Harrison Neurology in Clinical Medicine Second Edition

482 Superior sagittal sinus Treatment: EPIDURAL ABSCESS Transverse sinus Immediate neurosurgical drainage is indicated. Empiri- cal antimicrobial therapy, pending the results of Gram’s Straight stain and culture of the purulent material obtained at sinus surgery, should include a combination of a third-genera- tion cephalosporin, vancomycin, and metronidazole Sigmoid Superior (Table 35-1). Ceftazidime or meropenem should be sub- sinus ophthalmic stituted for ceftriaxone or cefotaxime in neurosurgical vein patients. When the organism has been identified, antimi- crobial therapy can be modified accordingly. Antibiotics Inferior should be continued for at least 3 weeks after surgical ophthalmic drainage. vein PROGNOSIS Internal Cavernous jugular sinus Mortality is <5% in modern series, and full recovery is vein the rule in most survivors. SECTION III Diseases of the Central Nervous System FIGURE 35-8 SUPPURATIVE THROMBOPHLEBITIS Anatomy of the cerebral venous sinuses. DEFINITION The superior sagittal sinus drains into the transverse sinuses (Fig. 35-8). The transverse sinuses also receive Suppurative intracranial thrombophlebitis is septic venous drainage from small veins from both the middle venous thrombosis of cortical veins and sinuses. This ear and mastoid cells. The transverse sinus becomes the may occur as a complication of bacterial meningitis; sigmoid sinus before draining into the internal jugular SDE; epidural abscess; or infection in the skin of the vein. Septic transverse/sigmoid sinus thrombosis can be face, paranasal sinuses, middle ear, or mastoid. a complication of acute and chronic otitis media or mastoiditis. Infection spreads from the mastoid air cells ANATOMY AND PATHOPHYSIOLOGY to the transverse sinus via the emissary veins or by direct invasion. The cavernous sinuses are inferior to the The cerebral veins and venous sinuses have no valves; superior sagittal sinus at the base of the skull. The cav- therefore, blood within them can flow in either direc- ernous sinuses receive blood from the facial veins via the tion. The superior sagittal sinus is the largest of the superior and inferior ophthalmic veins. Bacteria in the venous sinuses (Fig. 35-8). It receives blood from the facial veins enter the cavernous sinus via these veins. frontal, parietal, and occipital superior cerebral veins and Bacteria in the sphenoid and ethmoid sinuses can spread the diploic veins, which communicate with the meningeal to the cavernous sinuses via the small emissary veins. veins. Bacterial meningitis is a common predisposing con- The sphenoid and ethmoid sinuses are the most com- dition for septic thrombosis of the superior sagittal sinus. mon sites of primary infection resulting in septic cav- The diploic veins, which drain into the superior sagittal ernous sinus thrombosis. sinus, provide a route for the spread of infection from the meninges, especially in cases where there is purulent exu- CLINICAL MANIFESTATIONS date near areas of the superior sagittal sinus. Infection can also spread to the superior sagittal sinus from nearby SDE Septic thrombosis of the superior sagittal sinus presents with or epidural abscess. Dehydration from vomiting, hyperco- headache, fever, nausea and vomiting, confusion, and agulable states, and immunologic abnormalities, including focal or generalized seizures. There may be a rapid the presence of circulating antiphospholipid antibodies, development of stupor and coma.Weakness of the lower also contribute to cerebral venous sinus thrombosis. extremities with bilateral Babinski signs or hemiparesis is Thrombosis may extend from one sinus to another, and often present. When superior sagittal sinus thrombosis at autopsy thrombi of different histologic ages can often occurs as a complication of bacterial meningitis, nuchal be detected in several sinuses. Thrombosis of the rigidity and Kernig’s and Brudzinski’s signs may be superior sagittal sinus is often associated with thrombo- present. sis of superior cortical veins and small parenchymal hemorrhages. The oculomotor nerve, the trochlear nerve, the abducens nerve, the ophthalmic and maxillary branches of the trigeminal nerve, and the internal carotid artery all pass through the cavernous sinus (Fig. 29-4). The

symptoms of septic cavernous sinus thrombosis are fever, antibiotics are usually continued for 6 weeks or until 483 headache, frontal and retroorbital pain, and diplopia. there is radiographic evidence of resolution of thrombo- The classic signs are ptosis, proptosis, chemosis, and sis. Anticoagulation with dose-adjusted heparin has CHAPTER 35 Meningitis, Encephalitis, Brain Abscess, and Empyema extraocular dysmotility due to deficits of cranial been reported to be beneficial in patients with aseptic nerves III, IV, and VI; hyperesthesia of the ophthalmic venous sinus thrombosis; it is also used in the treatment and maxillary divisions of the fifth cranial nerve and a of septic venous sinus thrombosis complicating bacter- decreased corneal reflex may be detected. There may ial meningitis in patients who are worsening despite be evidence of dilated, tortuous retinal veins and antimicrobial therapy and intravenous fluids. The pres- papilledema. ence of a small intracerebral hemorrhage from septic thrombophlebitis is not an absolute contraindication to Headache and earache are the most frequent symp- heparin therapy. Successful management of aseptic toms of transverse sinus thrombosis. A transverse sinus venous sinus thrombosis has been reported with thrombosis may also present with otitis media, sixth catheter-directed urokinase therapy and with a combi- nerve palsy, and retroorbital or facial pain (Gradinego’s nation of intrathrombus recombinant tissue plasmino- syndrome). Sigmoid sinus and internal jugular vein gen activator (rtPA) and intravenous heparin, but there thrombosis may present with neck pain. has not been enough experience with these therapies in septic venous sinus thrombosis to make recommenda- DIAGNOSIS tions regarding their use. The diagnosis of septic venous sinus thrombosis is FURTHER READINGS suggested by an absent flow void within the affected venous sinus on MRI and confirmed by magnetic DE GANS J,VAN DE BEEK D: Dexamethasone in adults with bacterial resonance venography, CT angiogram, or the venous meningitis. N Engl J Med 347:1549, 2002 phase of cerebral angiography. The diagnosis of thrombophlebitis of intracerebral and meningeal veins HONDA H, WARREN DK: Central nervous system infections: menin- is suggested by the presence of intracerebral hemor- gitis and brain abscess. Infect Dis Clin North Am 23:609, 2009 rhage but requires cerebral angiography for definitive diagnosis. HSU HE et al: Effect of pneumococcal conjugate vaccine on pneu- mococcal meningitis. N Engl J Med 360:244, 2009 Treatment: SUPPURATIVE THROMBOPHLEBITIS ROSENSTEIN NE et al: Meningococcal disease. N Engl J Med 344:1378, 2001 Septic venous sinus thrombosis is treated with antibi- otics, hydration, and removal of infected tissue and STEPHENS DS et al: Epidemic meningitis, meningococcaemia, and thrombus in septic lateral or cavernous sinus thrombo- Neisseria meningitidis. Lancet 369:2196, 2007 sis. The choice of antimicrobial therapy is based on the bacteria responsible for the predisposing or associated TUNKEL AR et al: Practice guidelines for the management of bacter- condition. Optimal duration of therapy is unknown, but ial meningitis. Clin Infect Dis 39:1267, 2004 _______ et al: The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 47:303, 2008 TYLER KL: Emerging viral infections of the central nervous system: part 1.Arch Neurol 66:939, 2009 YAO K et al: Detection of human herpesvirus 6 in cerebrospinal fluid of patients with encephalitis.Ann Neurol 65:257, 2009

CHAPTER 36 CHRONIC AND RECURRENT MENINGITIS Walter J. Koroshetz I Morton N. Swartz Clinical Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . 484 The Immunosuppressed Patient . . . . . . . . . . . . . . . . . . . . . . 492 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 492 Chronic inflammation of the meninges (pia, arachnoid, cerebral ventricles, exits through narrow foramina into and dura) can produce profound neurologic disability the subarachnoid space surrounding the brain and spinal and may be fatal if not successfully treated. The condi- cord, circulates around the base of the brain and over tion is most commonly diagnosed when a characteristic the cerebral hemispheres, and is resorbed by arachnoid neurologic syndrome exists for >4 weeks and is associ- villi projecting into the superior sagittal sinus. CSF flow ated with a persistent inflammatory response in the provides a pathway for rapid spread of infectious and cerebrospinal fluid (CSF) (white blood cell count other infiltrative processes over the brain, spinal cord, >5/μL). The causes are varied, and appropriate treat- and cranial and spinal nerve roots. Spread from the sub- ment depends on identification of the etiology. Five arachnoid space into brain parenchyma may occur via categories of disease account for most cases of chronic the arachnoid cuffs that surround blood vessels that pen- meningitis: (1) meningeal infections, (2) malignancy, etrate brain tissue (Virchow-Robin spaces). (3) noninfectious inflammatory disorders, (4) chemical meningitis, and (5) parameningeal infections. Intracranial Meningitis CLINICAL PATHOPHYSIOLOGY Nociceptive fibers of the meninges are stimulated by the inflammatory process, resulting in headache or neck or Neurologic manifestations of chronic meningitis back pain. Obstruction of CSF pathways at the foramina (Table 36-1) are determined by the anatomic location or arachnoid villi may produce hydrocephalus and symp- of the inflammation and its consequences. Persistent toms of raised intracranial pressure (ICP), including headache with or without stiff neck, hydrocephalus, cra- headache, vomiting, apathy or drowsiness, gait instability, nial neuropathies, radiculopathies, and cognitive or per- papilledema, visual loss, impaired upgaze, or palsy of the sonality changes are the cardinal features. These can sixth cranial nerve (CN) (Chap. 29). Cognitive and occur alone or in combination. When they appear in behavioral changes during the course of chronic menin- combination, widespread dissemination of the inflam- gitis may also result from vascular damage, which may matory process along CSF pathways has occurred. In similarly produce seizures, stroke, or myelopathy. Inflam- some cases, the presence of an underlying systemic ill- matory deposits seeded via the CSF circulation are often ness points to a specific agent or class of agents as the prominent around the brainstem and cranial nerves and probable cause. The diagnosis of chronic meningitis is along the undersurface of the frontal and temporal usually made when the clinical presentation prompts the lobes. Such cases, termed basal meningitis, often present as astute physician to examine the CSF for signs of inflam- multiple cranial neuropathies, with visual loss (CN II), mation. CSF is produced by the choroid plexus of the facial weakness (CN VII), hearing loss (CN VIII), 484

TABLE 36-1 infection outside the nervous system. Infectious causes 485 SYMPTOMS AND SIGNS OF CHRONIC MENINGITIS are of major concern in the immunosuppressed patient, especially in patients with AIDS, in whom chronic SYMPTOM SIGN meningitis may present without headache or fever. CHAPTER 36 Chronic and Recurrent Meningitis Chronic headache Noninfectious inflammatory disorders often produce Neck or back pain ϩ/− Papilledema systemic manifestations, but meningitis may be the ini- Brudzinski’s or Kernig’s sign tial manifestation. Carcinomatous meningitis may or Change in personality of meningeal irritation may not be accompanied by clinical evidence of the pri- Altered mental status— mary neoplasm. Facial weakness drowsiness, inattention, Double vision disorientation, memory loss, Approach to the Patient: Visual loss frontal release signs (grasp, CHRONIC MENINGITIS Hearing loss suck, snout), perseveration Arm or leg weakness Peripheral seventh CN palsy The occurrence of chronic headache, hydrocephalus, Numbness in arms Palsy of CN III, IV, VI cranial neuropathy, radiculopathy, and/or cognitive Papilledema, optic atrophy decline in a patient should prompt consideration of a or legs Eighth CN palsy lumbar puncture for evidence of meningeal inflam- Sphincter dysfunction Myelopathy or radiculopathy mation. On occasion the diagnosis is made when an Myelopathy or radiculopathy imaging study (CT or MRI) shows contrast enhance- Clumsiness ment of the meninges, which is always abnormal with Myelopathy or radiculopathy the exception of dural enhancement after lumbar Frontal lobe dysfunction puncture, neurosurgical procedures, or spontaneous (hydrocephalus) CSF leakage. Once chronic meningitis is confirmed Ataxia by CSF examination, effort is focused on identifying the cause (Tables 36-2 and 36-3) by (1) further Note: CN, cranial nerve. analysis of the CSF, (2) diagnosis of an underlying sys- temic infection or noninfectious inflammatory con- diplopia (CNs III, IV, and VI), sensory or motor abnor- dition, or (3) pathologic examination of meningeal malities of the oropharynx (CNs IX, X, and XII), biopsy specimens. decreased olfaction (CN I), or facial sensory loss and masseter weakness (CN V). Two clinical forms of chronic meningitis exist. In the first, the symptoms are chronic and persistent, Spinal Meningitis whereas in the second there are recurrent, discrete episodes of illness. In the latter group, all symptoms, Injury may occur to motor and sensory roots as they tra- signs, and CSF parameters of meningeal inflammation verse the subarachnoid space and penetrate the meninges. resolve completely between episodes without specific These cases present as multiple radiculopathies with com- therapy. In such patients, the likely etiologies include binations of radicular pain, sensory loss, motor weakness, herpes simplex virus (HSV) type 2; chemical meningi- and sphincter dysfunction. Meningeal inflammation can tis due to leakage into CSF of contents from an epi- encircle the cord, resulting in myelopathy. Patients with dermoid tumor, craniopharyngioma, or cholesteatoma; slowly progressive involvement of multiple cranial nerves primary inflammatory conditions, including Vogt- and/or spinal nerve roots are likely to have chronic Koyanagi-Harada syndrome, Behçet’s syndrome, sys- meningitis. Electrophysiologic testing (electromyography, temic lupus erythematosus; and drug hypersensitivity nerve conduction studies, and evoked response testing) with repeated administration of the offending agent. may be helpful in determining whether there is involve- ment of cranial and spinal nerve roots. The epidemiologic history is of considerable importance and may provide direction for selection Systemic Manifestations of laboratory studies. Pertinent features include a his- tory of tuberculosis or exposure to a likely case; past In some patients, evidence of systemic disease provides travel to areas endemic for fungal infections (the San clues to the underlying cause of chronic meningitis. A Joaquin Valley in California and southwestern states careful history and physical examination are essential for coccidioidomycosis, midwestern states for histo- before embarking on a diagnostic workup, which may plasmosis, southeastern states for blastomycosis); be costly, prolonged, and associated with risk from inva- travel to the Mediterranean region or ingestion of sive procedures. A complete history of travel, sexual imported unpasteurized dairy products (Brucella); practice, and exposure to infectious agents should be time spent in wooded areas endemic for Lyme disease; sought. Infectious causes are often associated with fever, malaise, anorexia, and signs of localized or disseminated

486 TABLE 36-2 INFECTIOUS CAUSES OF CHRONIC MENINGITIS CAUSATIVE AGENT CSF FORMULA HELPFUL RISK FACTORS AND SYSTEMIC DIAGNOSTIC TESTS MANIFESTATIONS Common Bacterial Causes Partially treated Mononuclear or mixed CSF culture and Gram stain History consistent with suppurative meningitis mononuclear- acute bacterial meningitis Parameningeal infection polymorphonuclear cells and incomplete treatment Mycobacterium tuberculosis Mononuclear or mixed Contrast-enhanced CT or Otitis media, pleuropulmonary Lyme disease polymorphonuclear- MRI to detect parenchymal, infection, right-to-left (Bannwarth’s syndrome) Borrelia burgdorferi mononuclear cells subdural, epidural, or cardiopulmonary shunt for Syphilis (secondary, sinus infection brain abscess; focal tertiary) Treponema pallidum neurologic signs; neck, back, ear, or sinus tenderness Mononuclear cells except Tuberculin skin test may be Exposure history; previous SECTION III Clinical Manifestations of Neurologic Disease polymorphonuclear cells negative; AFB culture of CSF tuberculous illness; in early infection (commonly (sputum, urine, gastric immunosuppressed or AIDS; <500 WBC/μL); low CSF contents if indicated); young children; fever, glucose, high protein tuberculostearic acid detection meningismus, night sweats, in CSF; identify tubercle miliary TB on x-ray or liver bacillus on acid-fast stain biopsy; stroke due to arteritis CSF or protein pellicle; of PCR Mononuclear cells; elevated Serum Lyme antibody titer; History of tick bite or protein Western blot confirmation; appropriate exposure (patients with syphilis may history; erythema chronicum have false-positive Lyme titer) migrans skin rash; arthritis, radiculopathy, Bell’s palsy, meningoencephalitis–multiple sclerosis-like syndrome Mononuclear cells; CSF VDRL; serum VDRL Appropriate exposure history; elevated protein (or RPR); fluorescent HIV seropositive individuals treponemal antibody- at increased risk of aggressive absorbed (FTA) or MHA-TP; infection; “dementia”; cerebral serum VDRL may be negative infarction due to endarteritis in tertiary syphilis Uncommon Bacterial Causes Actinomyces Polymorphonuclear cells Anaerobic culture Parameningeal abscess or sinus tract (oral or dental focus); Nocardia Polymorphonuclear; Isolation may require weeks; pneumonitis Brucella occasionally mononuclear weakly acid fast Associated brain abscess cells; often low glucose may be present Whipple’s disease Mononuclear cells CSF antibody detection; Tropherema whippelii (rarely polymorphonuclear); serum antibody detection Intake of unpasteurized dairy elevated protein; often products; exposure to goats, low glucose sheep, cows; fever, arthralgia, myalgia, vertebral Mononuclear cells Biopsy of small bowel or osteomyelitis lymph node; CSF PCR for Diarrhea, weight loss, T. whippelii; brain and arthralgias, fever; dementia, meningeal biopsy ataxia, paresis, (with PAS stain and ophthalmoplegia, EM examination) oculomasticatory myoclonus Rare Bacterial Causes Leptospirosis (occasionally if left untreated may last 3–4 weeks)

TABLE 36-2 (CONTINUED) 487 INFECTIOUS CAUSES OF CHRONIC MENINGITIS CAUSATIVE AGENT CSF FORMULA HELPFUL RISK FACTORS AND SYSTEMIC DIAGNOSTIC TESTS MANIFESTATIONS Fungal Causes Mononuclear cells; count India ink or fungal wet AIDS and immune suppression; Cryptococcus neoformans not elevated in some mount of CSF (budding pigeon exposure; skin and patients with AIDS yeast); blood and urine other organ involvement cultures; antigen detection due to disseminated infection Coccidioides immitis Mononuclear cells in CSF Candida sp. (sometimes 10–20% Antibody detection in Exposure history— eosinophils); often CSF and serum southwestern US; low glucose increased virulence Polymorphonuclear Fungal stain and culture in dark-skinned races or mononuclear of CSF IV drug abuse; post surgery; prolonged intravenous Histoplasma capsulatum Mononuclear cells; Fungal stain and culture of therapy; disseminated CHAPTER 36 Chronic and Recurrent Meningitis low glucose large volumes of CSF; candidiasis antigen detection in CSF, Exposure history—Ohio and Blastomyces dermatitidis Mononuclear cells serum, and urine; antibody central Mississippi River detection in serum, CSF Valley; AIDS; mucosal Aspergillus sp. Mononuclear or Fungal stain and culture lesions Sporothrix schenckii polymorphonuclear of CSF; biopsy and culture Mononuclear cells of skin, lung lesions; Midwestern and southeastern antibody detection USA; usually systemic in serum infection; abscesses, CSF culture draining sinus, ulcers Antibody detection in CSF Sinusitis; granulocytopenia and serum; CSF culture or immunosuppression Traumatic inoculation; IV drug use; ulcerated skin lesion Rare Fungal Causes Xylohypha (formerly Cladosporium) trichoides and other dark-walled (demateaceous) fungi such as Curvularia, Drechslera; Mucor, Pseudoallescheria boydii Protozoal Causes Mononuclear cells Biopsy or response to Usually with intracerebral Toxoplasma gondii empirical therapy in clinically abscesses; common in appropriate context HIV seropositive patients Trypanosomiasis Mononuclear cells, (including presence of antibody in serum) Endemic in Africa; chancre, Trypanosoma gambiense, elevated protein Elevated CSF IgM; lymphadenopathy; identification of prominent sleep disorder T. rhodesiense trypanosomes in CSF and blood smear Rare Protozoal Causes Acanthamoeba sp. causing granulomatous amebic encephalitis and meningoencephalitis in immunocompromised and debilitated individuals Helminthic Causes Mononuclear cells; may Indirect hemagglutination Usually with multiple cysts have eosinophils; glucose assay in CSF; ELISA in basal meninges and Cysticercosis level may be low immunoblotting in serum hydrocephalus; cerebral (infection with cysts cysts, muscle of Taenia solium) calcification (Continued)

488 TABLE 36-2 (CONTINUED) INFECTIOUS CAUSES OF CHRONIC MENINGITIS CAUSATIVE AGENT CSF FORMULA HELPFUL RISK FACTORS AND SYSTEMIC DIAGNOSTIC TESTS MANIFESTATIONS Helminthic Causes Eosinophils, mononuclear Peripheral eosinophilia History of eating raw fish; Gnathostoma spinigerum cells common in Thailand and Japan; subarachnoid Angiostrongylus Eosinophils, mononuclear Recovery of worms hemorrhage; painful cantonensis cells from CSF radiculopathy History of eating raw shellfish; Baylisascaris procyonis Eosinophils, mononuclear common in tropical Pacific (raccoon ascarid) cells regions; often benign Infection follows accidental SECTION III Clinical Manifestations of Neurologic Disease ingestion of B. procyonis eggs from raccoon feces; fatal meningoencephalitis Rare Helminthic Causes Trichinella spiralis (trichinosis); Echinococcus cysts; Schistosoma sp. The former may produce a lymphocytic pleocytosis whereas the latter two may produce an eosinophilic response in CSF associated with cerebral cysts (Echinococcus) or gran- ulomatous lesions of brain or spinal cord Viral Causes Mononuclear cells Antibody in serum No prior mumps or Mumps Mononuclear cells immunization; may produce Mononuclear cells; Antibody in serum meningoencephalitis; may Lymphocytic may have low glucose Virus isolation from CSF persist for 3–4 weeks choriomeningitis Mononuclear cells p24 antigen in serum and Echovirus CSF; high level of HIV viremia Contact with rodents or HIV (acute retroviral Mononuclear cells their excreta; may persist syndrome) PCR for HSV, CMV DNA; for 3–4 weeks CSF antibody for HSV, EBV Herpes simplex (HSV) Congenital hypogammaglobu- linemia; history of recurrent meningitis HIV risk factors; rash, fever, lymphadenopathy; lymphope- nia in peripheral blood; syndrome may persist long enough to be considered as “chronic meningitis”; or chronic meningitis may develop in later stages (AIDS) due to HIV Recurrent meningitis due to HSV-2 (rarely HSV-1) often associated with genital recur- rences; EBV associated with myeloradiculopathy, CMV with polyradiculopathy Note: AFB, acid-fast bacillus; CMV, cytomegalovirus; CSF, cerebrospinal fluid; CT, computed tomography; EBV, Epstein-Barr virus; ELISA, enzyme-linked immunosorbent assay; EM, electron microscopy; FTA, fluorescent treponemal antibody absorption test; HSV, herpes simplex virus; MHA-TP, microhemagglutination assay–T. pallidum; MRI, magnetic resonance imaging; PAS, periodic acid–Schiff; PCR, polymerase chain reaction; RPR, rapid plasma reagin test; TB, tuberculosis; VDRL, Venereal Disease Research Laboratories test. exposure to sexually transmitted disease (syphilis); residence in Thailand or Japan (Gnathostoma exposure of an immunocompromised host to spinigerum), Latin America (Paracoccidioides brasiliiensis), pigeons and their droppings (Cryptococcus); gardening or the South Pacific (Angiostrongylus cantonensis); rural (Sporothrix schenkii); ingestion of poorly cooked meat residence and raccoon exposure (Baylisascaris procyo- or contact with a household cat (Toxoplasma gondii); nis); and residence in Latin America, the Philippines,

TABLE 36-3 489 NONINFECTIOUS CAUSES OF CHRONIC MENINGITIS CAUSATIVE AGENT CSF FORMULA HELPFUL RISK FACTORS AND SYSTEMIC Malignancy Mononuclear cells, DIAGNOSTIC TESTS MANIFESTATIONS Chemical compounds elevated protein, Repeated cytologic Metastatic cancer of breast, (may cause recurrent low glucose meningitis) examination of large volumes lung, stomach, or pancreas; Mononuclear or PMNs, Primary inflammation low glucose, elevated of CSF; CSF exam by melanoma, lymphoma, CNS sarcoidosis protein; xanthochromia from subarachnoid polarizing microscopy; leukemia; meningeal Vogt-Koyanagi-Harada hemorrhage in week prior syndrome (recurrent to presentation with clonal lymphocyte markers; gliomatosis; meningeal meningitis) “meningitis” deposits on nerve roots or sarcoma; cerebral Isolated granulomatous angiitis of the nervous meninges seen on myelogram dysgerminoma; meningeal system or contrast-enhanced MRI; melanoma or B cell lymphoma Systemic lupus erythematosus meningeal biopsy Behçet’s syndrome (recurrent meningitis) Contrast-enhanced CT scan History of recent injection into Chronic benign or MRI Cerebral angiogram the subarachnoid space; lymphocytic meningitis to detect aneurysm history of sudden onset of Mollaret’s meningitis (recurrent meningitis) headache; recent resection Drug hypersensitivity of acoustic neuroma or CHAPTER 36 Chronic and Recurrent Meningitis craniopharyngioma; epidermoid tumor of brain or spine, sometimes with dermoid sinus tract; pituitary apoplexy Mononuclear cells; elevated Serum and CSF angiotensin- CN palsy, especially of CN VII; protein; often low glucose converting enzyme levels; hypothalamic dysfunction, Mononuclear cells biopsy of extraneural affected especially diabetes insipidus; Mononuclear cells, elevated protein tissues or brain lesion/ abnormal chest radiograph; Mononuclear or PMNs meningeal biopsy peripheral neuropathy or Mononuclear or PMNs, elevated protein myopathy Mononuclear cells Recurrent meningoencephalitis Large endothelial cells with uveitis, retinal and PMNs in first hours, followed by mononuclear detachment, alopecia, cells PMNs; occasionally lightening of eyebrows and mononuclear cells or eosinophils lashes, dysacousia, cataracts, glaucoma Angiography or meningeal Subacute dementia; multiple biopsy cerebral infarctions; recent zoster ophthalmicus Anti-DNA antibody, Encephalopathy; seizures; antinuclear antibodies stroke; transverse myelopathy; rash; arthritis Oral and genital aphthous ulcers; iridocyclitis; retinal hemorrhages; pathergic lesions at site of skin puncture Recovery in 2–6 months, diagnosis by exclusion PCR for herpes; MRI/CT to Recurrent meningitis; exclude rule out epidermoid tumor HSV-2; rare cases due to or dural cyst HSV-1; occasional case associated with dural cyst Exposure to ibuprofen, sulfonamides, isoniazid, tolmetin, ciprofloxacin, phenazopyridine; improvement after discontinuation of drug; recurrent episodes with recurrent exposure (Continued)

490 TABLE 36-3 (CONTINUED) NONINFECTIOUS CAUSES OF CHRONIC MENINGITIS CAUSATIVE AGENT CSF FORMULA HELPFUL RISK FACTORS AND SYSTEMIC DIAGNOSTIC TESTS MANIFESTATIONS Wegener’s Mononuclear cells Chest and sinus radiographs; Associated sinus, pulmonary, granulomatosis urinalysis; ANCA antibodies or renal lesions; CN palsies; in serum skin lesions; peripheral neuropathy Other: multiple sclerosis, Sjögren’s syndrome, neonatal onset multisystemic inflammatory disease (NOMID), and rarer forms of vasculitis (e.g., Cogan’s syndrome) Note: ANCA, anti-neutrophil cytoplasmic antibodies; CN, cranial nerve; CSF, cerebrospinal fluid; CT, computed tomography; HSV, herpes sim- plex virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PMNs, polymorphonuclear cells. SECTION III Clinical Manifestations of Neurologic Disease or Southeast Asia when eosinophilic meningitis is CSF flow pathways, elevated ICP can still occur due present (Taenia solium). to impaired resorption of CSF by arachnoid villi. In such patients, lumbar puncture is usually safe, but The presence of focal cerebral signs in a patient repetitive or continuous lumbar drainage may be with chronic meningitis suggests the possibility of a necessary to prevent relatively sudden death from brain abscess or other parameningeal infection; iden- raised ICP. In some patients, especially those with tification of a potential source of infection (chronic cryptococcal meningitis, fatal levels of raised ICP can draining ear, sinusitis, right-to-left cardiac or pul- occur without enlarged ventricles. monary shunt, chronic pleuropulmonary infection) supports this diagnosis. In some cases, diagnosis may Contrast-enhanced MRI or CT studies of the be established by recognition and biopsy of unusual brain and spinal cord can identify meningeal skin lesions (Behçet’s syndrome, cryptococcosis, blas- enhancement, parameningeal infections (including tomycosis, SLE, Lyme disease, IV drug use, sporotri- brain abscess), encasement of the spinal cord (malig- chosis, trypanosomiasis) or enlarged lymph nodes nancy or inflammation and infection), or nodular (lymphoma, tuberculosis, sarcoid, infection with HIV, deposits on the meninges or nerve roots (malignancy secondary syphilis, or Whipple’s disease). A careful or sarcoidosis) (Fig. 36-1). Imaging studies are also ophthalmologic examination may reveal uveitis useful to localize areas of meningeal disease prior to [Vogt-Koyanagi-Harada syndrome, sarcoid, or central meningeal biopsy. nervous system (CNS) lymphoma], keratoconjunc- tivitis sicca (Sjögren’s syndrome), or iridocyclitis Cerebral angiography may be indicated in patients (Behçet’s syndrome) and is essential to assess visual with chronic meningitis and stroke to identify cere- loss from papilledema. Aphthous oral lesions, genital bral arteritis (granulomatous angiitis, other inflamma- ulcers, and hypopyon suggest Behçet’s syndrome. tory arteritides, or infectious arteritis). Hepatosplenomegaly suggests lymphoma, sarcoid, tuberculosis, or brucellosis. Herpetic lesions in the CEREBROSPINAL FLUID ANALYSIS The genital area or on the thighs suggest HSV-2 infection. CSF pressure should be measured and samples sent A breast nodule, a suspicious pigmented skin lesion, for bacterial, fungal, and tuberculous culture;Venereal focal bone pain, or an abdominal mass directs atten- Disease Research Laboratories (VDRL) test; cell tion to possible carcinomatous meningitis. count and differential; Gram’s stain; and measurement of glucose and protein. Wet mount for fungus and IMAGING Once the clinical syndrome is recog- parasites, India ink preparation and culture, culture for nized as a potential manifestation of chronic menin- fastidious bacteria and fungi, assays for cryptococcal gitis, proper analysis of the CSF is essential. However, antigen and oligoclonal immunoglobulin bands, and if the possibility of raised ICP exists, a brain imaging cytology should be performed. Other specific CSF study should be performed before lumbar puncture. If tests (Tables 36-2 and 36-3) or blood tests and cul- ICP is elevated because of a mass lesion, brain tures should be ordered as indicated on the basis of swelling, or a block in ventricular CSF outflow the history, physical examination, or preliminary CSF (obstructive hydrocephalus), then lumbar puncture results (i.e., eosinophilic, mononuclear, or polymor- carries the potential risk of brain herniation. phonuclear meningitis). Rapid diagnosis may be facil- Obstructive hydrocephalus usually requires direct itated by serologic tests and polymerase chain reaction ventricular drainage of CSF. In patients with open (PCR) testing to identify DNA sequences in the CSF that are specific for the suspected pathogen.

from a large volume of CSF. The diagnosis of fungal 491 meningitis may require large volumes of CSF for cul- ture of sediment. If standard lumbar puncture is unre- warding, a cervical cisternal tap to sample CSF near to the basal meninges may be fruitful. FIGURE 36-1 LABORATORY INVESTIGATION In addition to CHAPTER 36 Chronic and Recurrent Meningitis Primary central nervous system lymphoma. A 24-year-old the CSF examination, an attempt should be made to man, immunosuppressed due to intestinal lymphangiecta- uncover pertinent underlying illnesses. Tuberculin sia, developed multiple cranial neuropathies. CSF findings skin test, chest radiograph, urine analysis and culture, consisted of 100 lymphocytes/μL and a protein of 2.5 g/L blood count and differential, renal and liver function (250 mg/dL); cytology and cultures were negative. Gadolin- tests, alkaline phosphatase, sedimentation rate, antinu- ium-enhanced T1 MRI revealed diffuse, multifocal meningeal clear antibody, anti-Ro, anti-La antibody and serum enhancement surrounding the brainstem (A), spinal cord and angiotensin-converting enzyme level are often indi- cauda equina (B). cated. Liver or bone marrow biopsy may be diagnos- tic in some cases of miliary tuberculosis, disseminated In most categories of chronic (not recurrent) fungal infection, sarcoidosis, or metastatic malignancy. meningitis, mononuclear cells predominate in the Abnormalities discovered on chest radiograph or CSF. When neutrophils predominate after 3 weeks of chest CT can be pursued by bronchoscopy or illness, the principal etiologic considerations are transthoracic needle biopsy. Nocardia asteroides, Actinomyces israelii, Brucella, Mycobac- terium tuberculosis (5–10% of early cases only), various MENINGEAL BIOPSY A meningeal biopsy should fungi (Blastomyces dermatitidis, Candida albicans, Histo- be strongly considered in patients who are severely dis- plasma capsulatum, Aspergillus spp., Pseudallescheria boy- abled, who need chronic ventricular decompression, or dii, Cladophialophora bantiana), and noninfectious whose illness is progressing rapidly.The activities of the causes (SLE, exogenous chemical meningitis). When surgeon, pathologist, microbiologist, and cytologist eosinophils predominate or are present in limited should be coordinated so that a large enough sample is numbers in a primarily mononuclear cell response in obtained and the appropriate cultures and histologic the CSF, the differential diagnosis includes parasitic and molecular studies, including electron-microscopic diseases (A. cantonensis, G. spinigerum, B. procyonis, or and PCR studies, are performed. The diagnostic yield Toxocara canis infection, cysticercosis, schistosomiasis, of meningeal biopsy can be increased by targeting echinococcal disease, T. gondii infection), fungal infec- regions that enhance with contrast on MRI or CT. tions (6–20% eosinophils along with a predominantly With current microsurgical techniques, most areas of lymphocyte pleocytosis, particularly with coccidioidal the basal meninges can be accessed for biopsy via a meningitis), neoplastic disease (lymphoma, leukemia, limited craniotomy. In a series from the Mayo Clinic metastatic carcinoma), or other inflammatory processes reported by Cheng et al., MRI demonstrated (sarcoidosis, hypereosinophilic syndrome). meningeal enhancement in 47% of patients undergo- ing meningeal biopsy. Biopsy of an enhancing region It is often necessary to broaden the number of diag- was diagnostic in 80% of patients; biopsy of nonen- nostic tests if the initial workup does not reveal the hancing regions was diagnostic in only 9%; sarcoid cause. In addition, repeated samples of large volumes (31%) and metastatic adenocarcinoma (25%) were the of CSF may be required to diagnose certain infectious most common conditions identified.Tuberculosis is the and malignant causes of chronic meningitis. For most common condition identified in many reports instance, lymphomatous or carcinomatous meningitis from outside the United States. may be diagnosed by examination of sections cut from a cell block formed by spinning down the sediment APPROACH TO THE ENIGMATIC CASE In approximately one-third of patients, the diagnosis is not known despite careful evaluation of CSF and potential extraneural sites of disease. A number of the organisms that cause chronic meningitis may take weeks to be identified by cultures. In enigmatic cases several options are available, determined by the extent of the clinical deficits and rate of progression. It is prudent to wait until cultures are finalized if the patient is asympto- matic or symptoms are mild and not progressive. Unfortunately, in many patients progressive neurologic

SECTION III Clinical Manifestations of Neurologic Disease492 deterioration occurs, and rapid treatment is required. commonly presents as intracranial abscesses and may Ventricular-peritoneal shunts may be placed to relieve also be associated with meningitis. Other important hydrocephalus, but the risk of disseminating the undi- causes of chronic meningitis in AIDS include infection agnosed inflammatory process into the abdomen must with Cryptococcus, Nocardia, Candida, or other fungi; be considered. syphilis; and lymphoma (Fig. 36-1). Toxoplasmosis, cryptococcosis, nocardiosis, and other fungal infections EMPIRICAL TREATMENT Diagnosis of the are important etiologic considerations in individuals causative agent is essential because effective therapies with immunodeficiency states other than AIDS, includ- exist for many etiologies of chronic meningitis, but if ing those due to immunosuppressive medications. Because the condition is left untreated, progressive damage to of the increased risk of chronic meningitis and the the CNS and cranial nerves and roots is likely to attenuation of clinical signs of meningeal irritation in occur. Occasionally, empirical therapy must be initi- immunosuppressed individuals, CSF examination should ated when all attempts at diagnosis fail. In general, be performed for any persistent headache or unex- empirical therapy in the United States consists of plained change in mental state. antimycobacterial agents, amphotericin for fungal infection, or glucocorticoids for noninfectious inflam- FURTHER READINGS matory causes. It is important to direct empirical therapy of lymphocytic meningitis at tuberculosis, GILDEN DH et al: Herpesvirus infections of the nervous system. Nat particularly if the condition is associated with hypo- Clin Pract Neurol 3:82, 2007 glycorrhachia and sixth and other CN palsies, since untreated disease is fatal in 4–8 weeks. In the Mayo HALPERIN JJ et al: Practice parameter: Treatment of nervous system Clinic series, the most useful empirical therapy was Lyme disease (an evidence-based review): Report of the Quality administration of glucocorticoids rather than antitu- Standards Subcomittee of the American Academy of Neurology. berculous therapy. Carcinomatous or lymphomatous Neurology 69:91, 2007 meningitis may be difficult to diagnose initially, but the diagnosis becomes evident with time. LAN SH et al: Cerebral infarction in chronic meningitis: A compari- son of tuberculous meningitis and cryptococcal meningitis. Q J THE IMMUNOSUPPRESSED PATIENT Med 94(5):247, 2001 Chronic meningitis is not uncommon in the course of LILIANG PC et al: Use of ventriculoperitoneal shunts to treat uncon- HIV infection. Pleocytosis and mild meningeal signs trollable intracranial hypertension in patients who have cryptococ- often occur at the onset of HIV infection, and occa- cal meningitis without hydrocephalus. Clin Infect Dis 34(12):E64, sionally low-grade meningitis persists. Toxoplasmosis 2002 SHAPIRO WR et al: Treatment modalities for leptomeningeal metas- tases. Semin Oncol 36:S46 2009 TALATI NJ et al: Spectrum of CNS disease caused by rapidly growing mycobacteria. Lancet Infect Dis 8:390, 2008 VINNARD C, Macgregor RR:Tuberculous meningitis in HIV-infected individuals. Curr HIV/AIDS Rep 6:139, 2009

CHAPTER 37 HIV NEUROLOGY Anthony S. Fauci I H. Clifford Lane I Aids Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493 I Etiologic Agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 493 Morphology of HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494 Replication Cycle of HIV . . . . . . . . . . . . . . . . . . . . . . . . . . . . 494 I Pathophysiology and Pathogenesis . . . . . . . . . . . . . . . . . . . 497 Neuropathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 497 I Clinical Manifestation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498 Neurologic Disease Caused by HIV . . . . . . . . . . . . . . . . . . . . 498 Specific Neurologic Presentations . . . . . . . . . . . . . . . . . . . . . 505 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506 Clinical disease of the nervous system accounts for a signifi- condition resolves; the same holds true for category C in cant degree of morbidity in a high percentage of patients relation to category B. with HIV infection. Neurologic problems occur through- out the course of infection and may be inflammatory, The definition of AIDS is indeed complex and com- demyelinating, or degenerative in nature. The problems prehensive and was established not for the practical care fall into four basic categories: neurologic disease caused by of patients, but for surveillance purposes.Thus, the clini- HIV itself, HIV-related neoplasms, opportunistic infections cian should not focus on whether or not the patient ful- of the nervous system, and adverse effects of medical fills the strict definition of AIDS, but should view HIV therapy (Table 37-1). disease as a spectrum ranging from primary infection, with or without the acute syndrome, to the asympto- matic stage, to advanced disease. AIDS CLASSIFICATION The current U.S. Centers for Disease Control and Pre- ETIOLOGIC AGENT vention (CDC) classification system for HIV-infected The etiologic agent of AIDS is HIV, which belongs to adolescents and adults categorizes persons on the basis the family of human retroviruses (Retroviridae) and the of clinical conditions associated with HIV infection and subfamily of lentiviruses. Nononcogenic lentiviruses CD4+ T lymphocyte counts. The system is based on cause disease in other animal species, including sheep, three ranges of CD4+ T lymphocyte counts and three horses, goats, cattle, cats, and monkeys. The four recog- clinical categories and is represented by a matrix of nine nized human retroviruses belong to two distinct groups: mutually exclusive categories (Tables 37-2 and 37-3). the human T lymphotropic viruses (HTLV)-I and Using this system, any HIV-infected individual with a HTLV-II, which are transforming retroviruses; and the CD4+ T cell count of <200/μL has AIDS by definition, human immunodeficiency viruses, HIV-1 and HIV-2, regardless of the presence of symptoms or opportunistic which cause cytopathic effects either directly or indi- diseases (Table 37-2). Once individuals have had a rectly.The most common cause of HIV disease through- clinical condition in category B, their disease classifica- out the world, and certainly in the United States, is tion cannot be reverted back to category A, even if the HIV-1, which comprises several subtypes with different 493

494 TABLE 37-1 external spikes formed by the two major envelope pro- teins, the external gp120 and the transmembrane gp41. NEUROLOGIC DISEASES IN PATIENTS WITH HIV The virion buds form the surface of the infected cell INFECTION and incorporates a variety of host proteins, including major histocompatibility complex (MHC) class I and II Opportunistic infections Myelopathy antigens, into its lipid bilayer. The structure of HIV-1 is Toxoplasmosis Vacuolar myelopathy schematically diagrammed in Fig. 37-1B. Cryptococcosis Pure sensory ataxia Progressive multifocal Paresthesia/dysesthesia REPLICATION CYCLE OF HIV leukoencephalopathy Peripheral neuropathy Cytomegalovirus Acute inflammatory demyeli- HIV is an RNA virus whose hallmark is the reverse Syphilis nating polyneuropathy transcription of its genomic RNA to DNA by the Mycobacterium (Guillain-Barré syndrome) enzyme reverse transcriptase. The replication cycle of HIV tuberculosis Chronic inflammatory begins with the high-affinity binding of the gp120 pro- HTLV-I infection demyelinating polyneu- tein via a portion of its V1 region near the N terminus Neoplasms ropathy (CIDP) to its receptor on the host cell surface, the CD4 mole- Primary CNS lymphoma Mononeuritis multiplex cule (Fig. 37-2). The CD4 molecule is a 55-kDa pro- Kaposi’s sarcoma Distal symmetric tein found predominantly on a subset of T lymphocytes Result of HIV-1 infection polyneuropathy that are responsible for helper function in the immune Aseptic meningitis Myopathy system. It is also expressed on the surface of mono- HIV-associated neurocogni- cytes/macrophages and dendritic/Langerhans cells. Once SECTION III Diseases of the Central Nervous System tive impairment, including gp120 binds to CD4, the gp120 undergoes a confor- HIV encephalopathy/ mational change that facilitates binding to one of a AIDS dementia complex group of co-receptors. The two major co-receptors for HIV-1 are CCR5 and CXCR4. Both receptors belong geographic distributions. HIV-2 was first identified in to the family of seven-transmembrane-domain G protein– 1986 in West African patients and was originally con- coupled cellular receptors, and the use of one or the fined to West Africa. However, a number of cases that other or both receptors by the virus for entry into the can be traced to West Africa or to sexual contacts with cell is an important determinant of the cellular tropism West Africans have been identified throughout the of the virus. Certain dendritic cells express a diversity of world. Both HIV-1 and HIV-2 are zoonotic infections. C-type lectin receptors on their surface, one of which is The Pan troglodytes troglodytes species of chimpanzees has called DC-SIGN, that also bind with high affinity to the been established as the natural reservoir of HIV-1 and HIV gp120 envelope protein, allowing the dendritic cell the most likely source of original human infection. to facilitate the binding of virus to the CD4+ T cell HIV-2 is more closely related phylogenetically to the upon engagement of dendritic cells with CD4+ T cells. simian immunodeficiency virus (SIV) found in sooty Following binding of the envelope protein to the CD4 mangabeys than it is to HIV-1. molecule associated with the above-mentioned confor- mational change in the viral envelope gp120, fusion with MORPHOLOGY OF HIV the host cell membrane occurs via the newly exposed Electron microscopy shows that the HIV virion is an icosahedral structure (Fig. 37-1A) containing numerous TABLE 37-2 1993 REVISED CLASSIFICATION SYSTEM FOR HIV INFECTION AND EXPANDED AIDS SURVEILLANCE CASE DEFINITION FOR ADOLESCENTS AND ADULTS CLINICAL CATEGORIES CD4+ T CELL A ASYMPTOMATIC, B SYMPTOMATIC, C AIDS- CATEGORIES ACUTE (PRIMARY) NOT A OR C INDICATOR HIV OR PGLa CONDITIONS CONDITIONS >500/μL 200–499/μL A1 B1 C1 <200/μL A2 B2 C2 A3 B3 C3 aPGL, progressive generalized lymphadenopathy. Source: MMWR 42(No. RR-17), December 18, 1992.

TABLE 37-3 495 CLINICAL CATEGORIES OF HIV INFECTION CHAPTER 37 HIV Neurology Category A: Consists of one or more of the conditions listed below in an adolescent or adult (>13 years) with documented HIV infection. Conditions listed in categories B and C must not have occurred. Asymptomatic HIV infection Persistent generalized lymphadenopathy Acute (primary) HIV infection with accompanying illness or history of acute HIV infection Category B: Consists of symptomatic conditions in an HIV-infected adolescent or adult that are not included among condi- tions listed in clinical category C and that meet at least one of the following criteria: (1) The conditions are attributed to HIV infection or are indicative of a defect in cell-mediated immunity; or (2) the conditions are considered by physicians to have a clinical course or to require management that is complicated by HIV infection. Examples include, but are not limited to, the following: Bacillary angiomatosis Candidiasis, oropharyngeal (thrush) Candidiasis, vulvovaginal; persistent, frequent, or poorly responsive to therapy Cervical dysplasia (moderate or severe)/cervical carcinoma in situ Constitutional symptoms, such as fever (38.5°C) or diarrhea lasting >1 month Hairy leukoplakia, oral Herpes zoster (shingles), involving at least two distinct episodes or more than one dermatome Idiopathic thrombocytopenic purpura Listeriosis Pelvic inflammatory disease, particularly if complicated by tuboovarian abscess Peripheral neuropathy Category C: Conditions listed in the AIDS surveillance case definition. Candidiasis of bronchi, trachea, or lungs Candidiasis, esophageal Cervical cancer, invasivea Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 month’s duration) Cytomegalovirus disease (other than liver, spleen, or nodes) Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV-related Herpes simplex: chronic ulcer(s) (>1 month’s duration); or bronchitis, pneumonia, or esophagitis Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month’s duration) Kaposi’s sarcoma Lymphoma, Burkitt’s (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pulmonarya or extrapulmonary) Mycobacterium, other species or unidentified species, disseminated or extrapulmonary Pneumocystis jiroveci pneumonia Pneumonia, recurrenta Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain Wasting syndrome due to HIV aAdded in the 1993 expansion of the AIDS surveillance case definition. Source: MMWR 42(No. RR-17), December 18, 1992. gp41 molecule penetrating the plasma membrane of the transcription of the genomic RNA into DNA, and the target cell and then coiling upon itself to bring the virion protein coat opens to release the resulting double-stranded and target cell together. Following fusion, the preintegra- HIV-DNA. At this point in the replication cycle, the viral tion complex, composed of viral RNA and viral enzymes genome is vulnerable to cellular factors that can block the and surrounded by a capsid protein coat, is released into progression of infection. In particular, the cytoplasmic the cytoplasm of the target cell. As the preintegration TRIM5-α protein in rhesus macaque cells blocks SIV complex traverses the cytoplasm to reach the nucleus, the replication at a point shortly after the virus fuses with the viral reverse transcriptase enzyme catalyzes the reverse host cell. Although the exact mechanisms of action of

496 gp41 Matrix Lipid Capsid membrane RNA gp120 Reverse transcriptase SECTION III Diseases of the Central Nervous System FIGURE 37-1 transmembrane components of the envelope, genomic RNA, A. Electron micrograph of HIV. Figure illustrates a typical enzyme reverse transcriptase, p18(17) inner membrane virion following budding from the surface of a CD4+ T lym- (matrix), and p24 core protein (capsid) (copyright by George phocyte, together with two additional incomplete virions in V. Kelvin). (Adapted from RC Gallo: Sci Am 256:46, 1987.) the process of budding from the cell membrane. B. Struc- ture of HIV-1, including the gp120 outer membrane, gp41 TRIM5-α remain unclear, the human form is inhibited by is still not clear whether (1) viral replication is inhibited cyclophilin A and is not effective in restricting HIV repli- by the binding of APOBEC to the virus genome with cation in human cells. The recently described APOBEC subsequent accumulation of reverse transcripts, or (2) by family of cellular proteins also inhibits progression of the hypermutations caused by the enzymatic deaminase virus infection after virus has entered the cell. APOBEC activity of APOBEC proteins. HIV has evolved a powerful proteins bind to nascent reverse transcripts and deaminate strategy to protect itself from APOBEC. The viral protein viral cytidine, causing hypermutation of HIV genomes. It Vif targets APOBEC for proteasomal degradation. Cellular DNA Unintegrated linear DNA Integrase Integrated mRNA Reverse gp120 proviral DNA transcriptase CD4 Genomic RNA Genomic HIV RNA Co-receptor Budding Protein synthesis, Fusion processing, and assembly Mature HIV virion FIGURE 37-2 The replication cycle of HIV. See text for description. (Adapted from Fauci, 1996.)

With activation of the cell, the viral DNA accesses receptor for HIV. When the number of CD4+ T cells 497 CHAPTER 37 HIV Neurology the nuclear pore and is exported from the cytoplasm to declines below a certain level, the patient is at high risk the nucleus, where it is integrated into the host cell for developing a variety of opportunistic diseases, particu- chromosomes through the action of another virally larly the infections and neoplasms that are AIDS-defining encoded enzyme, integrase. HIV provirus (DNA) selec- illnesses. Some features of AIDS, such as Kaposi sarcoma tively integrates into the nuclear DNA preferentially and neurologic abnormalities, cannot be explained com- within introns of active genes and regional hotspots. pletely by the immunosuppressive effects of HIV, since This provirus may remain transcriptionally inactive these complications may occur prior to the development (latent) or it may manifest varying levels of gene expres- of severe immunologic impairment. sion, up to active production of virus. NEUROPATHOGENESIS Cellular activation plays an important role in the replication cycle of HIV and is critical to the pathogene- Although there has been a remarkable decrease in the sis of HIV disease. Following initial binding and internal- incidence of HIV encephalopathy among those with ization of virions into the target cell, incompletely access to treatment in the era of effective ARV therapy, reverse-transcribed DNA intermediates are labile in qui- HIV-infected individuals can still experience a variety of escent cells and do not integrate efficiently into the host neurologic abnormalities due either to opportunistic cell genome unless cellular activation occurs shortly after infections and neoplasms or to direct effects of HIV or infection. Furthermore, some degree of activation of the its products. With regard to the latter, HIV has been host cell is required for the initiation of transcription of demonstrated in the brain and CSF of infected individu- the integrated proviral DNA into either genomic RNA als with and without neuropsychiatric abnormalities.The or mRNA. This latter process may not necessarily be main cell types that are infected in the brain in vivo are associated with the detectable expression of the classic the perivascular macrophages and the microglial cells; cell surface markers of activation. In this regard, activa- monocytes that have already been infected in the blood tion of HIV expression from the latent state depends on can migrate into the brain, where they then reside as the interaction of a number of cellular and viral factors. macrophages, or macrophages can be directly infected Following transcription, HIV mRNA is translated into within the brain. The precise mechanisms whereby HIV proteins that undergo modification through glycosyla- enters the brain are unclear; however, they are thought to tion, myristylation, phosphorylation, and cleavage. The relate, at least in part, to the ability of virus-infected and viral particle is formed by the assembly of HIV proteins, immune-activated macrophages to induce adhesion mol- enzymes, and genomic RNA at the plasma membrane of ecules such as E-selectin and vascular cell adhesion mole- the cells. Budding of the progeny virion occurs through cule-1 (VCAM-1) on brain endothelium. Other studies specialized regions in the lipid bilayer of the host cell have demonstrated that HIV gp120 enhances the expres- membrane known as lipid rafts, where the core acquires sion of intercellular adhesion molecule-1 (ICAM-1) in its external envelope. The virally encoded protease then glial cells; this effect may facilitate entry of HIV-infected catalyzes the cleavage of the gag-pol precursor to yield cells into the CNS and may promote syncytia formation. the mature virion. Progression through the virus replica- Virus isolates from the brain are preferentially R5 strains tion cycle is profoundly influenced by a variety of viral as opposed to X4 strains; in this regard, HIV-infected regulatory gene products. Likewise, each point in the individuals who are heterozygous for CCR5-Δ32 appear replication cycle of HIV is a real or potential target for to be relatively protected against the development of therapeutic intervention. Thus far, the reverse transcrip- HIV encephalopathy compared to wild-type individuals. tase, protease, and integrase enzymes as well as the process Distinct HIV envelope sequences are associated with the of virus–target cell binding and fusion have proven clini- clinical expression of the AIDS dementia complex.There cally to be susceptible to pharmacologic disruption. is no convincing evidence that brain cells other than Inhibitors of the maturation process of virions during those of monocyte/macrophage lineage can be produc- the latter phase of the replication cycle are currently tively infected in vivo. Astrocytes have been reported to being evaluated in clinical trials. be susceptible to HIV infection in vitro despite the fact that they do not express detectable levels of cell-surface PATHOPHYSIOLOGY CD4 or the main HIV co-receptors. Nonetheless, they AND PATHOGENESIS do not support active virus replication. There is no con- vincing evidence that oligodendrocytes or neurons can The hallmark of HIV disease is a profound immunode- be infected with HIV (see below). ficiency resulting primarily from a progressive quantitative and qualitative deficiency of the subset of T lympho- HIV-infected individuals may manifest white matter cytes referred to as helper T cells. This subset of T cells is lesions as well as neuronal loss. Given the absence of defined phenotypically by the presence on its surface of evidence of HIV infection of neurons either in vivo or the CD4 molecule, which serves as the primary cellular in vitro, it is highly unlikely that direct infection of these

SECTION III Diseases of the Central Nervous System498 cells accounts for their loss. Rather, the HIV-mediated opportunistic diseases that involve the CNS are toxoplas- effects on neurons and oligodendrocytes are thought to mosis, cryptococcosis, progressive multifocal leukoen- involve indirect pathways whereby viral proteins, partic- cephalopathy, and primary CNS lymphoma. Other less ularly gp120 and Tat, trigger the release of endogenous common problems include mycobacterial infections; neurotoxins from macrophages and to a lesser extent syphilis; and infection with CMV, HTLV-I, T. cruzi, or from astrocytes. In addition, it has been demonstrated Acanthamoeba. Overall, secondary diseases of the CNS that both HIV-1 Nef and Tat can induce chemotaxis of occur in approximately one-third of patients with AIDS. leukocytes, including monocytes, into the CNS. Neuro- These data antedate the widespread use of combination toxins can be released from monocytes as a consequence ARV therapy, and this frequency is considerably less in of infection and/or immune activation. Monocyte- patients receiving effective ARV drugs. derived neurotoxic factors have been reported to kill neurons via the N-methyl-d-aspartate (NMDA) receptor. NEUROLOGIC DISEASE CAUSED BY HIV In addition, HIV gp120 shed by virus-infected mono- cytes could cause neurotoxicity by antagonizing the HIV-Associated Cognitve Impairment function of vasoactive intestinal peptide (VIP), by elevat- ing intracellular calcium levels, and by decreasing nerve The term HIV-associated neurocognitive impairment (HNCI) growth factor levels in the cerebral cortex. A variety of is used to describe a spectrum of disorders that range from monocyte-derived cytokines can contribute directly or asymptomatic to apparent only through extensive neu- indirectly to the neurotoxic effects in HIV infection; ropsychiatric testing to clinically severe.The most severe these include TNF-α, IL-1, IL-6,TGF-β, IFN-γ, platelet- form, the AIDS dementia complex, or HIV encephalopathy, activating factor, and endothelin. Furthermore, among is considered an AIDS-defining illness. Most HIV-infected the CC-chemokines, elevated levels of monocyte chemo- patients have some neurologic problem during the course tactic protein (MCP)1 in the brain and CSF have been of their disease. As noted in the section on pathogenesis, shown to correlate best with the presence and degree of damage to the CNS may be a direct result of viral infec- HIV encephalopathy. In addition, infection and/or acti- tion of the CNS macrophages or glial cells or may be vation of monocyte-lineage cells can result in increased secondary to the release of neurotoxins and potentially production of eicosanoids, nitric oxide, and quinolinic toxic cytokines such as IL-1β,TNF-α, IL-6, and TGF-β. acid, which may contribute to neurotoxicity. Astrocytes It has been reported that HIV-infected individuals with may play diverse roles in HIV neuropathogenesis. Reac- the E4 allele for apo E are at increased risk for AIDS tive gliosis or astrocytosis has been demonstrated in the encephalopathy and peripheral neuropathy. Virtually all brains of HIV-infected individuals, and TNF-α and IL-6 patients with HIV infection have some degree of nervous have been shown to induce astrocyte proliferation. In system involvement with the virus. This is evidenced by addition, astrocyte-derived IL-6 can induce HIV expres- the fact that CSF findings are abnormal in ~90% of sion in infected cells in vitro. Furthermore, it has been patients, even during the asymptomatic phase of HIV suggested that astrocytes may downregulate macrophage- infection. CSF abnormalities include pleocytosis (50–65% produced neurotoxins. It has been reported that HIV- of patients), detection of viral RNA (~75%), elevated infected individuals with the E4 allele for apolipoprotein CSF protein (35%), and evidence of intrathecal synthesis E (apo E) are at increased risk for AIDS encephalopathy of anti-HIV antibodies (90%). It is important to point and peripheral neuropathy.The likelihood that HIV or its out that evidence of infection of the CNS with HIV products are involved in neuropathogenesis is supported does not imply impairment of cognitive function. The by the observation that neuropsychiatric abnormalities neurologic function of an HIV-infected individual should may undergo remarkable and rapid improvement upon be considered normal unless clinical signs and symptoms the initiation of ARV therapy. suggest otherwise. It has also been suggested that the CNS may serve as a relatively sequestered site for a reservoir of latently HIV encephalopathy, also called HIV-associated demen- infected cells and for the slow, continual replication of tia or AIDS dementia complex, consists of a constellation HIV that might be a barrier for the eradication of virus of signs and symptoms of CNS disease. Although this is by ARV therapy. generally a late complication of HIV infection that pro- gresses slowly over months, it can be seen in patients CLINICAL MANIFESTATIONS with CD4+ T cell counts >350 cells/μL.A major feature of this entity is the development of dementia, defined as The neurologic problems that occur in HIV-infected a decline in cognitive ability from a previous level. It individuals may be either primary to the pathogenic may present as impaired ability to concentrate, increased processes of HIV infection or secondary to opportunis- forgetfulness, difficulty reading, or increased difficulty tic infections or neoplasms. Among the more frequent performing complex tasks. Initially these symptoms may be indistinguishable from findings of situational depres- sion or fatigue. In contrast to “cortical” dementia (such

TABLE 37-4 499 CLINICAL STAGING OF HIV ENCEPHALOPATHY (AIDS DEMENTIA COMPLEX) STAGE DEFINITION CHAPTER 37 HIV Neurology Stage 0 (normal) Stage 0.5 (equivocal/ Normal mental and motor function Absent, minimal, or equivocal symptoms without subclinical) impairment of work or capacity to perform activities of daily living. Mild signs (snout response, slowed ocular or Stage 1 (mild) extremity movements) may be present. Gait and strength are normal. Stage 2 (moderate) Able to perform all but the more demanding aspects of Stage 3 (severe) work or activities of daily living but with unequivocal evi- dence (signs or symptoms that may include performance Stage 4 (end-stage) on neuropsychological testing) of functional, intellectual, or motor impairment. Can walk without assistance. Able to perform basic activities of self-care but cannot work or maintain the more demanding aspects of daily life. Ambulatory, but may require a single prop. Major intellectual incapacity (cannot follow news or personal events, cannot sustain complex conversation, considerable slowing of all output) or motor disability (cannot walk unassisted, usually with slowing and clum- siness of arms as well). Nearly vegetative. Intellectual and social comprehension and output are at a rudimentary level. Nearly or absolutely mute. Paraparetic or paraplegic with urinary and fecal incontinence. Source: Adapted from JJ Sidtis, RW Price, Neurology 40:197, 1990. as Alzheimer’s disease), aphasia, apraxia, and agnosia are encephalopathy; a commonly used clinical staging sys- uncommon, leading some investigators to classify HIV tem is outlined in Table 37-4. encephalopathy as a “subcortical dementia.” In addition to dementia, patients with HIV encephalopathy may The precise cause of HIV encephalopathy remains also have motor and behavioral abnormalities. Among unclear, although the condition is thought to be a result the motor problems are unsteady gait, poor balance, of a combination of direct effects of HIV on the CNS tremor, and difficulty with rapid alternating movements. and associated immune activation. HIV has been found Increased tone and deep tendon reflexes may be found in the brains of patients with HIV encephalopathy by in patients with spinal cord involvement. Late stages may Southern blot, in situ hybridization, PCR, and electron be complicated by bowel and/or bladder incontinence. microscopy. Multinucleated giant cells, macrophages, and Behavioral problems include apathy and lack of initia- microglial cells appear to be the main cell types harbor- tive, with progression to a vegetative state in some ing virus in the CNS. Histologically, the major changes instances. Some patients develop a state of agitation or are seen in the subcortical areas of the brain and include mild mania.These changes usually occur without signif- pallor and gliosis, multinucleated giant cell encephalitis, icant changes in level of alertness. This is in contrast to and vacuolar myelopathy. Less commonly, diffuse or the finding of somnolence in patients with dementia focal spongiform changes occur in the white matter. due to toxic/metabolic encephalopathies. Areas of the brain involved in motor, language, and judgment are most severely affected. HIV encephalopathy is the initial AIDS-defining ill- ness in ~3% of patients with HIV infection and thus There are no specific criteria for a diagnosis of HIV only rarely precedes clinical evidence of immunodefi- encephalopathy, and this syndrome must be differenti- ciency. Clinically significant encephalopathy eventually ated from a number of other diseases that affect the develops in ~25% of patients with AIDS. As immuno- CNS of HIV-infected patients.The diagnosis of demen- logic function declines, the risk and severity of HIV tia depends upon demonstrating a decline in cognitive encephalopathy increase. Autopsy series suggest that function. This can be accomplished objectively with the 80–90% of patients with HIV infection have histologic use of a Mini-Mental Status Examination (MMSE) in evidence of CNS involvement. Several classification patients for whom prior scores are available. For this rea- schemes have been developed for grading HIV son, it is advisable for all patients with a diagnosis of HIV infection to have a baseline MMSE. However,

500 TABLE 37-5 CLINICAL FINDINGS IN THE ACUTE HIV SYNDROME General Neurologic Fever Meningitis Pharyngitis Encephalitis Lymphadenopathy Peripheral neuropathy Headache/retroorbital pain Myelopathy Arthralgias/myalgias Lethargy/malaise Dermatologic Anorexia/weight loss Erythematous maculopapu- Nausea/vomiting/diarrhea lar rash Mucocutaneous ulceration Source: From B Tindall, DA Cooper: AIDS 5:1, 1991. SECTION III Diseases of the Central Nervous System FIGURE 37-3 this problem is quickly reversible, again supporting at AIDS dementia complex. Postcontrast CT scan through the least a partial role of soluble mediators in the pathogen- lateral ventricles of a 47-year-old man with AIDS, altered esis. It should also be noted that these patients have an mental status, and dementia. The lateral and third ventricles increased sensitivity to the side effects of neuroleptic and the cerebral sulci are abnormally prominent. Mild white drugs.The use of these drugs for symptomatic treatment matter hypodensity is also seen adjacent to the frontal horns is associated with an increased risk of extrapyramidal of the lateral ventricles. side effects; therefore, patients with HIV encephalopathy who receive these agents must be monitored carefully. changes in MMSE scores may be absent in patients with mild HIV encephalopathy. Imaging studies of the CNS, Asceptic Meningitis and Encephalitis by either MRI or CT, often demonstrate evidence of cerebral atrophy (Fig. 37-3). MRI may also reveal small Aseptic meningitis may be seen in any but the very late areas of increased density on T2-weighted images. Lum- stages of HIV infection. In the setting of acute primary bar puncture is an important element of the evaluation infection patients may experience a syndrome of headache, of patients with HIV infection and neurologic abnor- photophobia, and meningismus (Table 37-5). Rarely, an malities. It is generally most helpful in ruling out or acute encephalopathy due to encephalitis may occur. making a diagnosis of opportunistic infections. In HIV Cranial nerve involvement may be seen, predominantly encephalopathy, patients may have the nonspecific find- cranial nerve VII but occasionally V and/or VIII. CSF ings of an increase in CSF cells and protein level. findings include a lymphocytic pleocytosis, elevated pro- Although HIV RNA can often be detected in the spinal tein level, and normal glucose level.This syndrome, which fluid and HIV can be cultured from the CSF, this find- cannot be clinically differentiated from other viral menin- ing is not specific for HIV encephalopathy. There gitides (Chap. 35), usually resolves spontaneously within appears to be no correlation between the presence of 2–4 weeks; however, in some patients, signs and symp- HIV in the CSF and the presence of HIV encephalopa- toms may become chronic. Aseptic meningitis may occur thy. Elevated levels of macrophage chemoattractant pro- any time in the course of HIV infection; however, it is tein (MCP-1), β2-microglobulin, neopterin, and quinolinic rare following the development of AIDS. This fact sug- acid (a metabolite of tryptophan reported to cause CNS gests that clinical aseptic meningitis in the context of HIV injury) have been noted in the CSF of patients with infection is an immune-mediated disease. HIV encephalopathy. These findings suggest that these factors as well as inflammatory cytokines may be HIV Myelopathy involved in the pathogenesis of this syndrome. Spinal cord disease, or myelopathy, is present in ~20% of Combination ARV therapy is of benefit in patients patients with AIDS, often as part of HIV encephalopa- with HIV encephalopathy. Improvement in neuropsy- thy. In fact, 90% of the patients with HIV-associated chiatric test scores has been noted for both adult and myelopathy have some evidence of dementia, suggest- pediatric patients treated with ARVs.The rapid improve- ing that similar pathologic processes may be responsible ment in cognitive function noted with the initiation of for both conditions. Three main types of spinal cord ARV therapy suggests that at least some component of disease are seen in patients with AIDS.The first of these is a vacuolar myelopathy, as discussed above under HIV encephalopathy. This condition is pathologically similar to subacute combined degeneration of the cord such as

occurs with pernicious anemia. Although vitamin B12 they should be reserved for severe cases of CIDP refrac- 501CHAPTER 37 HIV Neurology deficiency can be seen in patients with AIDS as a pri- tory to other measures. Another autoimmune peripheral mary complication of HIV infection, it does not appear neuropathy seen in patients with AIDS is mononeuritis to be responsible for the myelopathy seen in the major- multiplex (Chap. 40) due to a necrotizing arteritis of ity of patients.Vacuolar myelopathy is characterized by a peripheral nerves. The most common peripheral neu- subacute onset and often presents with gait distur- ropathy in patients with HIV infection is a distal sen- bances, predominantly ataxia and spasticity; it may sory polyneuropathy that may be a direct consequence progress to include bladder and bowel dysfunction. of HIV infection or a side effect of dideoxynucleoside Physical findings include evidence of increased deep therapy. Two-thirds of patients with AIDS may be tendon reflexes and extensor plantar responses.The sec- shown by electrophysiologic studies to have some evi- ond form of spinal cord disease involves the dorsal dence of peripheral nerve disease. Presenting symptoms columns and presents as a pure sensory ataxia.The third are usually painful burning sensations in the feet and form is also sensory in nature and presents with pares- lower extremities. Findings on examination include a thesias and dysesthesias of the lower extremities. In stocking-type sensory loss to pinprick, temperature, and contrast to the cognitive problems seen in patients with touch sensation and a loss of ankle reflexes. Motor HIV encephalopathy, these spinal cord syndromes do changes are mild and are usually limited to weakness of not respond well to ARV drugs, and therapy is mainly the intrinsic foot muscles. Response of this condition to supportive. ARVs has been variable, perhaps because ARVs are responsible for the problem in some instances. When One important disease of the spinal cord that also due to dideoxynucleoside therapy, patients with lower involves the peripheral nerves is a myelopathy and extremity peripheral neuropathy may complain of a polyradiculopathy seen in association with CMV infection. sensation that they are walking on ice. Other entities in This entity is generally seen late in the course of HIV the differential diagnosis of peripheral neuropathy infection and is fulminant in onset, with lower extremity include diabetes mellitus, vitamin B12 deficiency, and and sacral paresthesias, difficulty in walking, areflexia, side effects from metronidazole or dapsone. For distal ascending sensory loss, and urinary retention.The clinical symmetric polyneuropathy that fails to resolve follow- course is rapidly progressive over a period of weeks. CSF ing the discontinuation of dideoxynucleosides, therapy examination reveals a predominantly neutrophilic pleo- is symptomatic; gabapentin, carbamazepine, tricyclics, cytosis, and CMV DNA can be detected by CSF PCR. or analgesics may be effective for dysesthesias. Treat- Therapy with ganciclovir or foscarnet can lead to rapid ment-naive patients may respond to combination ARV improvement, and prompt initiation of foscarnet or gan- therapy. ciclovir therapy is important in minimizing the degree of permanent neurologic damage. Combination therapy HIV Myopathy with both drugs should be considered in patients who have been previously treated for CMV disease. Other Myopathy may complicate the course of HIV infection; diseases involving the spinal cord in patients with HIV causes include HIV infection itself, zidovudine, and the infection include HTLV-I-associated myelopathy (HAM), generalized wasting syndrome. HIV-associated myopa- neurosyphilis, infection with herpes simplex or varicella- thy may range in severity from an asymptomatic eleva- zoster,TB, and lymphoma. tion in creatine kinase levels to a subacute syndrome characterized by proximal muscle weakness and myal- HIV Neuropathy gias. Quite pronounced elevations in creatine kinase may occur in asymptomatic patients, particularly after Peripheral neuropathies are common in patients with exercise. The clinical significance of this as an isolated HIV infection. They occur at all stages of illness and laboratory finding is unclear. A variety of both inflam- take a variety of forms. Early in the course of HIV matory and noninflammatory pathologic processes have infection, an acute inflammatory demyelinating polyneu- been noted in patients with more severe myopathy, ropathy resembling Guillain-Barré syndrome may occur including myofiber necrosis with inflammatory cells, (Chap. 41). In other patients, a progressive or relapsing- nemaline rod bodies, cytoplasmic bodies, and mito- remitting inflammatory neuropathy resembling chronic chondrial abnormalities. Profound muscle wasting, inflammatory demyelinating polyneuropathy (CIDP) has often with muscle pain, may be seen after prolonged been noted. Patients commonly present with progressive zidovudine therapy. This toxic side effect of the drug is weakness, areflexia, and minimal sensory changes. CSF dose-dependent and is related to its ability to interfere examination often reveals a mononuclear pleocytosis, with the function of mitochondrial polymerases. It is and peripheral nerve biopsy demonstrates a perivascular reversible following discontinuation of the drug. Red infiltrate suggesting an autoimmune etiology. Plasma ragged fibers are a histologic hallmark of zidovudine- exchange or IVIg has been tried with variable success. induced myopathy. Because of the immunosuppressive effects of glucocorticoids,

SECTION III Diseases of the Central Nervous System502 HIV-Related Neoplasms FIGURE 37-4 Systemic Lymphoma Central nervous system lymphoma. Postcontrast Lymphomas occur with an increased frequency in T1-weighted MR scan in a patient with AIDS, an altered men- patients with congenital or acquired T cell immunodefi- tal status, and hemiparesis. Multiple enhancing lesions, some ciencies. AIDS is no exception; at least 6% of all patients ring-enhancing, are present. The left Sylvian lesion shows with AIDS develop lymphoma at some time during the gyral and subcortical enhancement, and the lesions in the course of their illness.This is a 120-fold increase in inci- caudate and splenium (arrowheads) show enhancement of dence compared to the general population. In contrast adjacent ependymal surfaces. to the situation with KS, primary CNS lymphoma, and most opportunistic infections, the incidence of AIDS- Primary CNS lymphoma generally presents with associated systemic lymphomas has not experienced as focal neurologic deficits, including cranial nerve find- dramatic a decrease as a consequence of the widespread ings, headaches, and/or seizures. MRI or CT generally use of effective ARV therapy. Lymphoma occurs in all reveals a limited number (one to three) of 3- to 5-cm risk groups, with the highest incidence in patients with lesions (Fig. 37-4). The lesions often show ring hemophilia and the lowest incidence in patients from enhancement on contrast administration and may occur the Caribbean or Africa with heterosexually acquired in any location. Locations that are most commonly infection. Lymphoma is a late manifestation of HIV involved with CNS lymphoma are deep in the white infection, generally occurring in patients with CD4+ T matter. Contrast enhancement is usually less pronounced cell counts <200/μL. As HIV disease progresses, the risk than that seen with toxoplasmosis. The main diseases in of lymphoma increases. In contrast to KS, which occurs the differential diagnosis are cerebral toxoplasmosis and at a relatively constant rate throughout the course of cerebral Chagas’ disease. In addition to the 20% of lym- HIV disease, the attack rate for lymphoma increases phomas in HIV-infected individuals that are primary exponentially with increasing duration of HIV infection CNS lymphomas, CNS disease is also seen in HIV- and decreasing level of immunologic function. At 3 infected patients with systemic lymphoma. Approxi- years following a diagnosis of HIV infection, the risk of mately 20% of patients with systemic lymphoma have lymphoma is 0.8% per year; by 8 years after infection, it CNS disease in the form of leptomeningeal involve- is 2.6% per year. As individuals with HIV infection live ment. This fact underscores the importance of lumbar longer as a consequence of improved ARV therapy and puncture in the staging evaluation of patients with sys- better treatment and prophylaxis of opportunistic infec- temic lymphoma. tions, it is anticipated that the incidence of lymphomas may increase. Systemic lymphoma is seen at earlier stages of HIV infection than primary CNS lymphoma. In one series The clinical presentation of lymphoma in patients the mean CD4+ T cell count was 189/μL. In addition with HIV infection is quite varied, ranging from focal to lymph node involvement, systemic lymphoma may seizures to rapidly growing mass lesions in the oral commonly involve the gastrointestinal tract, bone mar- mucosa to persistent unexplained fever. At least 80% of row, liver, and lung. Gastrointestinal tract involvement is patients present with extranodal disease, and a similar seen in ~25% of patients. Any site in the gastrointestinal percentage have B-type symptoms of fever, night sweats, tract may be involved, and patients may complain of dif- or weight loss. Virtually any site in the body may be ficulty swallowing or abdominal pain. The diagnosis is involved.The most common extranodal site is the CNS, usually suspected on the basis of CT or MRI of the which is involved in approximately one-third of all abdomen. Bone marrow involvement is seen in ~20% of patients with lymphoma. Approximately 60% of these cases are primary CNS lymphoma. CNS lymphoma Primary CNS lymphoma accounts for ~20% of the cases of lymphoma in patients with HIV infection. In contrast to HIV-associated Burkitt’s lymphoma, primary CNS lymphomas are usually positive for EBV. In one study, the incidence of Epstein-Barr positivity was 100%. This malignancy does not have a predilection for any particu- lar age group. The median CD4+ T cell count at the time of diagnosis is ~50/μL.Thus, CNS lymphoma gen- erally presents at a later stage of HIV infection than sys- temic lymphoma. This fact may at least in part explain the poorer prognosis for this subset of patients.

503 300 CD4 (cells/μL3) * *200 100 * * * * * * * * * * * * * 0 HSV HZos Crp KS Cry Can PCP NHL DEM PML WS Tox CMV PCP2 MAC Opportunistic illness FIGURE 37-5 DEM, AIDS dementia complex; HSV, herpes simplex virus CHAPTER 37 HIV Neurology Relationship between CD4+ T cell counts and the devel- infection; HZos, herpes zoster; KS, Kaposi’s sarcoma; MAC, opment of opportunistic diseases. Boxplot of the median Mycobacterium avium complex bacteremia; NHL, non- (line inside the box), first quartile (bottom of the box), third Hodgkin’s lymphoma; PCP, primary Pneumocystis jiroveci quartile (top of the box), and mean (asterisk) CD4+ lympho- pneumonia; PCP2, secondary P. jiroveci pneumonia; PML, cyte count at the time of the development of opportunistic dis- progressive multifocal leukoencephalopathy; Tox, Toxoplasma ease. Can, candidal esophagitis; CMV, cytomegalovirus infec- gondii encephalitis; WS, wasting syndrome. (From RD Moore, tion; Crp, cryptosporidiosis; Cry, cryptococcal meningitis; RE Chaisson: Ann Intern Med 124:633, 1996.) patients and may lead to pancytopenia. Liver and lung such infections correlates well with the CD4+ T cell count involvement are each seen in ~10% of patients. Pul- (Figure 37-5). A selected group of common and impor- monary disease may present as either a mass lesion, mul- tant opportunistic infections of the nervous system in tiple nodules, or an interstitial infiltrate. patients with HIV is discussed below. Both conventional and unconventional approaches Cryptococcosis have been employed in an attempt to treat HIV-related C. neoformans is the leading infectious cause of meningi- lymphomas. Systemic lymphoma is generally treated by tis in patients with AIDS. It is the initial AIDS-defining the oncologist with combination chemotherapy. Earlier illness in ~2% of patients and generally occurs in disappointing figures are being replaced with more opti- patients with CD4+ T cell counts <100/μL. Crypto- mistic results for the treatment of systemic lymphoma coccal meningitis is particularly common in patients following the availability of more effective combination with AIDS in Africa, occurring in ~20% of patients. ARV therapy. As in most situations in patients with HIV Most patients present with a picture of subacute menin- disease, those with the higher CD4+ T cell counts tend goencephalitis with fever, nausea, vomiting, altered men- to do better. Response rates as high as 72% with a tal status, headache, and meningeal signs. The incidence median survival of 33 months and disease-free intervals of seizures and focal neurologic deficits is low. The CSF up to 9 years have been reported. Treatment of primary profile may be normal or may show only modest eleva- CNS lymphoma remains a significant challenge. Treat- tions in WBC or protein levels and decreases in glucose. ment is complicated by the fact that this illness usually In addition to meningitis, patients may develop crypto- occurs in patients with advanced HIV disease. Palliative coccomas and cranial nerve involvement. Approximately measures such as radiation therapy provide some relief. one-third of patients also have pulmonary disease. The prognosis remains poor in this group, with a 2-year Uncommon manifestations of cryptococcal infection survival of 29%. include skin lesions that resemble molluscum contagiosum, lymphadenopathy, palatal and glossal ulcers, arthritis, gas- HIV-Related Opportunistic Infections troenteritis, myocarditis, and prostatitis. The prostate gland may serve as a reservoir for smoldering cryptococ- Patients with HIV infection may present with focal neu- cal infection.The diagnosis of cryptococcal meningitis is rologic deficits from a variety of causes.The most common made by identification of organisms in spinal fluid with causes are toxoplasmosis, progressive multifocal leukoen- India ink examination or by the detection of cryptococ- cephalopathy, and CNS lymphoma. Other causes include cal antigen. A biopsy may be needed to make a diagnosis cryptococcal infections, stroke, and reactivation Chagas’ of CNS cryptococcoma. Treatment is with IV ampho- disease. A broad spectrum of opportunistic infections has tericin B, at a dose of 0.7 mg/kg daily, with flucytosine, been described in AIDS patients. The risk of many

SECTION III Diseases of the Central Nervous System504 25 mg/kg qid for 2 weeks, followed by fluconazole, FIGURE 37-6 400 mg/d PO for 10 weeks, and then fluconazole, Central nervous system toxoplasmosis. A coronal post- 200 mg/d until the CD4+ T cell count has increased to contrast T1-weighted MR scan demonstrates a peripheral >200 cells/μL for 6 months in response to HAART. enhancing lesion in the left frontal lobe, associated with an Repeated lumbar puncture may be required to manage eccentric nodular area of enhancement (arrow); this so-called increased intracranial pressure. Symptoms may recur eccentric target sign is typical of toxoplasmosis. with initiation of HAART as an immune reconstitution syndrome. Other fungi that may cause meningitis in sulfadiazine and pyrimethamine with leucovorin as patients with HIV infection are C. immitis and H. capsulatum. needed for a minimum of 4–6 weeks. Alternative thera- Meningoencephalitis has also been reported due to peutic regimens include clindamycin in combination with Acanthamoeba or Naegleria. pyrimethamine; atovaquone plus pyrimethamine; and azithromycin plus pyrimethamine plus rifabutin. Relapses Toxoplasmosis are common, and it is recommended that patients with a history of prior toxoplasmic encephalitis receive mainte- Toxoplasmosis has been one of the most common causes nance therapy with sulfadiazine, pyrimethamine, and of secondary CNS infections in patients with AIDS, but leucovorin as long as their CD4+ T cell counts remain its incidence is decreasing in the era of HAART. It is <200 cells/μL. Patients with CD4+ T cell counts most common in patients from the Caribbean and from <100/μL and IgG antibody to Toxoplasma should receive France.Toxoplasmosis is generally a late complication of primary prophylaxis for toxoplasmosis. Fortunately, the HIV infection and usually occurs in patients with same daily regimen of a single double-strength tablet of CD4+ T cell counts <200/μL. Cerebral toxoplasmosis is TMP/SMX used for P. jiroveci prophylaxis provides thought to represent a reactivation syndrome. It is 10 times adequate primary protection against toxoplasmosis. more common in patients with antibodies to the organism Secondary prophylaxis/maintenance therapy for toxo- than in patients who are seronegative. Patients diagnosed plasmosis may be discontinued in the setting of effec- with HIV infection should be screened for IgG antibod- tive ARV therapy and increases in CD4+ T cell counts ies to T. gondii during the time of their initial workup. to >200/μL for 6 months. Those who are seronegative should be counseled about ways to minimize the risk of primary infection includ- Progressive Multifocal ing avoiding the consumption of undercooked meat and Leukoencephalopathy (PML) careful hand washing after contact with soil or changing the cat litter box. The most common clinical presenta- JC virus, a human polyomavirus that is the etiologic tion of cerebral toxoplasmosis in patients with HIV agent of progressive multifocal leukoencephalopathy (PML), is infection is fever, headache, and focal neurologic deficits. an important opportunistic pathogen in patients with Patients may present with seizure, hemiparesis, or aphasia AIDS. Although ~70% of the general adult population as a manifestation of these focal deficits or with a picture have antibodies to JC virus, indicative of prior infection, more influenced by the accompanying cerebral edema <10% of healthy adults show any evidence of ongoing and characterized by confusion, dementia, and lethargy, viral replication. PML is the only known clinical mani- which can progress to coma.The diagnosis is usually sus- festation of JC virus infection. It is a late manifestation pected on the basis of MRI findings of multiple lesions in of AIDS and is seen in ~4% of patients with AIDS. The multiple locations, although in some cases only a single lesions of PML begin as small foci of demyelination in lesion is seen. Pathologically, these lesions generally exhibit inflammation and central necrosis and, as a result, demon- strate ring enhancement on contrast MRI (Fig. 37-6) or, if MRI is unavailable or contraindicated, on double- dose contrast CT.There is usually evidence of surround- ing edema. In addition to toxoplasmosis, the differential diagnosis of single or multiple enhancing mass lesions in the HIV-infected patient includes primary CNS lym- phoma (see below) and, less commonly, TB or fungal or bacterial abscesses.The definitive diagnostic procedure is brain biopsy. However, given the morbidity than can accompany this procedure, it is usually reserved for the patient who has failed 2–4 weeks of empirical therapy. If the patient is seronegative for T. gondii, the likelihood that a mass lesion is due to toxoplasmosis is <10%. In that setting, one may choose to be more aggressive and perform a brain biopsy sooner. Standard treatment is

subcortical white matter that eventually coalesce. The AIDS-defining condition and may be the initial AIDS- 505 CHAPTER 37 HIV Neurology cerebral hemispheres, cerebellum, and brainstem may all defining condition. Lesions appear radiographically as be involved. Patients typically have a protracted course single or multiple hypodense areas, typically with ring with multifocal neurologic deficits, with or without enhancement and edema.They are found predominantly changes in mental status. Approximately 20% of patients in the subcortical areas, a feature that differentiates them experience seizures. Ataxia, hemiparesis, visual field from the deeper lesions of toxoplasmosis. Trypanosoma defects, aphasia, and sensory defects may occur. MRI cruzi amastigotes, or trypanosomes, can be identified typically reveals multiple, nonenhancing white matter from biopsy specimens or CSF. Other CSF findings lesions that may coalesce and have a predilection for the include elevated protein and a mild (<100 cells/μL) occipital and parietal lobes. The lesions show signal lymphocytic pleocytosis. Organisms can also be identi- hyperintensity on T2-weighted images and diminished fied by direct examination of the blood.Treatment con- signal on T1-weighted images. The measurement of JC sists of benzimidazole (2.5 mg/kg bid) or nifurtimox virus DNA levels in CSF has a diagnostic sensitivity of (2 mg/kg qid) for at least 60 days, followed by mainte- 76% and a specificity of close to 100%. Prior to the nance therapy for the duration of immunodeficiency availability of potent ARV combination therapy, the with either drug at a dose of 5 mg/kg three times a majority of patients with PML died within 3–6 months week. As is the case with cerebral toxoplasmosis, success- of the onset of symptoms. Paradoxical worsening of ful therapy with ARVs may allow discontinuation of PML has been seen with initiation of HAART as an therapy for Chagas’ disease. immune reconstitution syndrome. There is no specific treatment for PML; however, a minimal median survival SPECIFIC NEUROLOGIC PRESENTATIONS of 18 months and survival of >7 years have been reported in patients with PML treated with HAART for Stroke their HIV disease. Unfortunately only ~50% of patients with HIV infection and PML show neurologic Stroke may occur in patients with HIV infection. In improvement with HAART. Studies with other antiviral contrast to the other causes of focal neurologic deficits agents such as cidofovir have failed to show clear bene- in patients with HIV infection, the symptoms of a stroke fit. Factors influencing a favorable prognosis for PML in are sudden in onset. Among the secondary infectious the setting of HIV infection include a CD4+ T cell diseases in patients with HIV infection that may be asso- count >100/μL at baseline and the ability to maintain ciated with stroke are vasculitis due to cerebral varicella an HIV viral load of <500 copies per mL. Baseline HIV- zoster or neurosyphilis and septic embolism in associa- 1 viral load does not have independent predictive value tion with fungal infection. Other elements of the dif- of survival. PML is one of the few opportunistic infec- ferential diagnosis of stroke in the patient with HIV tions that continues to occur with some frequency infection include atherosclerotic cerebral vascular disease, despite the widespread use of HAART. thrombotic thrombocytopenic purpura, and cocaine or amphetamine use. Chagas’ Disease Seizures Reactivation American trypanosomiasis may present as acute meningoencephalitis with focal neurologic signs, fever, Seizures may be a consequence of opportunistic infec- headache, vomiting, and seizures. In South America, tions, neoplasms, or HIV encephalopathy (Table 37-6). reactivation of Chagas’ disease is considered to be an The seizure threshold is often lower than normal in TABLE 37-6 CAUSES OF SEIZURES IN PATIENTS WITH HIV INFECTION DISEASE OVERALL FRACTION OF CONTRIBUTION TO PATIENTS WHO HIV encephalopathy FIRST SEIZURE, % HAVE SEIZURES, % Cerebral toxoplasmosis Cryptococcal meningitis 24–47 7–50 Primary central nervous 28 15–40 system lymphoma 13 Progressive multifocal 4 8 15–30 leukoencephalopathy 1 Source: From DM Holtzman et al: Am J Med 87:173, 1989.

SECTION III Diseases of the Central Nervous System506 patients with advanced HIV infection due to the fre- indicated in all patients with HIV infection and seizures quent presence of electrolyte abnormalities. Seizures are unless a rapidly correctable cause is found.While pheny- seen in 15–40% of patients with cerebral toxoplasmosis, toin remains the initial treatment of choice, hypersensi- 15–35% of patients with primary CNS lymphoma, 8% tivity reactions to this drug have been reported in >10% of patients with cryptococcal meningitis, and 7–50% of of patients with AIDS, and therefore the use of phenobar- patients with HIV encephalopathy. Seizures may also be bital or valproic acid must be considered as alternatives. seen in patients with CNS tuberculosis, aseptic menin- gitis, and progressive multifocal leukoencephalopathy. FURTHER READINGS Seizures may be the presenting clinical symptom of HIV disease. In one study of 100 patients with HIV BENSON CA et al: Treating opportunistic infections among HIV- infection presenting with a first seizure, cerebral mass infected adults and adolescents. Recommendations from CDC, the lesions were the most common cause, responsible for 32 National Institutes of Health, and the HIV Medicine Association/ of the 100 new-onset seizures. Of these 32 cases, 28 Infectious Diseases Society of America. MMWR 53(RR-15):1, were due to toxoplasmosis and 4 to lymphoma. HIV 2004. Updates available at http://www.aidsinfo.nih.gov encephalopathy accounted for an additional 24 new- onset seizures. Cryptococcal meningitis was the third BOISSE L et al: HIV infection of the central nervous system: clinical most common diagnosis, responsible for 13 of the 100 features and neuropathogenesis. Neurol Clin 26:799, 2008 seizures. In 23 cases, no cause could be found, and it is possible that these cases represent a subcategory of HIV GONZALEZ-SCARANO F, MARTIN-GARCIA J: The neuropathogenesis encephalopathy. Of these 23 cases, 16 (70%) had two or of AIDS. Nat Rev Immunol 5:69, 2005 more seizures, suggesting that anticonvulsant therapy is KAUL M: HIV-1 associated dementia: update on pathological mecha- nisms and therapeutic approaches. Curr Opin Neurol 22:315, 2009 PRICE RW, SPUDICH S: Antiretroviral therapy and central nervous system HIV type 1 infection. J Infect Dis 197Suppl3:S294, 2008

CHAPTER 38 PRION DISEASES Stanley B. Prusiner I Bruce L. Miller I Spectrum of Prion Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 507 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 508 Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 513 Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 I Sporadic and Inherited Prion Diseases . . . . . . . . . . . . . . . . . 511 Care of CJD Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 Human PRNP Gene Polymorphisms . . . . . . . . . . . . . . . . . . . 511 Decontamination of CJD Prions . . . . . . . . . . . . . . . . . . . . . . 515 Prevention and Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . 515 I Infectious Prion Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515 Iatrogenic CJD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 511 Variant CJD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 Neuropathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 512 Prions are infectious proteins that cause degeneration of from that of its precursor, PrPC. (4) PrPSc can exist in a the central nervous system (CNS). Prion diseases are disorders of protein conformation, the most common of variety of different conformations, each of which seems which in humans is called Creutzfeldt-Jakob disease (CJD). CJD typically presents with dementia and to specify a particular disease phenotype. How a specific myoclonus, is relentlessly progressive, and generally conformation of a PrPSc molecule is imparted to PrPC causes death within a year of onset. Most CJD patients during prion replication to produce nascent PrPSc with are between 50 and 75 years of age; however, patients as young as 17 and as old as 83 have been recorded. the same conformation is unknown. Additionally, it is unclear what factors determine where in the CNS a particular PrPSc molecule will be deposited. In mammals, prions reproduce by binding to the nor- SPECTRUM OF PRION DISEASES mal, cellular isoform of the prion protein (PrPC) and stimulating conversion of PrPC into the disease-causing The sporadic form of CJD is the most common prion dis- isoform (PrPSc). PrPC is rich in α-helix and has little order in humans. Sporadic CJD (sCJD) accounts for ~85% β-structure, while PrPSc has less α-helix and a high of all cases of human prion disease, while inherited prion amount of β-structure (Fig. 38-1). This α-to-β struc- diseases account for 10–15% of all cases (Table 38-2). tural transition in the prion protein (PrP) is the funda- Familial CJD (fCJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI) are all mental event underlying prion diseases (Table 38-1). dominantly inherited prion diseases that are caused by mutations in the PrP gene. Although infectious prion Four new concepts have emerged from studies of pri- diseases account for <1% of all cases and infection does not seem to play an important role in the natural history ons: (1) Prions are the only known infectious pathogens of these illnesses, the transmissibility of prions is an important biologic feature. Kuru of the Fore people of that are devoid of nucleic acid; all other infectious agents New Guinea is thought to have resulted from the con- sumption of brains from dead relatives during ritualistic possess genomes composed of either RNA or DNA that cannibalism. With the cessation of ritualistic cannibalism in the late 1950s, kuru has nearly disappeared, with the direct the synthesis of their progeny. (2) Prion diseases may be manifest as infectious, genetic, and sporadic dis- orders; no other group of illnesses with a single etiology presents with such a wide spectrum of clinical manifes- tations. (3) Prion diseases result from the accumulation of PrPSc, the conformation of which differs substantially 507

508 Helix A Helix B exception of a few recent patients exhibiting incubation Helix C Helix C periods of >40 years. Iatrogenic CJD (iCJD) seems to be Helix B the result of the accidental inoculation of patients with prions.Variant CJD (vCJD) in teenagers and young adults A Recombinant PrP B PrPSc model in Europe is the result of exposure to tainted beef from cattle with bovine spongiform encephalopathy (BSE). SECTION III Diseases of the Central Nervous System FIGURE 38-1 Six diseases of animals are caused by prions (Table 38-2). Structures of prion proteins. A. NMR structure of Syrian Scrapie of sheep and goats is the prototypic prion disease. hamster recombinant (rec) PrP(90–231). Presumably, the Mink encephalopathy, BSE, feline spongiform encephalopa- structure of the α-helical form of recPrP(90–231) resembles thy, and exotic ungulate encephalopathy are all thought to that of PrPC. recPrP(90–231) is viewed from the interface occur after the consumption of prion-infected foodstuffs. where PrPSc is thought to bind to PrPC. Shown are: α-helices The BSE epidemic emerged in Britain in the late 1980s and A (residues 144–157), B (172–193), and C (200–227). Flat rib- was shown to be due to industrial cannibalism. Whether bons depict β-strands S1 (129–131) and S2 (161–163). BSE began as a sporadic case of BSE in a cow or started ( A, from SB Prusiner: N Engl J Med 344:1516, 2006; with with scrapie in sheep is unknown. The origin of chronic permission.) B. Structural model of PrPSc. The 90–160 region wasting disease (CWD), a prion disease endemic in deer has been modeled onto a β-helical architecture while the and elk in regions of North America, is uncertain. COOH terminal helices B and C are preserved as in PrPC. (Image prepared by C. Govaerts.) EPIDEMIOLOGY TABLE 38-1 CJD is found throughout the world. The incidence of sCJD is approximately one case per million population, GLOSSARY OF PRION TERMINOLOGY and thus it accounts for about one in every 10,000 deaths. Because sCJD is an age-dependent neurodegen- Prion Proteinaceous infectious particle that erative disease, its incidence is expected to increase lacks nucleic acid. Prions are composed steadily as older segments of populations in developed PrPSc largely, if not entirely, of PrPSc molecules. and developing countries continue to expand. Although PrPC They can cause scrapie in sheep and many geographic clusters of CJD have been reported, PrP 27-30 goats, and related neurodegenerative each has been shown to segregate with a PrP gene PRNP diseases of humans such as Creutzfeldt- mutation. Attempts to identify common exposure to Prion rod Jakob disease (CJD). some etiologic agent have been unsuccessful for both the sporadic and familial cases. Ingestion of scrapie- PrP amyloid Disease-causing isoform of the prion infected sheep or goat meat as a cause of CJD in protein. This protein is the only identifi- humans has not been demonstrated by epidemiologic able macromolecule in purified prepara- studies, although speculation about this potential route tions of scrapie prions. of inoculation continues. Of particular interest are deer hunters who develop CJD, because up to 90% of culled Cellular isoform of the prion protein. deer in some game herds have been shown to harbor PrPC is the precursor of PrPSc. CWD prions. Whether prion disease in deer or elk can A fragment of PrPSc, generated by be passed to cows, sheep, or directly to humans remains truncation of the NH2-terminus by limited unknown. Studies with Syrian hamsters demonstrate digestion with proteinase K. PrP 27-30 that oral infection with prions can occur, but the process retains prion infectivity and polymerizes is inefficient compared to intracerebral inoculation. into amyloid. PrP gene located on human PATHOGENESIS chromosome 20. An aggregate of prions composed largely The human prion diseases were initially classified as of PrP 27-30 molecules. Created by neurodegenerative disorders of unknown etiology on detergent extraction and limited proteol- the basis of pathologic changes being confined to the ysis of PrPSc. Morphologically and histo- CNS. With the transmission of kuru and CJD to apes, chemically indistinguishable from many investigators began to view these diseases as infectious amyloids. CNS illnesses caused by slow viruses. Even though the Amyloid containing PrP in the brains of familial nature of a subset of CJD cases was well animals or humans with prion disease; described, the significance of this observation became often accumulates as plaques. more obscure with the transmission of CJD to animals. Eventually the meaning of heritable CJD became clear

TABLE 38-2 509 THE PRION DISEASES HOST MECHANISM OF PATHOGENESIS DISEASE Fore people Infection through ritualistic cannibalism Human Humans Infection from prion-contaminated hGH, Kuru dura mater grafts, etc. iCJD Infection from bovine prions Germ-line mutations in PRNP vCJD Humans Germ-line mutations in PRNP fCJD Humans Germ-line mutation in PRNP (D178N, M129) GSS Humans Somatic mutation or spontaneous FFI Humans conversion of PrPC into PrPSc? sCJD Humans Somatic mutation or spontaneous conversion of PrPC into PrPSc? sFI Humans Infection in genetically susceptible sheep Animal Sheep, goats Infection with prion-contaminated MBM CHAPTER 38 Prion Diseases Scrapie Cattle Infection with prions from sheep or cattle BSE Mink Unknown Mule deer, elk Infection with prion-contaminated beef TME Cats Infection with prion-contaminated MBM CWD Greater kudu, FSE Exotic ungulate nyala, or oryx encephalopathy Note: BSE, bovine spongiform encephalopathy; CJD, Creutzfeldt-Jakob disease; fCJD, familial Creutzfeldt-Jakob disease; iCJD, iatrogenic Creutzfeldt-Jakob disease; sCJD, sporadic Creutzfeldt-Jakob disease; vCJD, variant Creutzfeldt-Jakob disease; CWD, chronic wasting disease; FFI, fatal familial insomnia; sFI, sporadic fatal insom- nia; FSE, feline spongiform encephalopathy; GSS, Gerstmann-Sträussler-Scheinker disease; hGH, human growth hormone; MBM, meat and bone meal; TME, transmissible mink encephalopathy. with the discovery of mutations in the PRNP gene of PrP Polypeptide CHO CHO GPI these patients.The prion concept explains how a disease can manifest as a heritable as well as an infectious illness. SS Moreover, the hallmark of all prion diseases, whether sporadic, dominantly inherited, or acquired by infection, PrPC 209 amino acids is that they involve the aberrant metabolism of PrP. PrPSc 209 amino acids A major feature that distinguishes prions from viruses is the finding that both PrP isoforms are encoded by a PrP 27-30 ~142 amino acids chromosomal gene. In humans, the PrP gene is desig- Codon nated PRNP and is located on the short arm of chro- mosome 20. Limited proteolysis of PrPSc produces a 1 23 50 94 131 188 231 254 smaller, protease-resistant molecule of ~142 amino acids designated PrP 27-30; PrPC is completely hydrolyzed FIGURE 38-2 under the same conditions (Fig. 38-2). In the presence of detergent, PrP 27-30 polymerizes into amyloid. Prion Prion protein isoforms. Bar diagram of Syrian hamster PrP, rods formed by limited proteolysis and detergent extrac- which consists of 254 amino acids. After processing of the tion are indistinguishable from the filaments that aggre- NH2 and COOH termini, both PrPC and PrPSc consist of 209 gate to form PrP amyloid plaques in the CNS. Both the residues. After limited proteolysis, the NH2 terminus of PrPSc rods and the PrP amyloid filaments found in brain tissue is truncated to form PrP 27–30 composed of ~142 amino exhibit similar ultrastructural morphology and green- acids. gold birefringence after staining with Congo red dye. in a molecule other than nucleic acid.Various strains of Prion Strains prions have been defined by incubation times and the distribution of neuronal vacuolation. Subsequently, the The existence of prion strains raised the question of patterns of PrPSc deposition were found to correlate how heritable biologic information can be enciphered with vacuolation profiles, and these patterns were also used to characterize prion strains.

510 TABLE 38-3 DISTINCT PRION STRAINS GENERATED IN HUMANS WITH INHERITED PRION DISEASES AND TRANSMITTED TO TRANSGENIC MICEa INOCULUM HOST SPECIES HOST PrP GENOTYPE INCUBATION TIME PrPSc (kDa) [DAYS ± SEM] (n/n0) None Human FFI(D178N, M129) 19 FFI Mouse Tg(MHu2M) 206 ± 7 (7/7) 19 FFI → Tg(MHu2M) Mouse Tg(MHu2M) 136 ± 1 (6/6) 19 None Human fCJD(E200K) 21 fCJD Mouse Tg(MHu2M) 170 ± 2 (10/10) 21 fCJD → Tg(MHu2M) Mouse Tg(MHu2M) 167 ± 3 (15/15) 21 aTg(MHu2M) mice express a chimeric mouse-human PrP gene. Note: Clinicopathologic phenotype is determined by the conformation of PrPSc in accord with the results of the transmission of human prions from patients with FFI to transgenic mice. FFI, fatal familial insomnia; fCJD, familial Creutzfeldt-Jakob disease. SECTION III Diseases of the Central Nervous System Persuasive evidence that strain-specific information is New strains of prions were also generated from enciphered in the tertiary structure of PrPSc comes from recombinant (rec) PrP produced in bacteria. In these studies, recPrP was polymerized into amyloid fibrils and transmission of two different inherited human prion dis- inoculated into transgenic mice expressing very high levels of truncated mouse PrPC; about 500 days later, the eases to mice expressing a chimeric human-mouse PrP mice died of prion disease. These “synthetic prions” were found to be much more stable than any prions transgene. In FFI, the protease-resistant fragment of previously isolated from animals or humans with natu- PrPSc after deglycosylation has a molecular mass of 19 rally occurring prion diseases. Surprisingly, studies of synthetic and naturally occurring prions indicate that kDa, whereas in fCJD and most sporadic prion diseases, the incubation time is directly proportional to the stabil- ity of the prion. As the stability increases, the incubation it is 21 kDa (Table 38-3). This difference in molecular time lengthens; thus, less-stable prions replicate more rapidly.These studies also showed that PrPSc can adopt a mass was shown to be due to different sites of prote- continuum of conformational states, each of which enciphers a distinct incubation-time phenotype. olytic cleavage at the NH2 termini of the two human PrPSc molecules, reflecting different tertiary structures. Species Barrier These distinct conformations were not unexpected Studies on the role of the primary and tertiary structures of PrP in the transmission of prion disease have given because the amino acid sequences of the PrPs differ. new insights into the pathogenesis of these maladies.The amino acid sequence of PrP encodes the species of the Extracts from the brains of patients with FFI transmit- prion, and the prion derives its PrPSc sequence from the last mammal in which it was passaged. While the ted disease into mice expressing a chimeric human-mouse primary structure of PrP is likely to be the most impor- tant or even sole determinant of the tertiary structure of PrP transgene and induced formation of the 19-kDa PrPC, PrPSc seems to function as a template in determin- PrPSc, whereas brain extracts from fCJD and sCJD ing the tertiary structure of nascent PrPSc molecules as patients produced the 21-kDa PrPSc in mice expressing they are formed from PrPC. In turn, prion diversity appears to be enciphered in the conformation of PrPSc, the same transgene. On second passage, these differences and thus prion strains seem to represent different con- were maintained, demonstrating that chimeric PrPSc can formers of PrPSc. exist in two different conformations based on the sizes In general, transmission of prion disease from one species to another is inefficient, in that not all intracere- of the protease-resistant fragments, even though the brally inoculated animals develop disease, and those that amino acid sequence of PrPSc is invariant. fall ill do so only after long incubation times that can approach the natural life span of the animal.This “species This analysis was extended when patients with spo- barrier” to transmission is correlated with the degree of radic fatal insomnia (sFI) were identified. Although they did not carry a PRNP gene mutation, the patients demonstrated a clinical and pathologic phenotype that was indistinguishable from that of patients with FFI. Furthermore, 19-kDa PrPSc was found in their brains, and on passage of prion disease to mice expressing a chimeric human-mouse PrP transgene, 19-kDa PrPSc was also found. These findings indicate that the disease phenotype is dictated by the conformation of PrPSc and not the amino acid sequence. PrPSc acts as a template for the conversion of PrPC into nascent PrPSc. On the pas- sage of prions into mice expressing a chimeric hamster- mouse PrP transgene, a change in the conformation of PrPSc was accompanied by the emergence of a new strain of prions.

similarity between the amino acid sequences of PrPC in condition indistinguishable from sCJD to a slowly pro- 511 CHAPTER 38 Prion Diseases the inoculated host and of PrPSc in the prion inoculum. gressive dementing illness of many years’ duration to an The importance of sequence similarity between the host early-age-of-onset disorder that is similar to Alzheimer’s and donor PrP argues that PrPC directly interacts with disease. A mutation at codon 178 resulting in substitu- PrPSc in the prion conversion process. tion of asparagine for aspartic acid produces FFI if a methionine is encoded at the polymorphic 129 residue SPORADIC AND INHERITED on the same allele. Typical CJD is seen if a valine is PRION DISEASES encoded at position 129 of the same allele. Several different scenarios might explain the initiation of HUMAN PRNP GENE POLYMORPHISMS sporadic prion disease: (1) A somatic mutation may be the cause and thus follow a path similar to that for Polymorphisms influence the susceptibility to sporadic, germ-line mutations in inherited disease. In this situa- inherited, and infectious forms of prion disease. The tion, the mutant PrPSc must be capable of targeting methionine/valine polymorphism at position 129 not wild-type PrPC, a process known to be possible for some only modulates the age of onset of some inherited mutations but less likely for others. (2) The activation prion diseases but can also determine the clinical phe- barrier separating wild-type PrPC from PrPSc could be notype. The finding that homozygosity at codon 129 crossed on rare occasions when viewed in the context of predisposes to sCJD supports a model of prion produc- a population. Most individuals would be spared while tion that favors PrP interactions between homologous presentations in the elderly with an incidence of ~1 per proteins. million would be seen. (3) PrPSc may be present at very low levels in some normal cells, where it performs some Substitution of the basic residue lysine at position 218 important, as yet unknown, function. The level of PrPSc in mouse PrP produced dominant-negative inhibition of in such cells is hypothesized to be sufficiently low as to prion replication in transgenic mice. This same lysine at be not detected by bioassay. In some altered metabolic position 219 in human PrP has been found in 12% of states, the cellular mechanisms for clearing PrPSc might the Japanese population, and this group appears to be become compromised and the rate of PrPSc formation resistant to prion disease. Dominant-negative inhibition would then begin to exceed the capacity of the cell to of prion replication was also found with substitution of clear it. The third possible mechanism is attractive since the basic residue arginine at position 171; sheep with it suggests PrPSc is not simply a misfolded protein, as arginine are resistant to scrapie prions but are susceptible proposed for the first and second mechanisms, but that it to BSE prions that were inoculated intracerebrally. is an alternatively folded molecule with a function. Moreover, the multitude of conformational states that INFECTIOUS PRION DISEASES PrPSc can adopt, as described above, raises the possibility that PrPSc or another prion-like protein might function IATROGENIC CJD in a process like short-term memory where information storage occurs in the absence of new protein synthesis. Accidental transmission of CJD to humans appears to have occurred with corneal transplantation, contami- More than 30 different mutations resulting in non- nated electroencephalogram (EEG) electrode implanta- conservative substitutions in the human PRNP gene tion, and surgical procedures. Corneas from donors with have been found to segregate with inherited human inapparent CJD have been transplanted to apparently prion diseases. Missense mutations and expansions in the healthy recipients who developed CJD after prolonged octapeptide repeat region of the gene are responsible for incubation periods. The same improperly decontami- familial forms of prion disease. Five different mutations nated EEG electrodes that caused CJD in two young of the PRNP gene have been linked genetically to heri- patients with intractable epilepsy caused CJD in a chim- table prion disease. panzee 18 months after their experimental implantation. Although phenotypes may vary dramatically within Surgical procedures may have resulted in accidental families, specific phenotypes tend to be observed with inoculation of patients with prions, presumably because certain mutations. A clinical phenotype indistinguishable some instrument or apparatus in the operating theater from typical sCJD is usually seen with substitutions at became contaminated when a CJD patient underwent codons 180, 183, 200, 208, 210, and 232. Substitutions at surgery. Although the epidemiology of these studies is codons 102, 105, 117, 198, and 217 are associated with highly suggestive, no proof for such episodes exists. the GSS variant of prion disease.The normal human PrP sequence contains five repeats of an eight-amino-acid Dura Mater Grafts sequence. Insertions from two to nine extra octarepeats frequently cause variable phenotypes ranging from a More than 160 cases of CJD after implantation of dura mater grafts have been recorded. All of the grafts were

SECTION III Diseases of the Central Nervous System512 thought to have been acquired from a single manufac- conformation and glycosylation of PrPSc. One scenario turer whose preparative procedures were inadequate to suggests that a particular conformation of bovine PrPSc inactivate human prions. One case of CJD occurred was selected for heat resistance during the rendering after repair of an eardrum perforation with a peri- process and was then reselected multiple times as cattle cardium graft. infected by ingesting prion-contaminated meat and bone meal (MBM) were slaughtered and their offal ren- Human Growth Hormone and Pituitary dered into more MBM. Gonadotropin Therapy NEUROPATHOLOGY The possibility of transmission of CJD from contami- nated human growth hormone (hGH) preparations Frequently the brains of patients with CJD have no rec- derived from human pituitaries has been raised by the ognizable abnormalities on gross examination. Patients occurrence of fatal cerebellar disorders with dementia in who survive for several years have variable degrees of >180 patients ranging from 10 to 41 years of age.These cerebral atrophy. patients received injections of hGH every 2–4 days for 4–12 years. If it is assumed that these patients developed On light microscopy, the pathologic hallmarks of CJD from injections of prion-contaminated hGH CJD are spongiform degeneration and astrocytic gliosis. preparations, the possible incubation periods range from The lack of an inflammatory response in CJD and other 4 to 30 years. Even though several investigations argue prion diseases is an important pathologic feature of these for the efficacy of inactivating prions in hGH fractions degenerative disorders. Spongiform degeneration is prepared from human pituitaries with 6 M urea, it seems characterized by many 1- to 5-μm vacuoles in the neu- doubtful that such protocols will be used for purifying ropil between nerve cell bodies. Generally the spongi- hGH because recombinant hGH is available. Four cases form changes occur in the cerebral cortex, putamen, of CJD have occurred in women receiving human pitu- caudate nucleus, thalamus, and molecular layer of the itary gonadotropin. cerebellum. Astrocytic gliosis is a constant but nonspe- cific feature of prion diseases. Widespread proliferation VARIANT CJD of fibrous astrocytes is found throughout the gray matter of brains infected with CJD prions. Astrocytic processes The restricted geographic occurrence and chronology filled with glial filaments form extensive networks. of vCJD raised the possibility that BSE prions have been transmitted to humans through the consumption of Amyloid plaques have been found in ~10% of CJD tainted beef. More than 190 cases of vCJD have cases. Purified CJD prions from humans and animals occurred, with >90% of these in Britain. vCJD has also exhibit the ultrastructural and histochemical characteris- been reported in people either living in or originating tics of amyloid when treated with detergents during from France, Ireland, Italy, Netherlands, Portugal, Spain, limited proteolysis. In first passage from some human Saudi Arabia, United States, Canada, and Japan. Japanese CJD cases, amyloid plaques have been found in mouse brains. These plaques stain with antibodies raised Because the number of vCJD cases is still small, it not against PrP. possible to decide if we are at the beginning of a prion disease epidemic in Europe, similar to those seen for BSE The amyloid plaques of GSS disease are morpholog- and kuru, or if the number of vCJD cases will remain ically distinct from those seen in kuru or scrapie. GSS small. What is certain is that prion-tainted meat should plaques consist of a central dense core of amyloid sur- be prevented from entering the human food supply. rounded by smaller globules of amyloid. Ultrastruc- turally, they consist of a radiating fibrillar network of The most compelling evidence that vCJD is caused by amyloid fibrils, with scant or no neuritic degeneration. BSE prions was obtained from experiments in mice The plaques can be distributed throughout the brain expressing the bovine PrP transgene. Both BSE and vCJD but are most frequently found in the cerebellum. They prions were efficiently transmitted to these transgenic are often located adjacent to blood vessels. Con- mice and with similar incubation periods. In contrast to gophilic angiopathy has been noted in some cases of sCJD prions, vCJD prions did not transmit disease effi- GSS disease. ciently to mice expressing a chimeric human-mouse PrP transgene. Earlier studies with nontransgenic mice sug- In vCJD, a characteristic feature is the presence of gested that vCJD and BSE might be derived from the “florid plaques.”These are composed of a central core of same source because both inocula transmitted disease PrP amyloid, surrounded by vacuoles in a pattern sug- with similar but very long incubation periods. gesting petals on a flower. Attempts to determine the origin of BSE and vCJD CLINICAL FEATURES prions have relied on passaging studies in mice, some of which are described above, as well as studies of the Nonspecific prodromal symptoms occur in about a third of patients with CJD and may include fatigue, sleep

disturbance, weight loss, headache, malaise, and ill- usually a prominent and presenting feature, with demen- 513 CHAPTER 38 Prion Diseases defined pain. Most patients with CJD present with tia occurring late in the disease course. GSS disease typi- deficits in higher cortical function. These deficits almost cally presents earlier than CJD (mean age 43 years) and always progress over weeks or months to a state of pro- is typically more slowly progressive than CJD; death found dementia characterized by memory loss, impaired usually occurs within 5 years of onset. FFI is character- judgment, and a decline in virtually all aspects of intel- ized by insomnia and dysautonomia; dementia occurs lectual function. A few patients present with either only in the terminal phase of the illness. Rare sporadic visual impairment or cerebellar gait and coordination cases have been identified. vCJD has an unusual clinical deficits. Frequently the cerebellar deficits are rapidly fol- course, with a prominent psychiatric prodrome that may lowed by progressive dementia. Visual problems often include visual hallucinations and early ataxia, while begin with blurred vision and diminished acuity, rapidly frank dementia is usually a late sign of vCJD. followed by dementia. DIFFERENTIAL DIAGNOSIS Other symptoms and signs include extrapyramidal dysfunction manifested as rigidity, masklike facies, or Many conditions may mimic CJD superficially. Demen- choreoathetoid movements; pyramidal signs (usually tia with Lewy bodies (Chap. 23) is the most common mild); seizures (usually major motor) and, less com- disorder to be mistaken for CJD. It can present in a sub- monly, hypoesthesia; supranuclear gaze palsy; optic atro- acute fashion with delirium, myoclonus, and extrapyra- phy; and vegetative signs such as changes in weight, tem- midal features. Other neurodegenerative disorders to perature, sweating, or menstruation. consider include AD, frontotemporal dementia, progres- sive supranuclear palsy, ceroid lipofuscinosis (Chap. 23), Myoclonus and myoclonic epilepsy with Lafora bodies (Chap. 20). The absence of abnormalities on diffusion-weighted and Most patients (~90%) with CJD exhibit myoclonus that FLAIR MRI will usually distinguish these dementing appears at various times throughout the illness. Unlike conditions from CJD. other involuntary movements, myoclonus persists during sleep. Startle myoclonus elicited by loud sounds or bright Hashimoto’s encephalopathy, which presents as a sub- lights is frequent. It is important to stress that myoclonus acute progressive encephalopathy with myoclonus and is neither specific nor confined to CJD. Dementia with periodic triphasic complexes on the EEG, should be myoclonus can also be due to Alzheimer’s disease (AD) excluded in every case of suspected CJD. It is diagnosed (Chap. 23), dementia with Lewy bodies (Chap. 23), cryp- by the finding of high titers of antithyroglobulin or tococcal encephalitis, or the myoclonic epilepsy disorder antithyroid peroxidase (antimicrosomal) antibodies in Unverricht-Lundborg disease (Chap. 20). the blood and improves with glucocorticoid therapy. Unlike CJD, fluctuations in severity typically occur in Clinical Course Hashimoto’s encephalopathy. In documented cases of accidental transmission of CJD Intracranial vasculitides may produce nearly all of the to humans, an incubation period of 1.5–2.0 years pre- symptoms and signs associated with CJD, sometimes ceded the development of clinical disease. In other cases, without systemic abnormalities. Myoclonus is excep- incubation periods of up to 30 years have been sug- tional with cerebral vasculitis, but focal seizures may con- gested. Most patients with CJD live 6–12 months after fuse the picture. Prominent headache, absence of the onset of clinical signs and symptoms, whereas some myoclonus, stepwise change in deficits, abnormal CSF, live for up to 5 years. and focal white matter changes on MRI or angiographic abnormalities all favor vasculitis. DIAGNOSIS Paraneoplastic conditions, particularly limbic encephali- The constellation of dementia, myoclonus, and periodic tis and cortical encephalitis, can also mimic CJD. In many electrical bursts in an afebrile 60-year-old patient gener- of these patients, dementia appears prior to the diagnosis ally indicates CJD. Clinical abnormalities in CJD are of a tumor, and in some, no tumor is ever found. Detec- confined to the CNS. Fever, elevated sedimentation rate, tion of the paraneoplastic antibodies is often the only way leukocytosis in blood, or a pleocytosis in cerebrospinal to distinguish these cases from CJD. fluid (CSF) should alert the physician to another etiol- ogy to explain the patient’s CNS dysfunction. Other diseases that can simulate CJD include neu- rosyphilis, AIDS dementia complex (Chap. 37), progressive Variations in the typical course appear in inherited multifocal leukoencephalopathy (Chap. 35), subacute scle- and transmitted forms of the disease. fCJD has an earlier rosing panencephalitis, progressive rubella panencephalitis, mean age of onset than sCJD. In GSS disease, ataxia is herpes simplex encephalitis, diffuse intracranial tumor (gliomatosis cerebri; Chap. 32), anoxic encephalopathy, dialysis dementia, uremia, hepatic encephalopathy, and lithium or bismuth intoxication.

SECTION III Diseases of the Central Nervous System514 LABORATORY TESTS FIGURE 38-3 T2-weighted (FLAIR) MRI showing hyperintensity in the cor- The only specific diagnostic tests for CJD and other tex in a patient with sporadic CJD. This so-called “cortical human prion diseases measure PrPSc. The most widely ribboning” along with increased intensity in the basal ganglia used method involves limited proteolysis that generates on T2 or diffusion-weighted imaging can aid in the diagnosis PrP 27-30, which is detected by immunoassay after of CJD. denaturation. The conformation-dependent immunoas- say (CDI) is based on immunoreactive epitopes that are stereotyped periodic bursts of <200 ms duration, occur- exposed in PrPC but buried in PrPSc. The CDI is ring every 1–2 s, makes the diagnosis of CJD very likely. extremely sensitive and quantitative and is likely to find These discharges are frequently but not always symmet- wide application in both the post- and antemortem ric; there may be a one-sided predominance in ampli- detection of prions. In humans, the diagnosis of CJD tude. As CJD progresses, normal background rhythms can be established by brain biopsy if PrPSc is detected. If become fragmentary and slower. no attempt is made to measure PrPSc, but the constella- tion of pathologic changes frequently found in CJD is CARE OF CJD PATIENTS seen in a brain biopsy, then the diagnosis is reasonably secure (see “Neuropathology,” above). Because PrPSc is Although CJD should not be considered either conta- not uniformly distributed throughout the CNS, the gious or communicable, it is transmissible. The risk of apparent absence of PrPSc in a limited sample such as a accidental inoculation by aerosols is very small; nonethe- biopsy does not rule out prion disease. At autopsy, suffi- less, procedures producing aerosols should be performed cient brain samples should be taken for both PrPSc in certified biosafety cabinets. Biosafety level 2 practices, immunoassay, preferably by CDI, and immunohisto- containment equipment, and facilities are recommended chemistry of tissue sections. by the Centers for Disease Control and Prevention and the National Institutes of Health. The primary problem To establish the diagnosis of either sCJD or familial in caring for patients with CJD is the inadvertent infec- prion disease, sequencing the PRNP gene must be per- tion of health care workers by needle and stab wounds. formed. Finding the wild-type PRNP gene sequence The transmission of prions through the air has never permits the diagnosis of sCJD if there is no history to been documented. Electroencephalographic and elec- suggest infection from an exogenous source of prions. tromyographic needles should not be reused after studies The identification of a mutation in the PRNP gene on patients with CJD have been performed. sequence that encodes a nonconservative amino acid substitution argues for familial prion disease. There is no reason for pathologists or other morgue employees to resist performing autopsies on patients CT may be normal or show cortical atrophy. MRI is whose clinical diagnosis was CJD. Standard microbio- valuable for distinguishing sCJD from most other condi- logic practices outlined here, along with specific recom- tions. On FLAIR sequences and diffusion-weighted mendations for decontamination, seem to be adequate imaging, ~90% of patients show increased intensity in precautions for the care of patients with CJD and the the basal ganglia and cortical ribboning (Fig. 38-3).This handling of infected specimens. pattern is not seen with other neurodegenerative disor- ders but has been seen infrequently with viral encephalitis, paraneoplastic syndromes, or seizures.When the typical MRI pattern is present, in the proper clinical setting, diagnosis is facilitated. However, some cases of sCJD do not show this typical pattern, and other early diagnostic approaches are still needed. CSF is nearly always normal but may show protein elevation and, rarely, mild pleocytosis. Although the stress protein 14-3-3 is elevated in the CSF of some patients with CJD, similar elevations of 14-3-3 are found in patients with other disorders; thus this elevation is not specific. The EEG is often useful in the diagnosis of CJD, although only about 60% of individuals show the typical pattern. During the early phase of CJD, the EEG is usu- ally normal or shows only scattered theta activity. In most advanced cases, repetitive, high-voltage, triphasic, and polyphasic sharp discharges are seen, but in many cases their presence is transient. The presence of these

DECONTAMINATION OF CJD PRIONS such antibodies in mice, either administered by injection 515 CHAPTER 38 Prion Diseases or produced from a transgene, have been shown to pre- Prions are extremely resistant to common inactivation vent prion disease when prions are introduced by a procedures, and there is some disagreement about the peripheral route, such as intraperitoneal inoculation. optimal conditions for sterilization. Some investigators Unfortunately, the antibodies were ineffective in mice recommend treating CJD-contaminated materials once inoculated intracerebrally with prions. Several drugs, with 1 N NaOH at room temperature, but we believe including pentosan polysulfate and porphyrin deriva- this procedure may be inadequate for sterilization. Auto- tives, delay the onset of disease in animals inoculated claving at 134°C for 5 h or treatment with 2 N NaOH intracerebrally with prions if the drugs are given intrac- for several hours is recommended for sterilization of erebrally beginning soon after inoculation. prions. The term sterilization implies complete destruc- tion of prions; any residual infectivity can be hazardous. Structure-based drug design predicated on dominant- Recent studies show that sCJD prions bound to stainless negative inhibition of prion formation has produced steel surfaces are resistant to inactivation by autoclaving several promising compounds. Modified quinacrine at 134°C for 2 h; exposure of bound prions to an acidic compounds that are more potent than the parent drug detergent solution prior to autoclaving rendered prions have been found. Whether improving the efficacy of susceptible to inactivation. such small molecules will provide general methods for developing novel therapeutics for other neurodegenera- PREVENTION AND THERAPEUTICS tive disorders, including AD and Parkinson’s disease as well as amyotrophic lateral sclerosis (ALS), remains to be There is no known effective therapy for preventing or established. treating CJD. The finding that phenothiazines and acridines inhibit PrPSc formation in cultured cells led to Disclosure: SBP has a financial interest in InPro Biotech- clinical studies of quinacrine in CJD patients. Although nology, Inc. quinacrine seems to slow the rate of decline in some CJD patients, no cure of the disease has been observed. FURTHER READINGS In wild-type mice, quinacrine treatment has been inef- fective. Recent studies indicate that inhibition of the HEAD MW, IRONSIDE JW: Sporadic Creutzfeldt-Jakob disease: dis- P-glycoprotein (Pgp) transport system results in substan- crete subtypes or a spectrum of disease? 132:2627, 2009 tially increased quinacrine levels in the brains of mice. Whether such an approach can be used to treat CJD PRUSINER SB: Prions, in Fields Virology, 5th ed., DM Knipe, PM remains to be established. Howley (eds.), Philadelphia, Lippincott Williams & Wilkins, 2007, pp 3059–3092 Like the acridines, anti-PrP antibodies have been shown to eliminate PrPSc from cultured cells. Additionally, SAFAR JG et al: Diagnosis of human prion disease. Proc Natl Acad Sci USA 102:3501, 2005 WILL RG et al: Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 47:575, 2000

CHAPTER 39 PARANEOPLASTIC NEUROLOGIC SYNDROMES Josep Dalmau I Myrna R. Rosenfeld Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516 Paraneoplastic Peripheral Neuropathies . . . . . . . . . . . . . . . . 523 Paraneoplastic Encephalomyelitis and Focal Encephalitis . . . 519 Lambert-Eaton Myasthenic Syndrome . . . . . . . . . . . . . . . . . 523 Paraneoplastic Cerebellar Degeneration . . . . . . . . . . . . . . . . 521 Myasthenia Gravis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 523 Paraneoplastic Opsoclonus-Myoclonus Syndrome . . . . . . . . 521 Polymyositis-Dermatomyositis . . . . . . . . . . . . . . . . . . . . . . . 523 Paraneoplastic Syndromes of the Spinal Cord . . . . . . . . . . . 522 Acute Necrotizing Myopathy . . . . . . . . . . . . . . . . . . . . . . . . . 524 Paraneoplastic Stiff-Person Syndrome . . . . . . . . . . . . . . . . . 522 Paraneoplastic Visual Syndromes . . . . . . . . . . . . . . . . . . . . . 524 Paraneoplastic Sensory Neuronopathy or Dorsal Root I Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 524 Ganglionopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 522 Paraneoplastic neurologic disorders (PNDs) are cancer- function and leading to neuronal apoptosis. In addition related syndromes that can affect any part of the nervous to onconeuronal antibodies, most PNDs of the CNS are system (Table 39-1). They are remote effects of cancer, associated with infiltrates of CD4+ and CD8+ T cells, caused by mechanisms other than metastasis or by any of microglial activation, gliosis, and variable neuronal loss. the complications of cancer such as coagulopathy, stroke, The infiltrating T cells are often in close contact with metabolic and nutritional conditions, infections, and side neurons undergoing degeneration, suggesting a primary effects of cancer therapy. In 60% of patients the neuro- pathogenic role. T cell–mediated cytotoxicity may con- logic symptoms precede the cancer diagnosis. Overall, tribute directly to cell death in these PNDs. Thus both clinically disabling PNDs occur in 0.5–1% of all cancer humoral and cellular immune mechanisms participate patients, but they occur in 2–3% of patients with neu- in the pathogenesis of many PNDs. This complex roblastoma or small cell lung cancer (SCLC), and in immunopathogenesis may underlie the resistance of many 30–50% of patients with thymoma or sclerotic of these conditions to therapy. myeloma. Neuronal cell-surface antigens can be the target of PATHOGENESIS antibodies in some patients with paraneoplastic encephalitis. A few of these antigens have been identi- Most PNDs are mediated by immune responses triggered fied, including the NR1/NR2 subunits of NMDA by neuronal proteins (onconeuronal antigens) expressed receptors (Fig. 39-1) and voltage-gated potassium chan- by tumors. In PNDs of the central nervous system nels (VGKC). These disorders are more responsive to (CNS), many antibody-associated immune responses have immunotherapy than those associated with immune been identified (Table 39-2). These antibodies usually responses to intracellular antigens. react with the patient’s tumor, and their detection in serum or cerebrospinal fluid (CSF) strongly predicts the Only four of the antibodies listed in Table 39-2 have presence of cancer. The target antigens are usually intra- been shown to play a direct pathogenic role in PNDs; all cellular proteins with roles in neuronal development and produce distinctive disorders of the peripheral nervous function. Some of the antibodies react with epitopes system. These are: antibodies to P/Q-type voltage-gated located in critical protein domains, disrupting protein calcium channels (VGCC) in patients with the Lambert- Eaton myasthenic syndrome (LEMS); antibodies to acetylcholine receptors in patients with myasthenia 516

TABLE 39-1 In addition, many patients with typical PND syndromes 517 CHAPTER 39 Paraneoplastic Neurologic Syndromes are antibody-negative. PARANEOPLASTIC SYNDROMES OF THE NERVOUS SYSTEM For still other PNDs, the cause remains quite obscure. These include, among others, several neuropathies that Syndromes of the brain, brainstem, and cerebellum occur in the terminal stages of cancer and a number of Focal encephalitis neuropathies associated with plasma cell dyscrasias or Cortical encephalitis lymphoma without evidence of inflammatory infiltrates Limbic encephalitis or deposits of immunoglobulin, cryoglobulin, or amyloid. Brainstem encephalitis Cerebellar dysfunction Approach to the Patient: Autonomic dysfunction PARANEOPLASTIC NEUROLOGIC Paraneoplastic cerebellar degeneration DISORDERS Opsoclonus-myoclonus The diagnosis and management of PNDs may be dif- Syndromes of the spinal cord ficult for several reasons. First, it is common for Subacute necrotizing myelopathy symptoms to appear before the presence of a tumor is Motor neuron dysfunction known. Second, the neurologic syndrome can evolve Myelitis in a rapidly progressive fashion, producing a severe Stiff-person syndrome and usually irreversible neurologic deficit in a short period of time. There is evidence that prompt tumor Syndromes of dorsal root ganglia control improves the course of PNDs. Therefore, the Sensory neuronopathy major concern of the physician is to recognize a dis- order promptly as paraneoplastic in order to identify Multiple levels of involvement and treat the tumor. Encephalomyelitisa, sensory neuronopathy, autonomic dysfunction PND OF THE CENTRAL NERVOUS SYSTEM Syndromes of peripheral nerve AND DORSAL ROOT GANGLIA When symp- Chronic and subacute sensorimotor peripheral toms involve brain, spinal cord, or dorsal root ganglia, neuropathy the suspicion of PND is usually based on a combina- Vasculitis of nerve and muscle tion of clinical, radiologic, and CSF findings. In these Neuropathy associated with malignant monoclonal cases, a biopsy of the affected tissue is often difficult to gammopathies obtain, and although useful to rule out other disorders Peripheral nerve hyperexcitability (e.g., metastasis, infection), neuropathologic findings Autonomic neuropathy are not specific for PND. Furthermore, there are no specific radiologic or electrophysiologic tests that are Syndromes of the neuromuscular junction diagnostic of PND.The presence of antineuronal anti- Lambert-Eaton myasthenic syndrome bodies (Table 39-2) may help in the diagnosis with Myasthenia gravis the following caveats: (1) antibodies are detected in only 60–70% of PNDs of the CNS; (2) antibodies Syndromes of the muscle may be present in both the serum and CSF, but in Polymyositis/dermatomyositis some patients only the CSF is positive (especially with Acute necrotizing myopathy antibodies to Tr and Ma proteins); (3) antibodies (usu- ally at low titer) are present in a variable proportion of Syndromes affecting the visual system cancer patients without PND; (4) there is an imperfect Cancer-associated retinopathy (CAR) correlation between antibody titers and the course of Melanoma-associated retinopathy (MAR) the neurologic disorder; (5) several antibodies may Uveitis (usually in association with encephalomyelitis) associate with a similar syndrome, with the antibody specificity often correlating with the tumor type (e.g., aIncludes cortical, limbic, or brainstem encephalitis, cerebellar dys- cerebellar degeneration is associated with anti-Tr anti- function, myelitis. bodies if the tumor is Hodgkin’s disease but with anti- Yo antibodies if the tumor is ovarian or breast cancer); gravis; antibodies to VGKC in some patients with and (6) several antibodies may be present in the serum peripheral nerve hyperexcitability (neuromyotonia); and or CSF of the same patient (e.g., anti-Hu and anti- antibodies to ganglionic acetylcholine receptors in some CV2/CRMP5). patients with autonomic neuropathy. Common features of these four antibodies are that they target cell-surface molecules and that their passive transfer to animals repro- duces the disorders. Plasma exchange or immunomodu- lation with intravenous immunoglobulin (IVIg) usually produces neurologic improvement. Each of these disor- ders can occur without cancer, and therefore detection of these antibodies does not predict the presence of cancer. Other PNDs are likely immune-mediated, although their antigens are unknown. These include several syndromes of inflammatory neuropathies and myopathies.

518 TABLE 39-2 PARANEOPLASTIC ANTINEURONAL ANTIBODIES, ASSOCIATED SYNDROMES AND CANCERS SECTION III Diseases of the Central Nervous System ANTIBODY SYNDROME ASSOCIATED CANCERS SCLC, other neuroendocrine tumors Anti-Hu (ANNA-1) PEM (including cortical, limbic, brainstem encephalitis, cerebellar dysfunction, Ovary and other gynecologic cancers, breast Anti-Yo (PCA-1) myelitis), PSN, autonomic dysfunction Breast, gynecological, SCLC Anti-Ri (ANNA-2) PCD PCD, brainstem encephalitis, Hodgkin’s lymphoma Anti-Tr opsoclonus-myoclonus SCLC and other neuroendocrine tumors Anti-Zic PCD SCLC, thymoma, other Anti-CV2/CRMP5 PCD, encephalomyelitis PEM, PCD, chorea, peripheral Germ-cell tumors of testis, lung cancer, Anti-Ma proteinsa neuropathy, uveitis other solid tumors Limbic, hypothalamic, brainstem Ovarian teratoma Anti-NR1/NR2 subunits encephalitis (infrequently PCD) of NMDA receptor Encephalitis with prominent psychiatric Breast, SCLC Anti-amphiphysin symptoms, seizures, hypoventilation SCLC, lymphoma Anti-VGCCb Stiff-person syndrome, PEM Thymoma Anti-AChRb LEMS, PCD Thymoma, SCLC, others Anti-VGKCb MG Peripheral nerve hyperexcitability SCLC and other Anti-recoverin (neuromyotonia), limbic encephalitis Melanoma Anti-bipolar cells of the retina Cancer-associated retinopathy (CAR) Melanoma-associated retinopathy (MAR) aPatients with antibodies to Ma2 are usually men with testicular cancer. Patients with additional antibodies to other Ma proteins are men or women with a variety of solid tumors. bThese antibodies can occur with or without a cancer association. Note: PEM: paraneoplastic encephalomyelitis; PCD, paraneoplastic cerebellar degeneration; PSN, paraneoplastic sensory neuronopathy; LEMS, Lambert-Eaton myasthenic syndrome; MG, myasthenia gravis; VGCC, voltage-gated calcium channel; AChR, acetylcholine receptor; VGKC, voltage-gated potassium channel; SCLC, small-cell lung cancer; NMDA, N-methyl-D-aspartate. FIGURE 39-1 layer, which is highly enriched in dendritic processes. Antibodies to NR1/NR2 subunits of the NMDA receptor Panel B shows the antibody reactivity with cultures of rat in a patient with paraneoplastic encephalitis and ovarian hippocampal neurons; the intense green immunolabeling is teratoma. Panel A is a section of dentate gyrus of rat hip- due to the antibodies against the NR1/NR2 subunits of pocampus immunolabeled (brown staining) with the patient’s NMDA receptors. antibodies. The reactivity predominates in the molecular

MRI and CSF studies are important to rule out cancer screenings in this situation. Serum and urine 519 neurologic complications due to the direct spread of immunofixation studies should be considered in cancer, particularly metastatic and leptomeningeal dis- patients with peripheral neuropathy of unknown ease. In most PNDs the MRI findings are nonspecific. cause; detection of a monoclonal gammopathy suggests Paraneoplastic limbic encephalitis is usually associated the need for additional studies to uncover a B cell or with characteristic MRI abnormalities in the mesial plasma cell malignancy. In paraneoplastic neuropathies, temporal lobes (see later), but similar findings can diagnostically useful antineuronal antibodies are limited occur with other disorders [e.g., nonparaneoplastic to anti-CV2/CRMP5 and anti-Hu. limbic encephalitis with antibodies to VGKC, human herpesvirus (HHV) 6 encephalitis] (Fig. 39-2). The For any type of PND, if antineuronal antibodies are CSF profile of patients with PND of the CNS or dor- negative, the diagnosis relies on the demonstration of sal root ganglia typically consists of mild to moderate cancer and the exclusion of other cancer-related or pleocytosis (<200 mononuclear cells, predominantly independent neurologic disorders. Body PET scans lymphocytes), an increase in the protein concentra- often uncover tumors undetected by other tests. tion, intrathecal synthesis of IgG, and a variable pres- ence of oligoclonal bands. SPECIFIC PARANEOPLASTIC CHAPTER 39 Paraneoplastic Neurologic Syndromes PND OF NERVE AND MUSCLE If symptoms NEUROLOGIC SYNDROMES ( Table 39-3) involve peripheral nerve, neuromuscular junction, or muscle, the diagnosis of a specific PND is usually PARANEOPLASTIC ENCEPHALOMYELITIS established on clinical, electrophysiologic, and patho- AND FOCAL ENCEPHALITIS logic grounds. The clinical history, accompanying symptoms (e.g., anorexia, weight loss), and type of syn- The term encephalomyelitis describes an inflammatory drome dictate the studies and degree of effort needed process with multifocal involvement of the nervous sys- to demonstrate a neoplasm. For example, the frequent tem, including brain, brainstem, cerebellum, and spinal association of LEMS with SCLC should lead to a chest cord. It is often associated with dorsal root ganglia and and abdomen CT or body positron emission tomogra- autonomic dysfunction. For any given patient, the clini- phy (PET) scan and, if negative, periodic tumor cal manifestations are determined by the area or areas screening for at least 3 years after the neurologic diag- predominantly involved, but pathology almost always nosis. In contrast, the weak association of polymyositis reveals abnormalities (inflammatory infiltrates, neuronal with cancer calls into question the need for repeated loss, gliosis) beyond the symptomatic regions. Several clinicopathologic syndromes may occur alone or in FIGURE 39-2 combination: (1) cortical encephalitis, which may present as Fluid-attenuated inversion recovery sequence MRI of a “epilepsia partialis continua”; (2) limbic encephalitis, char- patient with limbic encephalitis and voltage-gated potassium acterized by confusion, depression, agitation, anxiety, channel antibodies. Note the abnormal hyperintensity involv- severe short-term memory deficits, partial complex ing the medial aspect of the temporal lobes. seizures, and dementia; the MRI usually shows unilateral or bilateral medial temporal lobe abnormalities, best seen with T2 and fluid-attenuated inversion recovery sequences, and occasionally enhancing with gadolinium; (3) brainstem encephalitis, resulting in eye movement dis- orders (nystagmus, opsoclonus, supranuclear or nuclear paresis), cranial nerve paresis, dysarthria, dysphagia, and central autonomic dysfunction; (4) cerebellar gait and limb ataxia; (5) myelitis, which may cause lower or upper motor neuron symptoms, myoclonus, muscle rigidity, and spasms; and (6) autonomic dysfunction as a result of involvement of the neuraxis at multiple levels, including hypothalamus, brainstem, and autonomic nerves (see autonomic neuropathy). Cardiac arrhythmias, postural hypotension, or central hypoventilation are frequent causes of death in patients with encephalomyelitis. Paraneoplastic encephalomyelitis and focal encephali- tis are usually associated with SCLC, but many other cancers have also been reported. Patients with SCLC and these syndromes usually have anti-Hu antibodies in

520 TABLE 39-3 ANTIBODY-ASSOCIATED PARANEOPLASTIC AND NONPARANEOPLASTIC SYNDROMESa ANTIBODIES PARANEOPLASTIC SYNDROME FREQUENT INFREQUENT NONPARANEOPLASTIC Tr, VGKC VGKC Limbic encephalitis Ma2, Hu, CV2/CRMP5, anti-NR1/NR2 of mGluR1, MAZ Gliadin, GAD Cerebellar degeneration NMDA receptor SECTION III Diseases of the Central Nervous System Yo, Tr, P/Q VGCC, Hu, Zic, CV2/CRMP5 GAD Hypothalamic, Ri, CV2/CRMP5, Ma1-2 CV2/CRMP5, Ri, amphiphysin brainstem encephalitis Ma2, Hu Hu, Ma2, Yo, VGKC Encephalomyelitis Gephyrin, Ri AChR, MuSK Chorea Hu, Zic P/Q-type VGCC Opsoclonus-myoclonus CV2/CRMP5 MysB Stiff-person syndrome Ri PNH (neuromyotonia) Amphiphysin CV2/CRMP5, ganglionic AChR Monoclonal gammopathy Myasthenia gravis VGKC (M protein)b LEMS AChR MAG, ganglioside antibodies: Ganglionic AChR Sensory neuronopathy P/Q-type VGCC often present with MAG, ganglioside antibodies, Axonal sensorimotor Hu Waldenström’s often present with MGUS neuropathy Hu, CV2/CRMP5 macroglobulinemia Autonomic neuropathy Tubby-like protein 1, PNR Anti-enolase Predominant sensory Hu demyelinating neuropathy Recoverin (CAR), anti-bipolar cell Paraneoplastic antibodies (MAR), retinopathy anti-enolase aAntibodies have been validated by more than one laboratory and/or the protein sequence of the target antigen is known. bThe M protein usually does not have specific antibody activity. Note: Italics indicate that commercial testing for these antibodies is not available. PNH, peripheral nerve hyperexcitability; CAR, cancer-associ- ated retinopathy; MAR, melanoma-associated retinopathy; PNR, photoreceptor-specific nuclear receptor; MGUS, monoclonal gammopathy of uncertain significance; VGKC, voltage-gated potassium channel; GAD, glutamic acid decarboxylase; AChR, acetylcholine receptor; LEMS, Lam- bert-Eaton myasthenic syndrome; VGCC, voltage-gated calcium channel; MAG, myelin-associated glycoprotein; NMDA, N-methyl-D-aspartate. serum and CSF. Anti-CV2/CRMP5 antibodies occur less Treatment: frequently; some of these patients may develop chorea or ENCEPHALITIS uveitis. Antibodies to Ma proteins are associated with AND ENCEPHALOMYELITIS limbic, hypothalamic and brainstem encephalitis and occasionally with cerebellar symptoms (Fig. 39-3); some Most types of paraneoplastic encephalitis and patients develop hypersomnia, cataplexy, and severe encephalomyelitis respond poorly to treatment. Stabiliza- hypokinesia. MRI abnormalities are frequent, including tion of symptoms or partial neurologic improvement may those described with limbic encephalitis and variable occasionally occur, particularly if there is a satisfactory involvement of the hypothalamus, basal ganglia, or upper response of the tumor to treatment. The roles of plasma brainstem. Antibodies to NR1/NR2 subunits of the exchange, IVIg, and immunosuppression have not been NMDA receptor associate with a severe, potentially established. Approximately 30% of patients with anti- lethal, but treatment-responsive encephalitis.The affected Ma2-associated encephalitis respond to treatment of the patients are young women who develop combinations of tumor (usually a germ-cell neoplasm of the testis) and psychiatric symptoms, seizures, dyskinesias, stupor and immunotherapy. Two other syndromes that are respon- hypoventilation.The oncologic associations of these anti- sive to treatment of the tumor and immunotherapy are bodies are shown in Table 39-2.

521 FIGURE 39-3 brainstem. Panel C corresponds to a section of the patient’s CHAPTER 39 Paraneoplastic Neurologic Syndromes MRI and tumor of a patient with anti-Ma2-associated orchiectomy incubated with a specific marker (Oct4) of encephalitis. Panels A and B are fluid-attenuated inversion germ-cell tumors. The positive (brown) cells correspond to recovery MRI sequences showing abnormal hyperintensities an intratubular germ-cell neoplasm. in the medial temporal lobes, hypothalamus and upper the encephalitis that associates with antibodies to the Treatment: NR1/NR2 subunits of NMDA receptors in patients with CEREBELLAR DEGENERATION teratoma of the ovary, and the encephalitis that associ- ates with VGKC antibodies in some patients with thy- A number of single case reports have described neu- moma or SCLC. rologic improvement after tumor removal, plasma exchange, IVIg, cyclophosphamide, rituximab, or glu- PARANEOPLASTIC CEREBELLAR cocorticoids. However, large series of patients with DEGENERATION antibody-positive paraneoplastic cerebellar degenera- tion show that this disorder rarely improves with any This disorder is often preceded by a prodrome that may treatment. include dizziness, oscillopsia, blurry or double vision, nausea, and vomiting. A few days or weeks later, PARANEOPLASTIC OPSOCLONUS- dysarthria, gait and limb ataxia, and variable dysphagia MYOCLONUS SYNDROME can appear.The examination usually shows downbeating nystagmus and, rarely, opsoclonus. Brainstem dysfunc- Opsoclonus is a disorder of eye movement characterized tion, upgoing toes, or a mild neuropathy may occur, but by involuntary, chaotic saccades that occur in all direc- more often the symptoms and signs are restricted to the tions of gaze; it is frequently associated with myoclonus cerebellum. Early in the course, MRI studies are usually and ataxia. Opsoclonus-myoclonus may be cancer- normal; later, the MRI typically reveals cerebellar atro- related or idiopathic. When the cause is paraneoplastic, phy. The disorder results from extensive degeneration of the tumors involved are usually cancer of the lung and Purkinje cells, with variable involvement of other cere- breast in adults and neuroblastoma in children. The bellar cortical neurons, deep cerebellar nuclei, and spin- pathologic substrate of opsoclonus-myoclonus is unclear. ocerebellar tracts. The tumors more frequently involved Most SCLC patients do not have detectable antineu- are SCLC, cancer of the breast and ovary, and Hodgkin’s ronal antibodies. A small subset of patients with ataxia, lymphoma. opsoclonus, and other eye movement disorders develop anti-Ri antibodies; in rare instances muscle rigidity, Anti-Yo antibodies in patients with breast and gyne- autonomic dysfunction, and dementia also occur. The cologic cancers and anti-Tr antibodies in patients with tumor most frequently involved in anti-Ri-associated Hodgkin’s lymphoma are the two paraneoplastic anti- syndromes is breast cancer. bodies typically associated with prominent or pure cere- bellar degeneration. Antibodies to P/Q-type VGCC If the tumor is not successfully treated, the paraneo- occur in some patients with SCLC and cerebellar dys- plastic opsoclonus-myoclonus syndrome in adults often function; only some of these patients develop LEMS. Of progresses to encephalopathy, coma, and death. In addi- note, a variable degree of cerebellar dysfunction can be tion to treating the tumor, symptoms may respond to associated with virtually any type of antibody-related immunotherapy (glucocorticoids, plasma exchange, and/ PND of the CNS (Table 39-2). or IVIg).

SECTION III Diseases of the Central Nervous System522 At least 50% of children with opsoclonus-myoclonus sleep and general anesthetics. Electrophysiologic studies have an underlying neuroblastoma. Hypotonia, ataxia, demonstrate continuous motor unit activity. Antibodies behavioral changes, and irritability are frequent accom- associated with the stiff-person syndrome target proteins panying symptoms. Many patients harbor antibodies to [glutamic acid decarboxylase (GAD), amphiphysin] neuronal cell surface antigens of unknown identity. involved in the function of inhibitory synapses utilizing Neurologic symptoms often improve with treatment of γ-aminobutyric acid (GABA) or glycine as neurotrans- the tumor (including chemotherapy) and with glucocor- mitters. Paraneoplastic stiff-person syndrome and ticoids, adrenocorticotropic hormone (ACTH), plasma amphiphysin antibodies are often related to breast can- exchange, IVIg, and rituximab. Many patients are left cer. By contrast, antibodies to GAD may occur in some with psychomotor retardation and behavioral and sleep cancer patients but are much more frequently present in problems. the nonparaneoplastic disorder. PARANEOPLASTIC SYNDROMES Treatment: OF THE SPINAL CORD STIFF-PERSON SYNDROME The number of reports of paraneoplastic spinal cord Optimal treatment of stiff-person syndrome requires syndromes, such as subacute motor neuronopathy and acute therapy of the underlying tumor, glucocorticoids, and necrotizing myelopathy, has decreased in recent years. This symptomatic use of drugs that enhance GABA-ergic may represent a true decrease in incidence, due to transmission (diazepam, baclofen, sodium valproate, improved and prompt oncologic interventions, or may tiagabine, vigabatrin). A benefit of IVIg has been demon- be because of the identification of nonparaneoplastic strated for the nonparaneoplastic disorder but remains etiologies. to be established for the paraneoplastic syndrome. Some patients with cancer develop upper or lower PARANEOPLASTIC SENSORY motor neuron dysfunction or both, resembling amyotrophic NEURONOPATHY OR DORSAL lateral sclerosis. It is unclear whether these disorders ROOT GANGLIONOPATHY have a paraneoplastic etiology or simply coincide with the presence of cancer.There are isolated case reports of This syndrome is characterized by sensory deficits that cancer patients with motor neuron dysfunction who may be symmetric or asymmetric, painful dysesthesias, had neurologic improvement after tumor treatment. A radicular pain, and decreased or absent reflexes. All more than coincidental association occurs between lym- modalities of sensation and any part of the body includ- phoma and motor neuron dysfunction. A search for ing face and trunk can be involved. Specialized sensations lymphoma should be undertaken in patients with a such as taste and hearing can also be affected. Electro- motor neuron syndrome who are found to have a mon- physiologic studies show decreased or absent sensory oclonal protein in serum or CSF. nerve potentials with normal or near-normal motor conduction velocities. Symptoms result from an inflam- Paraneoplastic myelitis may present with upper or lower matory, likely immune-mediated, process that targets the motor neuron symptoms, segmental myoclonus, and dorsal root ganglia, causing neuronal loss, proliferation of rigidity. This syndrome can appear as the presenting satellite cells, and secondary degeneration of the poste- manifestation of encephalomyelitis and may be associ- rior columns of the spinal cord. The dorsal nerve roots, ated with SCLC and serum anti-Hu, anti-CV2/CRMP5, and less frequently the anterior nerve roots and periph- or anti-amphiphysin antibodies. eral nerves, may also be involved. Paraneoplastic myelopathy can also produce several Treatment: syndromes characterized by prominent muscle stiffness SENSORY NEUROPATHY and rigidity. The spectrum ranges from focal symptoms in one or several extremities (stiff-limb syndrome or stiff- This disorder often precedes or is associated with person syndrome) to a disorder that also affects the brain- encephalomyelitis and autonomic dysfunction and has stem (known as encephalomyelitis with rigidity) and likely the same immunologic and oncologic associations, e.g., has a different pathogenesis. anti-Hu antibodies and SCLC. As with anti-Hu-associated encephalomyelitis, the therapeutic approach focuses on PARANEOPLASTIC STIFF-PERSON prompt treatment of the tumor. Glucocorticoids occa- SYNDROME sionally produce clinical stabilization or improvement. The benefit of IVIg and plasma exchange is not proved. This disorder is characterized by progressive muscle rigidity, stiffness, and painful spasms triggered by audi- tory, sensory, or emotional stimuli. Rigidity mainly involves the lower trunk and legs, but it can affect the upper extremities and neck. Symptoms improve with

PARANEOPLASTIC PERIPHERAL tumors involved. Pathology demonstrates axonal degen- 523 CHAPTER 39 Paraneoplastic Neurologic Syndromes NEUROPATHIES eration and T cell infiltrates involving the small vessels of the nerve and muscle. Immunosuppressants (glucocorti- These disorders may develop any time during the coids and cyclophosphamide) often result in neurologic course of the neoplastic disease. Neuropathies occurring improvement. at late stages of cancer or lymphoma usually cause mild to moderate sensorimotor deficits due to axonal degen- Peripheral nerve hyperexcitability (neuromyotonia, or Isaacs’ eration of unclear etiology.These neuropathies are often syndrome) is characterized by spontaneous and continuous masked by concurrent neurotoxicity from chemotherapy muscle fiber activity of peripheral nerve origin. Clinical and other cancer therapies. In contrast, the neuropathies features include cramps, muscle twitching (fascicula- that develop in the early stages of cancer often show a tions or myokymia), stiffness, delayed muscle relaxation rapid progression, sometimes with a relapsing and remit- (pseudomyotonia), and spontaneous or evoked carpal or ting course, and evidence of inflammatory infiltrates and pedal spasms.The involved muscles may be hypertrophic, axonal loss or demyelination in biopsy studies. If and some patients develop paresthesias and hyperhydrosis. demyelinating features predominate (Chap. 34), IVIg or CNS dysfunction, including mood changes, sleep disor- glucocorticoids may improve symptoms. Occasionally der, or hallucinations, may occur. The electromyogram anti-CV2/CRMP5 antibodies are present; detection of (EMG) shows fibrillations; fasciculations; and doublet, anti-Hu suggests concurrent dorsal root ganglionitis. triplet, or multiplet single unit (myokymic) discharges that have a high intraburst frequency. An immune pathogenesis Guillain-Barré syndrome and brachial plexitis have occa- is suggested by the frequent presence of serum antibod- sionally been reported in patients with lymphoma, but ies to VGKC.The disorder often occurs without cancer; there is no clear evidence of a paraneoplastic association. if paraneoplastic, benign and malignant thymomas and SCLC are the usual tumors. Phenytoin, carbamazepine, Malignant monoclonal gammopathies include: (1) multiple and plasma exchange improve symptoms. myeloma and sclerotic myeloma associated with IgG or IgA monoclonal proteins; and (2) Waldenström’s Paraneoplastic autonomic neuropathy usually develops as a macroglobulinemia, B cell lymphoma, and chronic B cell component of other disorders, such as LEMS and lymphocytic leukemia associated with IgM monoclonal encephalomyelitis. It may rarely occur as a pure or pre- proteins.These disorders may cause neuropathy by a vari- dominantly autonomic neuropathy with adrenergic or ety of mechanisms, including compression of roots and cholinergic dysfunction at the pre- or postganglionic plexuses by metastasis to vertebral bodies and pelvis, levels. Patients can develop several life-threatening com- deposits of amyloid in peripheral nerves, and paraneo- plications, such as gastrointestinal paresis with pseudoob- plastic mechanisms.The paraneoplastic variety has several struction, cardiac dysrhythmias, and postural hypotension. distinctive features. Approximately half of patients with Other symptoms include dry mouth, erectile dysfunction, sclerotic myeloma develop a sensorimotor neuropathy anhidrosis, and sphincter dysfunction; abnormal pupillary with predominantly motor deficits, resembling a chronic responses may be found. The disorder has been reported inflammatory demyelinating neuropathy (Chap. 41); some to occur in association with several tumors, including patients develop elements of the POEMS syndrome SCLC, cancer of the pancreas or testis, carcinoid tumors, (polyneuropathy, organomegaly, endocrinopathy, M protein, and lymphoma. Because autonomic symptoms can also be skin changes). Treatment of the plasmacytoma or sclerotic the presenting feature of encephalomyelitis, serum anti- lesions usually improves the neuropathy. In contrast, the Hu and anti-CV2/CRMP5 antibodies should also be sensorimotor or sensory neuropathy associated with multi- sought. Serum antibodies to ganglionic acetylcholine ple myeloma rarely responds to treatment. Between 5 and receptors have been reported in this syndrome, but they 10% of patients with Waldenström’s macroglobulinemia also occur without a cancer association. (See Chap. 28.) develop a distal symmetric sensorimotor neuropathy with predominant involvement of large sensory fibers. These LAMBERT-EATON MYASTHENIC patients may have IgM antibodies in their serum against SYNDROME myelin-associated glycoprotein and various gangliosides (Chap. 41). In addition to treating the Waldenström’s LEMS is discussed in Chap. 42. macroglobulinemia, other therapies may improve the neu- ropathy, including plasma exchange, IVIg, chlorambucil, MYASTHENIA GRAVIS cyclophosphamide, fludarabine, or rituximab. Myasthenia gravis is discussed in Chap. 42. Vasculitis of the nerve and muscle causes a painful sym- metric or asymmetric distal sensorimotor neuropathy POLYMYOSITIS-DERMATOMYOSITIS with variable proximal weakness. It predominantly affects elderly men and is associated with an elevated ery- Polymyositis and dermatomyositis are discussed in detail throcyte sedimentation rate and increased CSF protein in Chap. 44. concentration. SCLC and lymphoma are the primary

SECTION III Diseases of the Central Nervous System524 ACUTE NECROTIZING MYOPATHY photopsias that often progress to visual loss. The ERG demonstrates reduction in the b-wave amplitude. Parane- Patients with this syndrome develop myalgias and rapid oplastic optic neuritis and uveitis are very uncommon progression of weakness involving the extremities and and can develop in association with encephalomyelitis. the pharyngeal and respiratory muscles, often resulting Some patients with paraneoplastic uveitis harbor anti- in death. Serum muscle enzymes are elevated, and mus- CV2/CRMP5 antibodies. cle biopsy shows extensive necrosis with minimal or absent inflammation and sometimes deposits of comple- Some paraneoplastic retinopathies are associated with ment.The disorder occurs as a paraneoplastic manifesta- serum antibodies that specifically react with the subset tion of a variety of cancers including SCLC and cancer of retinal cells undergoing degeneration, supporting an of the gastrointestinal tract, breast, kidney, and prostate, immune-mediated pathogenesis (Tables 39-2 and 39-3). among others. Glucocorticoids or treatment of the Paraneoplastic retinopathies usually fail to improve with underlying tumor rarely control the disorder. treatment, although rare responses to glucocorticoids, plasma exchange, and IVIg have been reported. PARANEOPLASTIC VISUAL SYNDROMES FURTHER READINGS This group of disorders involves the retina and, less fre- quently, the uvea and optic nerves. The term cancer- ANTOINE JC, CAMDESSANCHÉ JP: Peripheral nervous system involve- associated retinopathy is used to describe paraneoplastic cone ment in patients with cancer. Lancet Neurol 6:75, 2007 and rod dysfunction characterized by photosensitivity, pro- gressive loss of vision and color perception, central or ring DALMAU J et al: Anti-NMDA-receptor encephalitis: case series and scotomas, night blindness, and attenuation of photopic and analysis of the effects of antibodies. Lancet Neurol. 8:1091, 2008 scotopic responses in the electroretinogram (ERG). The most commonly associated tumor is SCLC. Melanoma- MATHEW RM et al: Orchiectomy for suspected microscopic tumor associated retinopathy affects patients with metastatic in patients with anti-Ma2-associated encephalitis. Neurology cutaneous melanoma. Patients develop the acute onset of 68:900, 2007 night blindness and shimmering, flickering, or pulsating ROSENFELD MR: Paraneoplastic syndromes of the CNS. Lancet Neurol 7:327, 2008 VEDELER CA, STORSTEIN A: Autoimmune limbic encephalitis. Acta Neurol Scand Suppl 189:63, 2009

CHAPTER 40 PERIPHERAL NEUROPATHY Vinay Chaudhry ■ Electrophysiologic Studies (See Chap. 3) . . . . . . . . . . . . . . . 529 Other Inherited Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . 544 ■ Mononeuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 530 ■ Special Peripheral Neuropathy Presentations . . . . . . . . . . . . 546 ■ Mononeuropathy Multiplex . . . . . . . . . . . . . . . . . . . . . . . . . . 532 ■ Polyneuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532 Autonomic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546 Pure Motor Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546 Diabetic Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532 Pure Sensory Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . 546 Toxic Including Chemotherapy-Induced Neuropathies . . . . . . 535 Plexopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546 Nutritional Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 538 Peripheral Nerve Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 548 Infections and Peripheral Neuropathy . . . . . . . . . . . . . . . . . . 539 Peripheral Nerve Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549 ■ Inherited Neuropathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 541 ■ Further Readings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549 Charcot-Marie-Tooth Disease . . . . . . . . . . . . . . . . . . . . . . . . 541 Peripheral neuropathy describes disorders of peripheral Approach to the Patient: nerves, including the dorsal or ventral nerve roots; dorsal PERIPHERAL NEUROPATHY root ganglia; brachial or lumbosacral plexus; cranial nerves (except I and II); and other sensory, motor, auto- A stepwise approach to diagnosis is presented in nomic, or mixed nerves; the term peripheral indicates that Fig. 40-1.The following questions should be addressed the disorder is outside the central nervous system (brain initially: and spinal cord). Peripheral neuropathy affects ~2–8% of adults; the incidence increases with age. Evaluation 1. Is this a peripheral neuropathy? The initial symptoms begins with a history focusing on the time course of the of peripheral neuropathy are often intermittent, illness, symptoms, medical conditions that predispose to and examination can be normal. Patients may pre- neuropathy (e.g., diabetes mellitus, connective tissue dis- sent with positive and/or negative symptoms ease, nutritional deficiency), toxic exposures (drug or (Table 40-1). In most situations, sensory symp- environmental), and family history. Physical examination toms precede motor symptoms. Small-fiber neu- assesses the function of small sensory fibers (pain and ropathies often present with dysesthesias and pares- temperature), large sensory fibers (vibration, propriocep- thesias, terms used interchangeably to describe tion, reflex changes), and/or motor nerves (weakness). unpleasant, unusual, or abnormal sensations such The distribution of sensory, motor, and reflex changes as burning or cutting pain, electric shock–like determines whether the neuropathy is asymmetric or sensations, tingling, pins and needles, formication, symmetric. Electrodiagnostic studies (EDx) help to clas- prickly feelings such as a limb falling asleep, or sify the neuropathy into one of three major categories: cramp-like sensations (Chap. 12). Large-fiber neu- axonal, demyelinating, or neuronal. Focused laboratory ropathies can present as numbness, tingling, or a tests are then performed based on the history, examina- gait disturbance (sensory ataxia). In most cases, the tion, and EDx. An underlying cause can be identified in abnormal sensation originates in the toes and feet ~75% of neuropathies. and ascends proximally to the legs in a stocking 525

526 Patient Complaint: Neuropathy No Mononeuropathy History and examination compatible with neuropathy? Evaluation of other EDx Yes disorder or reassurance and Mononeuropathy multiplex Polyneuropathy follow up EDx EDx Is the lesion axonal Axonal Demyelinating Axonal Demyelinating or demyelinating? with focal Is entrapment or Consider conduction block compression present? vasculitis or Is a contributing systemic other multifocal Consider Subacute Chronic Nonuniform slowing, disorder present? process multifocal course (months) course (years) conduction block form of SECTION III Diseases of the Central Nervous System CIDP Uniform slowing, chronic Decision on need Possible Review history for toxins; Test for paraprotein, If chronic or If acute: GBS for surgery (nerve repair, nerve test for associated if negative subacute: CIDP transposition, or release biopsy Test for paraprotein, systemic disease or procedure) HIV, Lyme disease intoxication Treatment appropriate If tests are Treatment appropriate Review family Treatment IVIg or for specific diagnosis negative, consider for specific diagnosis history; examine for CIDP; plasmapheresis; treatment for family members; see Ch.41 supportive CIDP genetic testing care including respiratory assistance Genetic counseling if appropriate FIGURE 40-1 Approach to the evaluation of peripheral neuropathies. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; GBS, Guillain-Barré syndrome. TABLE 40-1 SYMPTOMS, SIGNS, AND TESTS IN PERIPHERAL NEUROPATHY LARGE FIBER SMALL FIBER MOTOR AUTONOMIC Symptoms Pain: burning, shock-like, Cramps Decreased or increased Numbness stabbing, prickling, Weak grip sweating “Pins and needles” shooting, lancinating Footdrop Dry eyes, mouth, Tingling Allodynia Twitching Erectile dysfunction Poor balance Gastroparesis/diarrhea Decreased Reduced Faintness, light-headedness Signs Pin prick Strength Temperature sensation Reflexes Orthostasis Decreased Unequal pupil size Vibration Skin biopsy NCS-EMG Joint-position sense QST QSART Reflexes Nerve biopsy Tilt table R-R interval Tests Valsalva NCS-EMG Nerve biopsy LP Note: NCS-EMG, nerve conduction studies/electromyography; QSART, quantitative sudomotor axon reflex testing; QST, quantitative sensory test; LP, lumbar puncture.

distribution. Only when the sensation reaches the 3. Which fibers are affected? In a polyneuropathy, mani- 527 level of the knee or thigh do symptoms appear in festations can be classified as small-fiber sensory, the hands, producing a length-dependent, or large-fiber sensory, motor, and/or autonomic stocking-glove, pattern. Paresthesias that begin in (Table 40-3). Often there is overlap, but if there is one hand suggest an entrapment neuropathy such predominant involvement of one fiber group, the as carpal tunnel syndrome. differential diagnosis and evaluation can be nar- Motor symptoms usually have a later onset than rowed. For example, if a patient has burning pain in sensory symptoms. In long-standing inherited neu- the feet, a small-fiber neuropathy is likely and dia- ropathies, patients may present with isolated weak- betes mellitus is a possible etiology. If a patient has ness of the feet without sensory symptoms; the sensory ataxia, large fibers are likely affected and ankle jerk, the most distal deep tendon reflex, is Sjögren’s syndrome or a paraneoplastic process invariably absent. When confronted with a length- should be considered. dependent pattern of sensory symptoms, the diag- nosis of a peripheral neuropathy is not difficult. 4. What is the anatomic pattern? Clinical evaluation is However, in cases with pure motor weakness or often helpful in categorizing a neuropathy as axonal, wasting, localization may be difficult, and in such cases the presence of distal weakness is helpful in TABLE 40-3 CHAPTER 40 Peripheral Neuropathy differentiating a peripheral neuropathy from muscle or neuromuscular junction disorders, which typi- CLASSIFICATION OF NEUROPATHY BY FIBER TYPE cally present with proximal weakness. Motor neu- ron disease can also present with distal weakness Small-fiber sensory (painful neuropathies and dissociated and wasting; however, the findings are not in the sensory loss) distribution of an individual nerve. Hereditary sensory neuropathies (early) 2. What is its distribution? Polyneuropathy involves Lepromatous leprosy widespread and symmetric dysfunction of the Diabetic (includes glucose intolerance) small-fiber peripheral nerves; mononeuropathy involves a single neuropathy peripheral nerve; multiple mononeuropathy involves Amyloidosis multiple individual peripheral nerves (Table 40-2 Analphalipoproteinemia (Tangier disease) and Fig. 40-1). Mononeuropathies are usually due Fabry’s disease (pain predominates) to compression, trauma, or vascular causes. Multiple Dysautonomia (Riley-Day syndrome) mononeuropathies (also referred to as mononeuropa- HIV and antiretroviral therapy neuropathy thy multiplex) can be a result of multiple entrap- ments, infiltration, or vasculitis. Plexopathies (brachial Large-fiber sensory (ataxic-neuropathies) or lumbosacral) also involve multiple peripheral Sjögren’s syndrome nerves, in an asymmetric fashion. Vitamin B12 neuropathy (from dorsal column involvement) Cisplatin neuropathy TABLE 40-2 Pyridoxine toxicity CLASSIFICATION OF NEUROPATHY BY LOCATION Friedreich’s ataxia Polyneuropathy Multiple Mononeuropathy Small- and large-fiber: Global sensory loss Carcinomatous sensory neuropathy Fairly symmetric In distribution of single Hereditary sensory neuropathies (recessive and dominant) Diabetic sensory neuropathy Distal stocking-glove nerve(s) Vacor intoxication Xanthomatous neuropathy of primary biliary cirrhosis May or may not be painful Setting: diabetes, (tabes dorsalis) Sensorimotor pressure, vasculitis Motor-predominant neuropathies Immune neuropathies: acute (Guillain-Barré syndrome); Symmetrically decreased May or may not be painful relapsing Heritable motor-sensory neuropathies reflexes Isolated reflex loss Acute intermittent porphyria Diphtheritic neuropathy Plexopathy Not a Neuropathy Lead neuropathy Brachial neuritis Asymmetric Upper motor neuron signs Diabetic lumbosacralplexus neuropathy (diabetic amyotrophy) Painful onset (brisk reflexes) Autonomic Multiple nerves in a Prominent bladder and Acute: Acute pandysautonomic neuropathy, botulism, porphyria, GBS, vacore, amiodarone, vincristine single limb bowel involvement Chronic: Amyloid, diabetes, Sjögren’s, HSAN I and III (Riley-Day), Chagas, paraneoplastic Rapid onset of weakness, Unilateral (arm, leg, face) Note: GBS, Guillain-Barré syndrome; HSAN, hereditary sensory and atrophy symptoms autonomic neuropathy. Isolated reflex loss Sensory level Hyperventilation

528 TABLE 40-4 CLASSIFICATION OF NEUROPATHY BY HISTOPATHOLOGY SECTION III Diseases of the Central Nervous System Pattern DEMYELINATING AXONAL NEURONAL Onset Proximal = distal Distal > proximal; length- Non-length-dependent; Symptoms dependent UE, LE, face Acute/subacute Slow evolution Rapid Sensory signs Paresthesia and weakness Dysesthesias and distal Paresthesias, gait ataxia weakness Motor Vibration and proprio- Pain and temperature Vibration and proprio- ception > pain and affected > vibration and ception > pain and DTRs temperature proprioception temperature NCS Distal and proximal Distal weakness Proprioceptive weakness weakness Nerve biopsy Areflexia Distal areflexia Areflexia Velocity affected > Amplitudes affected > Sensory amplitudes Prognosis amplitude velocity affected; radial > sural Causes Demyelination and Axonal degeneration and Axonal degeneration but remyelination regeneration no regeneration Rapid recovery Slow recovery Poor recovery GBS, diphtheria, CIDP, Toxic, metabolic, HIV, Sjögren’s, cisplatin, DM, MMN CMT2, DM pyridoxine Note: UE, LE, upper, lower extremities; DTRs, deep tendon reflexes; NCS, nerve conduction studies; GBS, Guillain-Barré syndrome; CIDP, chronic inflammatory demyelinating neuropathy; DM, diabetes mellitus; MMN, multifocal motor neuropathy; CMT, Charcot-Marie-Tooth. demyelinating, or neuronal [dorsal root ganglion TABLE 40-5 (DRG)] (Table 40-4). Most axonal neuropathies follow a length-dependent (stocking-glove) pat- CLASSIFICATION OF NEUROPATHY BY TIME COURSE tern with sensory (small fiber more than large fiber) symptoms and signs predominating over Acute motor manifestations; distal reflexes are absent. In GBS, porphyria, toxic (triorthocresyl phosphate, vacor, contrast, most demyelinating neuropathies affect thallium), diphtheria, brachial neuritis motor fibers and sensory fibers (large fiber more than small fiber) equally, and areflexia or Subacute hyporeflexia is more generalized. DRG lesions Toxic (hexacarbon, acrylamid), angiopathic, nutritional, involve purely sensory fibers in a non-length- alcoholic dependent fashion; sensory ataxia and general- ized loss of reflexes are usually found. EDx studies Chronic are also important in defining the anatomy of a Diabetic, CIDP, paraneoplastic, paraprotein neuropathy. 5. What is the time course? Rapidly evolving peripheral Longstanding heritable neuropathies are usually inflammatory [Guillain- CMT, Friedreich’s ataxia Barré syndrome (GBS)] or toxic in origin. Suba- cute evolution suggests an inflammatory, toxic, or Recurrent nutritional cause (Table 40-5). Chronic neu- Relapsing CIDP, porphyria, Refsum’s disease, HNPP ropathies, especially those that are long-standing over many years, are usually hereditary, such as Note: GBS, Guillain-Barré syndrome; CIDP, chronic inflammatory Charcot-Marie-Tooth (CMT) disease. demyelinating neuropathy; CMT, Charcot-Marie-Tooth (disease); 6. What is the likely etiology? It is helpful to consider HNPP, hereditary neuropathy with pressure palsies. potential etiologies by category: metabolic (diabetes mellitus, renal failure, amyloid, porphyria); infec- chronic inflammatory demyelinating neuropathy tious [HIV, Lyme disease, cytomegalovirus (CMV), (CIDP), multifocal motor neuropathy, anti-myelin- syphilis, leprosy, diphtheria]; immune-mediated [GBS, associated glycoprotein (MAG) neuropathy]; hered- itary (CMT); toxic (HIV drugs, anticancer drugs, alcohol, heavy metals, tick bite); vasculitic (pol- yarteritis nodosa, Churg-Strauss syndrome, cryo- globulinemia, isolated vasculitis of the peripheral nervous system); paraneoplastic (especially lung); nutritional (vitamin B12, B1, B6 deficiencies); and

miscellaneous causes (celiac disease, Fabry disease, TABLE 40-6 529 hypothyroidism). TREATMENT OF PAINFUL NEUROPATHY 7. What tests are indicated? These may include fast- ing blood glucose and hemoglobin A1C (HbA1C); FIRST-LINE THERAPY CHAPTER 40 Peripheral Neuropathy serum vitamin B12; tests for systemic vasculitis or collagen vascular disease; measurement of neu- Antidepressants ropathy-associated autoantibodies; urine screen Tricyclic for heavy metals; spinal fluid analysis; autonomic Amitriptyline, nortriptyline, imipramine, desimipramine, function testing (Chap. 28); and genetic tests for doxepin (10–150 mg qd) hereditary neuropathies. An impaired glucose Serotonin-noradrenaline reuptake inhibitors (SNRI) tolerance test is found in more than half of Duloxetine (60–120 mg qd) patients with idiopathic sensory neuropathy and Venlafaxine (150–225 mg qd) is more sensitive than tests of fasting glucose or HbA1C. Diagnostic tests to further characterize Antiepileptics the neuropathy include quantitative sensory test- Carbamazepine 100–800 mg qd ing, EDx studies, sural nerve biopsy, and muscle Oxcarabazepine 1200–2400 mg qd biopsy. Diagnostic tests and procedures are more Lamotrigine 200–400 mg qd likely to be informative in patients with asym- Topiramate 300–400 mg qd metric, motor-predominant, rapid-onset or Gabapentin 900–3600 mg qd demyelinating neuropathies than in patients with Pregabalin 150–600 mg qd slowly evolving length-dependent sensory > Valproic acid 1000–1200 mg qd motor types. 8. What treatment is appropriate? Treatment of the SECOND-LINE THERAPY underlying disorder, pain management, and support- ive care to protect and rehabilitate damaged tissue all Opioids need to be considered. Examples of therapies Oxycodone 40–160 mg qd directed at the underlying etiology include glycemic Morphine 90–360 mg qd PO control for diabetic neuropathy, vitamin replacement Tramadol 50–400 mg qd for B12 deficiency, immunosuppression for vasculitis, Fentanyl patch 25–75 μg/h q 3 days surgery for entrapment neuropathy, enzyme replace- ment for Fabry disease, liver or bone marrow trans- Antiarrhythmics plant for amyloid neuropathy, and treatment for Mexilitine 600–1200 mg qd immune-mediated neuropathies (Chap. 41). Topical Pain management usually begins with tricyclic Capsaicin 0.075% topical tid or qid antidepressants (TCAs) such as amitriptyline, Lidocaine 5% patch bid imipramine, and desipramine, which can reduce Isosorbide dinitrate spray 30 mg qhs burning, aching, sharp, throbbing, and stinging (Table 40-6; see also Table 5-1). Duloxetine Others hydrochloride, a dual reuptake inhibitor of sero- Clonidine 0.1–2.4 mg qd tonin and norepinephrine, is approved for the Memantine 55 mg qd management of neuropathic pain from diabetes. Dextromethorphan 400 mg Tramadol is also effective for painful diabetic neu- Levodopa 100 mg tid ropathy. Anticonvulsants such as phenytoin, carba- Alpha-lipoic acid (thioctic acid) 600 mg mazepine, clonazepam, gabapentin, topiramate, Spinal cord stimulator lamotrigine, and pregabalin are effective for lanci- Transcutaneous electrical nerve stimulation (TENS) nating pains. Topical anesthetic agents including lidocaine, mexiletine, and capsaicin creams pro- Alternative vide transient relief for focal neuropathic pain. Acupuncture Narcotics may be required for severe cases of Pain psychologist/counselor refractory neuropathic pain. Treatment of pain is discussed in detail in Chap. 5. denervated/immobile extremity, combined with recurrent, unnoticed, painless trauma, predisposes to The role of physical therapy, occupational skin ulceration, poor healing, tissue resorption, neu- therapy, and assistive devices (such as a foot brace) rogenic arthropathy, and mutilation; amputation may should not be overlooked. Trophic changes in a be required. This unfortunate sequence of events is avoidable with proper care of the denervated areas. ELECTROPHYSIOLOGIC STUDIES (SEE CHAP. 3) Electrophysiologic studies serve as an extension of the neurologic examination and thus play an important role in the evaluation of peripheral neuropathies.The following

SECTION III Diseases of the Central Nervous System530 information should be obtained from nerve conduction permanent injury can result. Intrinsic factors such as studies and electromyography (NCS-EMG): arthritis, fluid retention (pregnancy), amyloid, tumors, and diabetes mellitus may make nerves at entrapment 1. Is the process axonal or demyelinating? This deter- sites more susceptible to injury. Often both extrinsic mination is one of the main goals of an NCS-EMG and intrinsic factors contribute to neuropathy, e.g., an study since approaches to management and progno- anatomically narrowed region coupled with repetitive sis hinge largely on this distinction. In general, activity, poor posture or position. Common entrapment axonal processes affect sensory fibers more than neuropathies include the median nerve at the wrist motor fibers, whereas equal involvement is charac- (carpal tunnel), ulnar nerve at the cubital tunnel or in teristic of most demyelinating processes. the ulnar groove, lower trunk of the brachial plexus at the thoracic outlet, common peroneal nerve at the 2. Are the findings focal or generalized and are they fibular head, posterior tibial nerve at the tarsal tunnel, symmetric or asymmetric? and lateral femoral cutaneous nerve at the inguinal liga- ment. Symptoms and signs of various entrapment neu- 3. Is this a length-dependent neuropathy? A distal ropathies are listed in Table 40-7. Histologic changes of axonopathy generally gives rise to length-dependent subacute compression consist of a mixture of segmental findings. The order of nerves affected, as measured demyelination and Wallerian degeneration reflecting by sensory NCS, for example, is sural, followed by retrograde axonal injury. ulnar, median, and radial. By contrast, a neuronopa- thy (or ganglionopathy) may affect the radial nerve Since most entrapped nerves contain both motor and before the sural or ulnar nerve. sensory fibers, both types of symptoms occur, usually in the distribution of the affected nerve. Sensory symptoms 4. How severe is the lesion? The complete absence of a may include numbness, pins and needles, tingling, prick- response may reflect complete loss of fibers or com- ling, burning, or electric shock sensations. Light touch is plete conduction block. often more affected than pinprick, and subtle sensory abnormalities may be revealed by measuring two-point 5. What is the approximate age of the lesion? In discrimination. Aching and nondescript pain can also axonal processes, the compound muscle action occur proximal to the site of nerve compression. In mild potential amplitudes are lost early (7 days) compared cases, no motor symptoms are evident, but in more with sensory amplitudes (10 days). In demyelinating affected patients, weakness, wasting, or fasciculations lesions it is often useful to follow progression of may occur. Knowledge of the anatomy of individual findings with serial studies (Chap. 41). nerves is important to be able to localize the site of the lesion to the root, plexus, or nerves or their branches. 6. Is this a hereditary or acquired neuropathy? A uni- Sensory testing may occasionally provoke paresthesias. form slowing of NCS suggests a hereditary neu- Reflexes are generally unaffected since most entrapped ropathy, although exceptions exist, such as x-linked nerves are distal to the deep tendon reflexes typically CMT and hereditary neuropathy with liability to examined. Percussion of the nerve at the affected site pressure palsies (HNPP). may induce paresthesias (Tinel’s sign); however, this may also occur in normal individuals and is not a reliable 7. Is there a subclinical neuropathy? In patients receiv- sign. Placing the limb in a posture known to aggravate ing chemotherapy or other potentially neurotoxic the compression may accentuate symptoms (e.g., drugs, directed examination and limited NCS may Phalen’s sign evoked by flexing the wrist for carpal tun- help the physician adjust therapy before a significant nel syndrome). neuropathy develops. EDx studies confirm the clinical diagnosis and provide 8. What is the prognosis? For both demyelinating and information about location, severity, and prognosis. Focal axonal neuropathies, the degree of axonal loss serves demyelination is detected as a focally reduced nerve con- as a guide to prognosis. duction velocity along the length of the sensory and/or motor fibers. Wallerian degeneration is reflected in a It is important to recognize that EDx studies have reduction of distal amplitudes and as denervation poten- limitations, and that not all patients with neuropathic tials. The latter is associated with a relatively poor prog- symptoms will have informative findings. nosis for recovery. Bone or joint abnormalities and soft tissue masses can be revealed by appropriate imaging MONONEUROPATHIES techniques. MR neurography and ultrasonography are useful in identifying thickening of nerves at sites of com- Mononeuropathy (Table 40-7) refers to disease or dam- pression; these studies are useful for proximal entrap- age of a single nerve. The most common causes are ments (brachial plexus, lumbosacral plexus, or sciatic or compression, entrapment, and trauma. Extrinsic com- gluteal nerve lesions). pression usually occurs when a limb is maintained in a fixed position that produces sustained pressure on the nerve. The neuropathy is often reversible if the posi- tion is changed. However, if the patient is unable to move (e.g., during anesthesia or with intoxication),

TABLE 40-7 531 MONONEUROPATHIES PRECIPITATING DIFFERENTIAL SYMPTOMS ACTIVITIES EXAMINATION ELECTRO-DIAGNOSIS DIAGNOSIS TREATMENT Carpal tunnel Numbness, pain Sleep or repeti- Sensory loss in thumb, Slowing of sensory C6 radiculopathy Splint syndrome or paresthesias tive hand second, and third fingers and motor conduc- Surgery definitive in fingers activity Weakness in thenar tion across carpal treatment muscles; inability to tunnel make a circle with thumb and index finger Tinel and Phalen signs Ulnar nerve Numbness or Elbow flexion Sensory loss in the little Focal slowing of Thoracic outlet Elbow pads entrapment paresthesias in during sleep; finger and ulnar half of nerve conduction syndrome Avoid further injury at the elbow ulnar aspect of elbow resting ring finger velocity at the elbow C8-T1 radicu- Surgery when con- (UNE) hand on desk Weakness of the lopathy servative treatment interossei and thumb fails adductor; claw-hand Ulnar nerve Numbness or Unusual hand Like UNE but sensory Prolongation of distal UNE Avoid precipitating entrapment weakness in the activities with examination spares motor latency in the activities CHAPTER 40 Peripheral Neuropathy at the wrist ulnar distribu- tools, bicycling dorsum of the hand, hand tion in the hand and selected hand muscles affected Radial neu- Wrist drop Sleeping on arm Wrist drop with sparing Early—conduction Posterior cord Splint ropathy at after inebriation of elbow extension block along the spi- lesion; deltoid Spontaneous the spiral with alcohol— (triceps sparing); finger ral groove also weak recovery provided groove “Saturday night and thumb extensors Late—denervation in Posterior no ongoing injury palsy” paralyzed; sensory loss radial muscles; interosseous in radial region of wrist reduced radial SNAP nerve (PIN); iso- lated finger drop C7 radiculopathy Thoracic Numbness, Lifting heavy Sensory loss resembles Absent ulnar sensory UNE Surgery if correctable outlet paresthesias in objects with ulnar nerve and motor response and lesion present syndrome medial arm, the hand loss resembles median reduced median forearm, hand, nerve motor response and fingers Femoral Buckling of knee, Abdominal hys- Wasting and weakness EMG of quadriceps, L2-4 radiculopa- Physiotherapy to neuropathy numbness or terectomy; litho- of quadriceps; absent iliopsoas, paraspinal thy strengthen quadri- tingling in tomy position; knee jerk; sensory loss muscles, adductor Lumbar ceps and mobilize thigh/medial leg hematoma, in medial thigh and muscles plexopathy hip joint diabetes lower leg Surgery if needed Obturator Weakness of the Stretch during Weakness of hip adduc- EMG—denervation L3-4 radiculopa- Conservative neuropathy leg, thigh hip surgery; tors; sensory loss in limited to hip adduc- thy management numbness pelvic fracture; upper medial thigh tors sparing the Lumbar Surgery if needed childbirth quadriceps plexopathy Meralgia Pain or numb- Standing or Sensory loss in the Sometimes slowing of L2 radiculopathy Usually resolves paresthetica ness in the ante- walking pocket of the pant sensory response spontaneously rior lateral thigh Recent weight distribution can be demon- gain strated across the inguinal ligament Peroneal Footdrop Usually an acute Weak dorsiflexion, ever- Focal slowing of L5 radiculopathy Foot brace; remove nerve compressive sion of the foot nerve conduction external source of entrapment episode identifi- Sensory loss in the across fibular head compression at the fibular able; weight anterolateral leg and Denervation in tibialis head loss dorsum of the foot anterior and peroneus longus muscles Sciatic Flail foot and Injection injury; Weakness of hamstring, NCS—abnormal sural, L5-S1 radicu- Conservative follow neuropathy numbness fracture/dislo- plantar and dorsiflexion peroneal, and tibial lopathies up for partial sci- in foot cation of hip; of foot; sensory loss in amplitudes Common per- atic nerve injuries prolonged tibial and peroneal EMG—denervation in oneal neuropa- Brace and physio- pressure on hip nerve distribution sciatic nerve distrib- thy (partial sci- therapy (comatose ution sparing glutei atic nerve injury) Surgical exploration patient) and paraspinal LS plexopathies if needed Tarsal tunnel Pain and paresthe- At the end of the Sensory loss in the sole Reduced amplitude in Polyneuropathy, Surgery if no exter- syndrome sias in the sole day after stand- of the foot sensory or motor foot deformity, nal cause identified of the foot but ing or walking; Tinel’s sign at tarsal components of medial poor circulation not in the heel nocturnal tunnel and planter nerves Note: UE, LE, upper, lower extremities; DTRs, deep tendon reflexes; NCS, nerve conduction studies; GBS, Guillain-Barré syndrome; CIDP, chronic inflammatory demyelinating neuropathy; DM, diabetes mellitus; MMN, multifocal motor neuropathy; CMT, Charcot-Marie-Tooth.