that leads to the production of a thick CSF in C. immitis meningitis. Large volumes of CSF are exudate that fills the basilar cisterns and surrounds the often required to demonstrate the organism on India ink cranial nerves and major blood vessels at the base of the smear or grow the organism in culture. If spinal fluid brain. examined by LP on two separate occasions fails to yield an organism, CSF should be obtained by high-cervical Fungal infections are typically acquired by the or cisternal puncture. inhalation of airborne fungal spores. The initial pulmonary infection may be asymptomatic or The cryptococcal polysaccharide antigen test is a present with fever, cough, sputum production, and chest highly sensitive and specific test for cryptococcal menin- pain. The pulmonary infection is often self-limited. gitis. A reactive CSF cryptococcal antigen test establishes the diagnosis. The detection of the histoplasma polysac- charide antigen in CSF establishes the diagnosis of a

fungal meningitis but is not specific for meningitis due monotherapy or intravenous amphotericin B (0.5–0.7 473 to H. capsulatum. It may be falsely positive in coccid- mg/kg per day) for >4 weeks. Intrathecal amphotericin B ioidal meningitis. The CSF complement fixation anti- (0.25–0.75 mg/d three times weekly) may be required to CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema body test is reported to have a specificity of 100% and a eradicate the infection. Lifelong therapy with flucona- sensitivity of 75% for coccidioidal meningitis. zole (200–400 mg daily) is recommended to prevent relapse. AmBisome (5 mg/kg per day) or amphotericin B The diagnosis of syphilitic meningitis is made when a lipid complex (5 mg/kg per day) can be substituted for reactive serum treponemal test [fluorescent treponemal amphotericin B in patients who have or who develop antibody absorption test (FTA-ABS) or microhemag- significant renal dysfunction. The most common com- glutination-T. pallidum (MHA-TP)] is associated with a plication of fungal meningitis is hydrocephalus. Patients CSF lymphocytic or mononuclear pleocytosis and an who develop hydrocephalus should receive a CSF diver- elevated protein concentration, or when the CSF VDRL sion device. A ventriculostomy can be used until CSF (Venereal Disease Research Laboratory) is positive. A fungal cultures are sterile, at which time the ventricu- reactive CSF FTA-ABS is not definitive evidence of lostomy is replaced by a ventriculoperitoneal shunt. neurosyphilis.The CSF FTA-ABS can be falsely positive from blood contamination. A negative CSF VDRL does Syphilitic meningitis is treated with aqueous peni- not rule out neurosyphilis. A negative CSF FTA-ABS or cillin G in a dose of 3–4 million units intravenously MHA-TP rules out neurosyphilis. every 4 h for 10–14 days. An alternative regimen is 2.4 million units of procaine penicillin G intramuscu- Treatment: larly daily with 500 mg of oral probenecid four times SUBACUTE MENINGITIS daily for 10–14 days. Either regimen is followed with 2.4 million units of benzathine penicillin G intramuscu- Empirical therapy of tuberculous meningitis is often ini- larly once a week for 3 weeks. The standard criterion for tiated on the basis of a high index of suspicion without treatment success is reexamination of the CSF. The adequate laboratory support. Initial therapy is a combi- CSF should be reexamined at 6-month intervals for nation of isoniazid (300 mg/d), rifampin (10 mg/kg per 2 years. The cell count is expected to normalize within day), pyrazinamide (30 mg/kg per day in divided doses), 12 months, and the VDRL titer to decrease by two dilu- ethambutol (15–25 mg/kg per day in divided doses), tions or revert to nonreactive within 2 years of comple- and pyridoxine (50 mg/d). If the clinical response is tion of therapy. Failure of the CSF pleocytosis to resolve good, pyrazinamide and ethambutol can be discontin- or an increase in the CSF VDRL titer by two or more ued after 8 weeks and isoniazid and rifampin continued dilutions requires retreatment. alone for the next 6–12 months. A 6-month course of therapy is acceptable, but therapy should be prolonged CHRONIC ENCEPHALITIS for 9–12 months in patients who have an inadequate resolution of symptoms of meningitis or who have posi- PROGRESSIVE MULTIFOCAL tive mycobacterial cultures of CSF during the course of LEUKOENCEPHALOPATHY therapy. Dexamethasone therapy is recommended for patients who develop hydrocephalus. Clinical Features and Pathology Meningitis due to C. neoformans is treated with Progressive multifocal leukoencephalopathy (PML) is a amphotericin B (0.7 mg/kg IV per day) or AmBisome progressive disorder characterized pathologically by (5 mg/kg per day), plus flucytosine (100 mg/kg per day multifocal areas of demyelination of varying size distrib- in four divided doses) for 2 weeks or until CSF culture is uted throughout the brain but sparing the spinal cord sterile. This treatment is followed by an 8–10-week and optic nerves. In addition to demyelination, there are course of fluconazole (400–800 mg/d PO). If the CSF cul- characteristic cytologic alterations in both astrocytes and ture is sterile after 10 weeks of acute therapy, the dose oligodendrocytes. Astrocytes are enlarged and contain of fluconazole is decreased to 200 mg/d for 6 months to hyperchromatic, deformed, and bizarre nuclei and fre- a year. Patients with HIV infection may require indefinite quent mitotic figures. Oligodendrocytes have enlarged, maintenance therapy. Meningitis due to H. capsulatum is densely staining nuclei that contain viral inclusions treated with amphotericin B (0.7–1.0 mg/kg per day) for formed by crystalline arrays of JC virus (JCV) particles. 4–12 weeks. A total dose of 30 mg/kg is recommended. Patients often present with visual deficits (45%), typically Therapy with amphotericin B is not discontinued until a homonymous hemianopia; mental impairment (38%) fungal cultures are sterile. After completing a course of (dementia, confusion, personality change); weakness, amphotericin B, maintenance therapy with itraconazole including hemi- or monoparesis; and ataxia. Seizures 200 mg twice daily is initiated and continued for at least occur in ~20% of patients, predominantly in those with 6 months to a year. C. immitis meningitis is treated with lesions abutting the cortex. either high-dose fluconazole (1000 mg daily) as

SECTION III Diseases of the Central Nervous System474 Almost all patients have an underlying immunosup- changes, since both antigen and genomic material have pressive disorder. In recent series, the most common asso- been found in the brains of normal patients. ciated conditions were AIDS (80%), hematologic malig- nancies (13%), transplant recipients (5%), and chronic Serologic studies are of no utility in diagnosis due to inflammatory diseases (2%). It has been estimated that up high basal seroprevalence level (>80%). to 5% of AIDS patients will develop PML. There have been nearly 2 dozen cases of PML occurring in patients Treatment: being treated for multiple sclerosis and inflammatory PROGRESSIVE MULTIFOCAL LEUKOEN- bowel disease with natalizumab, a humanized mono- CEPHALOPATHY clonal antibody that inhibits lymphocyte trafficking into CNS and bowel mucosa by binding to α4 integrins. Risk No effective therapy for PML is available. Intravenous in these patients has been estimated at 1 PML case per and/or intrathecal cytarabine were not shown to be 1000 treated patients after a mean of 18 months of ther- of benefit in a randomized controlled trial in HIV- apy. The basic clinical and diagnostic features are similar associated PML. Another randomized controlled trial of in AIDS and non-AIDS–associated PML. cidofovir in HIV-associated PML also failed to show sig- nificant benefit. Some patients with HIV-associated PML Diagnostic Studies have shown disease stabilization and, in rare cases, improvement associated with improvement in their The diagnosis of PML is frequently suggested by MRI. immune status following institution of HAART. In HIV- MRI reveals multifocal asymmetric, coalescing white positive patients treated with HAART, 1-year survival is matter lesions located periventricularly, in the centrum ~50%, although up to 80% of survivors may have signifi- semiovale, in the parietal-occipital region, and in the cant neurologic sequelae. HIV-positive patients with cerebellum.These lesions have increased signal on T2 and higher CD4 counts (>300 mm3) and low or nonde- FLAIR images and decreased signal on T1-weighted tectable HIV viral loads have a better prognosis than images. PML lesions are classically nonenhancing (90%) those with lower CD4 counts and higher viral loads. but may rarely show ring enhancement, especially in more immunocompetent patients. PML lesions are not SUBACUTE SCLEROSING typically associated with edema or mass effect. CT scans, PANENCEPHALITIS (SSPE) which are less sensitive than MRI for the diagnosis of PML, often show hypodense nonenhancing white mat- SSPE is a rare chronic, progressive demyelinating disease ter lesions. of the CNS associated with a chronic nonpermissive infection of brain tissue with measles virus. The fre- The CSF is typically normal, although mild elevation quency has been estimated at 1 in 100,000–500,000 in protein and/or IgG may be found. Pleocytosis occurs measles cases. An average of five cases per year are in <25% of cases, is predominantly mononuclear, and reported in the United States. The incidence has rarely exceeds 25 cells/μL. PCR amplification of JCV declined dramatically since the introduction of a measles DNA from CSF has become an important diagnostic vaccine. Most patients give a history of primary measles tool. The presence of a positive CSF PCR for JCV infection at an early age (2 years), which is followed DNA in association with typical MRI lesions in the after a latent interval of 6–8 years by the development of appropriate clinical setting is diagnostic of PML, reflect- progressive neurologic disorder. Some 85% of patients ing the assay’s relatively high specificity (92–100%); are between 5 and 15 years of age at diagnosis. Initial however, sensitivity is variable. In HIV-negative patients manifestations include poor school performance and and HIV-positive patients not receiving highly active mood and personality changes. Typical signs of a CNS antiviral therapy (HAART), sensitivity is likely 70–90%. viral infection, including fever and headache, do not In HAART-treated patients, sensitivity may be closer to occur. As the disease progresses, patients develop pro- 60%, reflecting the lower JCV CSF viral load in this rel- gressive intellectual deterioration, focal and/or general- atively more immunocompetent group. Studies with ized seizures, myoclonus, ataxia, and visual disturbances. quantitative JCV CSF PCR indicate that patients with In the late stage of the illness, patients are unresponsive, low JCV loads (<100 copies/μL) have a generally better quadriparetic, and spastic, with hyperactive tendon prognosis than those with higher viral loads. Patients reflexes and extensor plantar responses. with negative CSF PCR studies may require brain biopsy for definitive diagnosis. In biopsy or necropsy Diagnostic Studies specimens of brain, JCV antigen and nucleic acid can be detected by immunocytochemistry, in situ hybridization, MRI is often normal early, although areas of increased T2 or PCR amplification. Detection of JCV antigen or signal develop in the white matter of the brain and brain- genomic material should only be considered diagnostic stem as disease progresses. The EEG may initially show of PML if accompanied by characteristic pathologic

only nonspecific slowing, but with disease progression, ~0.3–1.3/100,000 persons per year. Predisposing condi- 475 CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema patients develop a characteristic periodic pattern with tions include otitis media and mastoiditis, paranasal bursts of high-voltage, sharp, slow waves every 3–8 s, fol- sinusitis, pyogenic infections in the chest or other body lowed by periods of attenuated (“flat”) background. The sites, penetrating head trauma or neurosurgical proce- CSF is acellular with a normal or mildly elevated protein dures, and dental infections. In immunocompetent indi- concentration and a markedly elevated gamma globulin viduals the most important pathogens are Streptococcus level (>20% of total CSF protein). CSF antimeasles anti- spp. [anaerobic, aerobic, and viridans (40%)], Enterobac- body levels are invariably elevated, and oligoclonal teriaceae [Proteus spp., E. coli sp., Klebsiella spp. (25%)], antimeasles antibodies are often present. Measles virus can anaerobes [e.g., Bacteroides spp., Fusobacterium spp. (30%)], be cultured from brain tissue using special cocultivation and staphylococci (10%). In immunocompromised hosts techniques.Viral antigen can be identified immunocyto- with underlying HIV infection, organ transplantation, chemically, and viral genome can be detected by in situ cancer, or immunosuppressive therapy, most brain hybridization or PCR amplification. abscesses are caused by Nocardia spp., Toxoplasma gondii, Aspergillus spp., Candida spp., and C. neoformans. In Latin Treatment: America and in immigrants from Latin America, the SUBACUTE SCLEROSING most common cause of brain abscess is Taenia solium PANENCEPHALITIS (neurocysticercosis). In India and the Far East, mycobac- No definitive therapy for SSPE is available. Treatment terial infection (tuberculoma) remains a major cause of with isoprinosine (Inosiplex, 100 mg/kg per day), alone focal CNS mass lesions. or in combination with intrathecal or intraventricular alpha interferon, has been reported to prolong survival ETIOLOGY and produce clinical improvement in some patients but has never been subjected to a controlled clinical trial. A brain abscess may develop (1) by direct spread from a contiguous cranial site of infection, such as paranasal PROGRESSIVE RUBELLA sinusitis, otitis media, mastoiditis, or dental infection; (2) PANENCEPHALITIS following head trauma or a neurosurgical procedure; or (3) as a result of hematogenous spread from a remote This is an extremely rare disorder that primarily affects site of infection. In up to 25% of cases, no obvious pri- males with congenital rubella syndrome, although isolated mary source of infection is apparent (cryptogenic brain cases have been reported following childhood rubella.After abscess). a latent period of 8–19 years, patients develop progressive neurologic deterioration. The manifestations are similar to Approximately one-third of brain abscesses are associ- those seen in SSPE. CSF shows a mild lymphocytic pleo- ated with otitis media and mastoiditis, often with an cytosis, slightly elevated protein concentration, markedly associated cholesteatoma. Otogenic abscesses occur pre- increased gamma globulin, and rubella virus–specific oligo- dominantly in the temporal lobe (55–75%) and cerebel- clonal bands. No therapy is available. Universal prevention lum (20–30%). In some series, up to 90% of cerebellar of both congenital and childhood rubella through the use abscesses are otogenic. Common organisms include strep- of the available live attenuated rubella vaccine would be tococci, Bacteroides spp., Pseudomonas spp., Haemophilus expected to eliminate the disease. spp., and Enterobacteriaceae. Abscesses that develop as a result of direct spread of infection from the frontal, eth- BRAIN ABSCESS moidal, or sphenoidal sinuses and those that occur due to dental infections are usually located in the frontal DEFINITION lobes. Approximately 10% of brain abscesses are associ- ated with paranasal sinusitis, and this association is par- A brain abscess is a focal, suppurative infection within ticularly strong in young males in their second and third the brain parenchyma, typically surrounded by a vascu- decades of life. The most common pathogens in brain larized capsule. The term cerebritis is often employed to abscesses associated with paranasal sinusitis are strepto- describe a nonencapsulated brain abscess. cocci (especially S. milleri), Haemophilus spp., Bacteroides spp., Pseudomonas spp., and S. aureus. Dental infections EPIDEMIOLOGY are associated with ~2% of brain abscesses, although it is often suggested that many “cryptogenic” abscesses are in A bacterial brain abscess is a relatively uncom- fact due to dental infections. The most common mon intracranial infection, with an incidence of pathogens in this setting are streptococci, staphylococci, Bacteroides spp., and Fusobacterium spp. Hematogenous abscesses account for ~25% of brain abscesses. Hematogenous abscesses are often multiple, and multiple abscesses often (50%) have a hematogenous

SECTION III Diseases of the Central Nervous System476 origin.These abscesses show a predilection for the terri- with the appearance of a ring-enhancing capsule on neu- tory of the middle cerebral artery (i.e., posterior frontal roimaging studies. The final stage, late capsule formation or parietal lobes). Hematogenous abscesses are often (day 14 and beyond), is defined by a well-formed necrotic located at the junction of the gray and white matter and center surrounded by a dense collagenous capsule. The are often poorly encapsulated. The microbiology of surrounding area of cerebral edema has regressed, but hematogenous abscesses is dependent on the primary marked gliosis with large numbers of reactive astrocytes source of infection. For example, brain abscesses that has developed outside the capsule. This gliotic process develop as a complication of infective endocarditis are may contribute to the development of seizures as a seque- often due to viridans streptococci or S. aureus. Abscesses lae of brain abscess. associated with pyogenic lung infections such as lung abscess or bronchiectasis are often due to streptococci, CLINICAL PRESENTATION staphylococci, Bacteroides spp., Fusobacterium spp., or Enterobacteriaceae.Abscesses that follow penetrating head A brain abscess typically presents as an expanding trauma or neurosurgical procedures are frequently due to intracranial mass lesion rather than as an infectious methicillin-resistant S. aureus (MRSA), S. epidermidis, process. Although the evolution of signs and symptoms Enterobacteriaceae, Pseudomonas spp., and Clostridium is extremely variable, ranging from hours to weeks or spp. Enterobacteriaceae and P. aeruginosa are important even months, most patients present to the hospital causes of abscesses associated with urinary sepsis. Con- 11–12 days following onset of symptoms. The classic genital cardiac malformations that produce a right-to- clinical triad of headache, fever, and a focal neurologic left shunt, such as tetralogy of Fallot, patent ductus arte- deficit is present in <50% of cases. The most common riosus, and atrial and ventricular septal defects, allow symptom in patients with a brain abscess is headache, bloodborne bacteria to bypass the pulmonary capillary occurring in >75% of patients. The headache is often bed and reach the brain. Similar phenomena can occur characterized as a constant, dull, aching sensation, either with pulmonary arteriovenous malformations. The hemicranial or generalized, and it becomes progressively decreased arterial oxygenation and saturation from the more severe and refractory to therapy. Fever is present in right-to-left shunt and polycythemia may cause focal only 50% of patients at the time of diagnosis, and its areas of cerebral ischemia, thus providing a nidus for absence should not exclude the diagnosis. The new microorganisms that bypassed the pulmonary circulation onset of focal or generalized seizure activity is a present- to multiply and form an abscess. Streptococci are the ing sign in 15–35% of patients. Focal neurologic deficits most common pathogens in this setting. including hemiparesis, aphasia, or visual field defects are part of the initial presentation in >60% of patients. PATHOGENESIS AND HISTOPATHOLOGY The clinical presentation of a brain abscess depends Results of experimental models of brain abscess forma- on its location, the nature of the primary infection if tion suggest that for bacterial invasion of brain present, and the level of the ICP. Hemiparesis is the most parenchyma to occur, there must be preexisting or con- common localizing sign of a frontal lobe abscess. A tem- comitant areas of ischemia, necrosis, or hypoxia in brain poral lobe abscess may present with a disturbance of tissue.The intact brain parenchyma is relatively resistant to language (dysphasia) or an upper homonymous quad- infection. Once bacteria have established infection, brain rantanopia. Nystagmus and ataxia are signs of a cerebel- abscess frequently evolves through a series of stages, influ- lar abscess. Signs of raised ICP—papilledema, nausea and enced by the nature of the infecting organism and by the vomiting, and drowsiness or confusion—can be the immunocompetence of the host.The early cerebritis stage dominant presentation of some abscesses, particularly (days 1–3) is characterized by a perivascular infiltration of those in the cerebellum. Meningismus is not present inflammatory cells, which surround a central core of unless the abscess has ruptured into the ventricle or the coagulative necrosis. Marked edema surrounds the lesion infection has spread to the subarachnoid space. at this stage. In the late cerebritis stage (days 4–9), pus for- mation leads to enlargement of the necrotic center, which DIAGNOSIS is surrounded at its border by an inflammatory infiltrate of macrophages and fibroblasts. A thin capsule of fibrob- Diagnosis is made by neuroimaging studies. MRI lasts and reticular fibers gradually develops, and the sur- (Fig. 35-4) is better than CT for demonstrating rounding area of cerebral edema becomes more distinct abscesses in the early (cerebritis) stages and is superior than in the previous stage. The third stage, early capsule to CT for identifying abscesses in the posterior fossa. formation (days 10–13), is characterized by the formation Cerebritis appears on MRI as an area of low-signal of a capsule that is better developed on the cortical than intensity on T1-weighted images with irregular post- on the ventricular side of the lesion. This stage correlates gadolinium enhancement and as an area of increased signal intensity on T2-weighted images. Cerebritis is

477 AB C CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema FIGURE 35-4 gadolinium administration on the coronal T1-weighted image Pneumococcal brain abscess. Note that the abscess wall (C). The abscess is surrounded by a large amount of vaso- has hyperintense signal on the axial T1-weighted MRI genic edema and has a small “daughter” abscess (C, white (A, black arrow), hypointense signal on the axial proton den- arrow). (Courtesy of Joseph Lurito, MD; with permission.) sity images (B, black arrow), and enhances prominently after often not visualized by CT scan but, when present, of cases overall but may be positive in >85% of patients appears as an area of hypodensity. On a contrast- with abscesses due to Listeria. enhanced CT scan, a mature brain abscess appears as a focal area of hypodensity surrounded by ring enhance- DIFFERENTIAL DIAGNOSIS ment with surrounding edema (hypodensity). On con- trast-enhanced T1-weighted MRI, a mature brain Conditions that can cause headache, fever, focal neuro- abscess has a capsule that enhances surrounding a logic signs, and seizure activity include brain abscess, hypodense center and surrounded by a hypodense area subdural empyema, bacterial meningitis, viral menin- of edema. On T2-weighted MRI, there is a hyperin- goencephalitis, superior sagittal sinus thrombosis, and tense central area of pus surrounded by a well-defined acute disseminated encephalomyelitis.When fever is absent, hypointense capsule and a hyperintense surrounding primary and metastatic brain tumors become the major area of edema. It is important to recognize that the CT differential diagnosis. Less commonly, cerebral infarction and MR appearance, particularly of the capsule, may be or hematoma can have an MRI or CT appearance altered by treatment with glucocorticoids. The distinc- resembling brain abscess. tion between a brain abscess and other focal CNS lesions such as primary or metastatic tumors may be Treatment: facilitated by the use of diffusion-weighted imaging BRAIN ABSCESS sequences on which brain abscesses typically show increased signal and low apparent diffusion coefficient. Optimal therapy of brain abscesses involves a combina- tion of high-dose parenteral antibiotics and neurosurgi- Microbiologic diagnosis of the etiologic agent is most cal drainage. Empirical therapy of community-acquired accurately determined by Gram’s stain and culture of brain abscess in an immunocompetent patient typically abscess material obtained by stereotactic needle aspira- includes a third-generation cephalosporin (e.g., cefo- tion. Aerobic and anaerobic bacterial cultures and taxime or ceftriaxone) and metronidazole (see Table 35-1 mycobacterial and fungal cultures should be obtained. for antibiotic dosages). In patients with penetrating Up to 10% of patients will also have positive blood cul- head trauma or recent neurosurgical procedures, treat- tures. LP should not be performed in patients with ment should include ceftazidime as the third-generation known or suspected focal intracranial infections such as cephalosporin to enhance coverage of Pseudomonas abscess or empyema; CSF analysis contributes nothing spp. and vancomycin for coverage of staphylococci. to diagnosis or therapy, and LP increases the risk of Meropenem plus vancomycin also provides good cov- herniation. erage in this setting. Additional laboratory studies may provide clues to Aspiration and drainage of the abscess under stereo- the diagnosis of brain abscess in patients with a CNS tactic guidance are beneficial for both diagnosis and mass lesion. About 50% of patients have a peripheral leukocytosis, 60% an elevated ESR, and 80% an elevated C-reactive protein. Blood cultures are positive in ~10%

SECTION III Diseases of the Central Nervous System478 therapy. Empirical antibiotic coverage should be modi- NONBACTERIAL CAUSES OF INFECTIOUS FOCAL CNS LESIONS fied based on the results of Gram’s stain and culture of the abscess contents. Complete excision of a bacterial ETIOLOGY abscess via craniotomy or craniectomy is generally reserved for multiloculated abscesses or those in which Neurocysticercosis is the most common parasitic disease stereotactic aspiration is unsuccessful. of the CNS worldwide. Humans acquire cysticercosis by the ingestion of food contaminated with the eggs of the Medical therapy alone is not optimal for treatment of parasite T. solium. Toxoplasmosis is a parasitic disease brain abscess and should be reserved for patients caused by T. gondii and acquired from the ingestion of whose abscesses are neurosurgically inaccessible, for undercooked meat and from handling cat feces. patients with small (<2–3 cm) or nonencapsulated abscesses (cerebritis), and patients whose condition is CLINICAL PRESENTATION too tenuous to allow performance of a neurosurgical procedure. All patients should receive a minimum of The most common manifestation of neurocysticercosis 6–8 weeks of parenteral antibiotic therapy. The role, if is new-onset partial seizures with or without secondary any, of supplemental oral antibiotic therapy following generalization. Cysticerci may develop in the brain completion of a standard course of parenteral therapy parenchyma and cause seizures or focal neurologic has never been adequately studied. deficits.When present in the subarachnoid or ventricular spaces, cysticerci can produce increased ICP by interfer- In addition to surgical drainage and antibiotic therapy, ence with CSF flow. Spinal cysticerci can mimic the patients should receive prophylactic anticonvulsant ther- presentation of intraspinal tumors. When the cysticerci apy because of the high risk (~35%) of focal or generalized first lodge in the brain, they frequently cause little in the seizures. Anticonvulsant therapy is continued for at least 3 way of an inflammatory response. As the cysticercal cyst months after resolution of the abscess, and decisions degenerates, it elicits an inflammatory response that may regarding withdrawal are then based on the EEG. If the EEG present clinically as a seizure. Eventually the cyst dies, a is abnormal, anticonvulsant therapy should be continued. If process that may take several years and is typically asso- the EEG is normal, anticonvulsant therapy can be slowly ciated with resolution of the inflammatory response withdrawn, with close follow-up and repeat EEG after the and, often, abatement of seizures. medication has been discontinued. Primary toxoplasma infection is often asymptomatic. Glucocorticoids should not be given routinely to However, during this phase parasites may spread to the patients with brain abscesses. Intravenous dexametha- CNS, where they become latent. Reactivation of CNS sone therapy (10 mg every 6 h) is usually reserved for infection is almost exclusively associated with immuno- patients with substantial periabscess edema and asso- compromised hosts, particularly those with HIV infec- ciated mass effect and increased ICP. Dexamethasone tion. During this phase patients present with headache, should be tapered as rapidly as possible to avoid fever, seizures, and focal neurologic deficits. delaying the natural process of encapsulation of the abscess. DIAGNOSIS Serial MRI or CT scans should be obtained on a The lesions of neurocysticercosis are readily visualized monthly or twice-monthly basis to document resolution by MRI or CT scans. Lesions with viable parasites of the abscess. More frequent studies (e.g., weekly) are appear as cystic lesions. The scolex can often be visu- probably warranted in the subset of patients who are alized on MRI. Lesions may appear as contrast- receiving antibiotic therapy alone. A small amount of enhancing lesions surrounded by edema. A very early enhancement may remain for months after the abscess sign of cyst death is hypointensity of the vesicular has been successfully treated. fluid on T2-weighted images when compared with CSF. Parenchymal brain calcifications are the most PROGNOSIS common finding and evidence that the parasite is no longer viable. MRI findings of toxoplasmosis consist The mortality of brain abscess has declined in parallel of multiple lesions in the deep white matter, the thala- with the development of enhanced neuroimaging tech- mus, and basal ganglia and at the gray-white junction niques, improved neurosurgical procedures for stereotac- in the cerebral hemispheres. With contrast administra- tic aspiration, and improved antibiotics. In modern tion, the majority of the lesions enhance in a ringed, series, the mortality is typically <15%. Significant seque- nodular, or homogeneous pattern and are surrounded lae, including seizures, persisting weakness, aphasia, or by edema. In the presence of the characteristic mental impairment, occur in Ն20% of survivors.

neuroimaging abnormalities of T. gondii infection, Subdural 479 serum IgG antibody to T. gondii should be obtained empyema and, when positive, the patient should be treated. Thrombosed Treatment: veins INFECTIOUS FOCAL CNS LESIONS Anticonvulsant therapy is initiated when the patient with Dura mater neurocysticercosis presents with a seizure. There is con- troversy about whether or not antihelminthic therapy Arachnoid should be given to all patients. Such therapy does not necessarily reduce the risk of seizure recurrence. Cys- FIGURE 35-5 CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema ticerci appearing as cystic lesions or as enhancing lesions Subdural empyema. in the brain parenchyma or in the subarachnoid space at the convexity of the cerebral hemispheres should be predisposing condition and typically involves the frontal treated with anticysticidal therapy. Cysticidal drugs sinuses, either alone or in combination with the eth- accelerate the destruction of the parasites, resulting in a moid and maxillary sinuses. Sinusitis-associated empyema faster resolution of the infection. Albendazole and prazi- has a striking predilection for young men, possibly quantel are used in the treatment of neurocysticercosis. reflecting sex-related differences in sinus anatomy and Approximately 85% of parenchymal cysts are destroyed development. It has been suggested that SDE may com- by a single course of albendazole, and ~75% are plicate 1–2% of cases of frontal sinusitis severe enough to destroyed by a single course of praziquantel. The dose of require hospitalization. As a consequence of this epi- albendazole is 15 mg/kg per day in two doses for 8 days. demiology, SDE shows an ~3:1 male:female predomi- The dose of praziquantel is 50 mg/kg per day for 15 days, nance, with 70% of cases occurring in the second and although a number of other dosage regimens are also third decades of life. SDE may also develop as a compli- frequently cited. Antiepileptic therapy can be stopped cation of head trauma or neurosurgery. Secondary infec- once the follow-up CT scan shows resolution of the tion of a subdural effusion may also result in empyema, lesion. Long-term antiepileptic therapy is recommended although secondary infection of hematomas, in the when seizures occur after resolution of edema and absence of a prior neurosurgical procedure, is rare. resorption or calcification of the degenerating cyst. CNS toxoplasmosis is treated with a combination of ETIOLOGY sulfadiazine, 1.5–2.0 g orally qid, plus pyrimethamine, 100 mg orally to load then 75–100 mg orally qd, plus Aerobic and anaerobic streptococci, staphylococci, folinic acid, 10–15 mg orally qd. Folinic acid is added to Enterobacteriaceae, and anaerobic bacteria are the most the regimen to prevent megaloblastic anemia.Therapy is common causative organisms of sinusitis-associated continued until there is no evidence of active disease on SDE. Staphylococci and gram-negative bacilli are often neuroimaging studies, which typically takes at least the etiologic organisms when SDE follows neurosurgi- 6 weeks, and then the dose of sulfadiazine is reduced to cal procedures or head trauma. Up to one-third of cases 2–4 g/d and pyrimethamine to 50 mg/d. Clindamycin are culture-negative, possibly reflecting difficulty in plus pyrimethamine is an alternative therapy for patients obtaining adequate anaerobic cultures. who cannot tolerate sulfadiazine, but the combination of pyrimethamine and sulfadiazine is more effective. PATHOPHYSIOLOGY SUBDURAL EMPYEMA Sinusitis-associated SDE develops as a result of either retro- grade spread of infection from septic thrombophlebitis of A subdural empyema (SDE) is a collection of pus between the dura and arachnoid membranes (Fig. 35-5). EPIDEMIOLOGY SDE is a rare disorder that accounts for 15–25% of focal suppurative CNS infections. Sinusitis is the most common

SECTION III Diseases of the Central Nervous System480 the mucosal veins draining the sinuses or contiguous spread infarction (see earlier). In untreated SDE, the increasing of infection to the brain from osteomyelitis in the posterior mass effect and increase in ICP cause progressive deterio- wall of the frontal or other sinuses. SDE may also develop ration in consciousness, leading ultimately to coma. from direct introduction of bacteria into the subdural space as a complication of a neurosurgical procedure.The evolu- DIAGNOSIS tion of SDE can be extremely rapid because the subdural space is a large compartment that offers few mechanical MRI (Fig. 35-6) is superior to CT in identifying SDE barriers to the spread of infection. In patients with sinusitis- and any associated intracranial infections.The administra- associated SDE, suppuration typically begins in the upper tion of gadolinium greatly improves diagnosis by and anterior portions of one cerebral hemisphere and then enhancing the rim of the empyema and allowing the extends posteriorly. SDE is often associated with other empyema to be clearly delineated from the underlying intracranial infections, including epidural empyema (40%), brain parenchyma. Cranial MRI is also extremely valu- cortical thrombophlebitis (35%), and intracranial abscess or able in identifying sinusitis, other focal CNS infections, cerebritis (>25%). Cortical venous infarction produces cortical venous infarction, cerebral edema, and cerebritis. necrosis of underlying cerebral cortex and subcortical white CT may show a crescent-shaped hypodense lesion over matter, with focal neurologic deficits and seizures (see later). one or both hemispheres or in the interhemispheric fis- sure. Frequently the degree of mass effect, exemplified by CLINICAL PRESENTATION midline shift, ventricular compression, and sulcal efface- ment, is far out of proportion to the mass of the SDE. A patient with SDE typically presents with fever and a progressively worsening headache. The diagnosis of SDE CSF examination should be avoided in patients with should always be suspected in a patient with known known or suspected SDE as it adds no useful informa- sinusitis who presents with new CNS signs or symptoms. tion and is associated with the risk of cerebral herniation. Patients with underlying sinusitis frequently have symp- toms related to this infection. As the infection progresses, DIFFERENTIAL DIAGNOSIS focal neurologic deficits, seizures, nuchal rigidity, and signs of increased ICP commonly occur. Headache is the The differential diagnosis of the combination of most common complaint at the time of presentation; ini- headache, fever, focal neurologic signs, and seizure activity tially it is localized to the side of the subdural infection, that progresses rapidly to an altered level of consciousness but then it becomes more severe and generalized. Con- includes subdural hematoma, bacterial meningitis, viral tralateral hemiparesis or hemiplegia is the most common encephalitis, brain abscess, superior sagittal sinus thrombo- focal neurologic deficit and can occur from the direct sis, and acute disseminated encephalomyelitis. The pres- effects of the SDE on the cortex or as a consequence of ence of nuchal rigidity is unusual with brain abscess or venous infarction. Seizures begin as partial motor seizures epidural empyema and should suggest the possibility of that then become secondarily generalized. Seizures SDE when associated with significant focal neurologic may be due to the direct irritative effect of the SDE on signs and fever. Patients with bacterial meningitis also the underlying cortex or result from cortical venous have nuchal rigidity but do not typically have focal deficits of the severity seen with SDE. AB C FIGURE 35-6 images (A, B) but markedly hyperintense on the proton Subdural empyema. There is marked enhancement of the density–weighted (C, curved arrow) image. (Courtesy of dura and leptomeninges (A, B, straight arrows) along the left Joseph Lurito, MD; with permission.) medial hemisphere. The pus is hypointense on T1-weighted

Treatment: infections. A cranial epidural abscess develops as a compli- 481CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema SUBDURAL EMPYEMA cation of a craniotomy or compound skull fracture or as a SDE is a medical emergency. Emergent neurosurgical result of spread of infection from the frontal sinuses, mid- evacuation of the empyema, either through burr-hole dle ear, mastoid, or orbit. An epidural abscess may develop drainage or craniotomy, is the definitive step in the man- contiguous to an area of osteomyelitis, when craniotomy is agement of this infection. Empirical antimicrobial ther- complicated by infection of the wound or bone flap, or as apy should include a combination of a third-generation a result of direct infection of the epidural space. Infection cephalosporin (e.g., cefotaxime or ceftriaxone), van- in the frontal sinus, middle ear, mastoid, or orbit can reach comycin, and metronidazole (Table 35-1 for dosages). the epidural space through retrograde spread of infection Parenteral antibiotic therapy should be continued for a from septic thrombophlebitis in the emissary veins that minimum of 4 weeks. Specific diagnosis of the etiologic drain these areas or by way of direct spread of infection organisms is made based on Gram’s stain and culture of through areas of osteomyelitis. Unlike the subdural space, fluid obtained via either burr holes or craniotomy; the the epidural space is really a potential rather than an actual initial empirical antibiotic coverage can be modified compartment.The dura is normally tightly adherent to the accordingly. inner skull table, and infection must dissect the dura away from the skull table as it spreads. As a result, epidural PROGNOSIS abscesses are often smaller than SDEs. Cranial epidural Prognosis is influenced by the level of consciousness of abscesses, unlike brain abscesses, only rarely result from the patient at the time of hospital presentation, the size hematogenous spread of infection from extracranial pri- of the empyema, and the speed with which therapy is mary sites.The bacteriology of a cranial epidural abscess is instituted. Long-term neurologic sequelae, which include similar to that of SDE (see earlier).The etiologic organisms seizures and hemiparesis, occur in up to 50% of cases. of an epidural abscess that arises from frontal sinusitis, mid- dle ear infections, or mastoiditis are usually streptococci or EPIDURAL ABSCESS anaerobic organisms. Staphylococci or gram-negative Cranial epidural abscess is a suppurative infection occur- organisms are the usual cause of an epidural abscess that ring in the potential space between the inner skull table develops as a complication of craniotomy or compound and dura (Fig. 35-7). skull fracture. ETIOLOGY AND PATHOPHYSIOLOGY CLINICAL PRESENTATION Epidural abscess is less common than either brain abscess or SDE and accounts for <2% of focal suppurative CNS Patients present with fever (60%), headache (40%), nuchal rigidity (35%), seizures (10%), and focal deficits Epidural abscess (5%). Periorbital edema and Potts puffy tumor, reflecting underlying associated frontal bone osteomyelitis, are pre- FIGURE 35-7 sent in ~40%. In patients with a recent neurosurgical Cranial epidural abscess is a collection of pus between the procedure, wound infection is invariably present, but dura and the inner table of the skull. altered mental status other symptoms may be subtle and can include (45%), fever (35%), and headache (20%). The diagnosis should also be considered when fever and headache follow DIAGNOSIS recent head trauma or occur in the setting of frontal sinusitis, mastoiditis, or otitis media. Cranial MRI is the procedure of choice to demon- strate a cranial epidural abscess.The sensitivity of CT is limited by the presence of signal artifacts arising from the bone of the inner skull table. The CT appearance of an epidural empyema is that of a lens or crescent- shaped hypodense extraaxial lesion. On MRI, an epidural empyema appears as a lentiform or crescent-shaped fluid collection that is hyperintense compared to CSF on T2-weighted images. On T1-weighted images, the fluid collection has a signal intensity that is intermedi- ate between that of brain tissue and CSF. Following the administration of gadolinium, a significant enhance- ment of the dura is seen on T1-weighted images. In distinction to subdural empyema, signs of mass effect or other parenchymal abnormalities are uncommon.