differential diagnosis of acute flaccid paralysis and its role in

Epidemiologic ReviewsCopyright © 2000 by The Johns Hopkins University School ot Hygiene and Public HealthAll rights reserved

Vol. 22, No. 2Pnnted in U.S.A.

Differential Diagnosis of Acute Flaccid Paralysis and Its Role in PoliomyelitisSurveillance

Arthur Marx,1 Jonathan D. Glass,2 and Roland W. Sutter1

DEFINITION OF ACUTE FLACCID PARALYSIS

Acute flaccid paralysis (AFP) is a clinical syndrome char-acterized by rapid onset of weakness, including (less fre-quently) weakness of the muscles of respiration and swal-lowing, progressing to maximum severity within severaldays to weeks. The term "flaccid" indicates the absence ofspasticity or other signs of disordered central nervous sys-tem motor tracts such as hyperreflexia, clonus, or extensorplantar responses (1). When applied to voluntary muscles,"paralysis" means loss of contraction due to interruption ofmotor pathways from the cortex to the muscle fiber. It ispreferable to use the term "paresis" for slight loss of motorstrength and "paralysis" or "plegia" for severe loss of motorstrength (1). The differential diagnosis of AFP varies con-siderably with age. No single operational clinical case defi-nition of AFP or paralytic poliomyelitis that combines bothhigh sensitivity and high specificity has emerged (2-4). Thecurrently used case definition increases sensitivity in detect-ing the existence of AFP but tends to decrease specificity indetecting paralytic poliomyelitis.

INTRODUCTION

AFP is a complex clinical syndrome with a broad array ofpotential etiologies. Accurate diagnosis of the cause of AFPhas profound implications for therapy and prognosis. Ifuntreated, AFP may not only persist but also lead to deathdue to failure of respiratory muscles. AFP, a syndrome that

Received for publication October 11,1999, and accepted for pub-lication June 9, 2000.

Abbreviations: AFP, acute flaccid paralysis; AIDP, acute inflam-matory demyelinating polyradiculoneuropathy; AIDS, acquiredimmunodeficiency syndrome; AMAN, acute motor axonal neuropa-thy; GM,, glycolipid ganglioside-monosialic acid; CIDP, chronicinflammatory demyelinating polyradiculoneuropathy; HIV, humanimmunodeficiency virus; SIDP, subacute inflammatory demyelinatingpolyradiculoneuropathy.

1 Centers for Disease Control and Prevention, NationalImmunization Program, Vaccine-Preventable Disease EradicationDivision, Atlanta, GA.

2 Emory University School of Medicine, Atlanta, GA.Correspondence to Dr. Roland W. Sutter, Centers for Disease

Control and Prevention, 1600 Clifton Road NE (Mailstop E-05),Atlanta, GA 30333 (e-mail: [email protected]).

Reprint requests to the Centers for Disease Control andPrevention, National Immunization Program, Publication Requests,1600 Clifton Road NE (Mailstop E-52), Atlanta, GA 30333.

encompasses all cases of paralytic poliomyelitis, also is ofgreat public health importance because of its use in surveil-lance for poliomyelitis in the context of the global polioeradication initiative.

In 1988, the World Health Assembly adopted a resolutioncalling for global eradication of poliomyelitis by the year2000 (5). At the end of 1999, 30 countries worldwideremained polio-endemic, and intense activity is currentlybeing directed towards interrupting virus transmission in 10remaining high priority countries facing particular chal-lenges (6). Despite these challenges, the goal of polio erad-ication appears to be within reach. AFP surveillance is a keystrategy for monitoring the progress of polio eradication andis a sensitive instrument for detecting potential poliomyelitiscases and poliovirus infection. Current levels of surveillancehave made it possible to document a substantial reduction inmorbidity due to poliomyelitis. To ensure the success of thepoliomyelitis eradication initiative, it has become criticalthat surveillance be intensified so that the absence of wildpoliovirus circulation can be verified with confidence incountries not reporting confirmed cases of poliomyelitis.

The objectives of this review are to describe 1) the clini-cal characteristics, epidemiology, and differential diagnosisof potential causes of AFP, including distribution by age,gender, time, ethnicity, and geographic region; 2) theanatomic, morphologic, and pathophysiologic mechanismsassociated with causes of AFP; 3) the region- or country-specific significance of these etiologies; 4) the potential ofthese etiologies to cause epidemics of AFP; and 5) an algo-rithm for determining the correct diagnosis and etiology ofAFP for use in clinical examinations and laboratory studies.

This review is intended to provide greater assurance toclinicians concerning the accuracy of the diagnosis of AFP,including the rational use of limited resources when it maynot be practical to conduct a detailed clinical assessment,and to raise awareness among health workers and surveil-lance coordinators about the importance of accurately diag-nosing and differentiating AFP. The presentation of our find-ings and the subsequent discussion provide an overview ofpossible causes of AFP and focus on diagnostically helpfulcharacteristics of AFP, as well as regional or country-specific experience.

For better understanding of the clinical characteristics anddifferential diagnosis of AFP, we focus in this review ongrouping causes of AFP by pathophysiologic mechanismsand anatomic sites of action, an aspect incompletely

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Differential Diagnosis of Acute Flaccid Paralysis 299

explored in previous review articles. We discuss etiologiesthat have emerged or become more significant recently—forinstance, neurologic complications in patients with acquiredimmunodeficiency syndrome (AIDS). We also provide anoverview of causes of paralytic illness in developing coun-tries that are commonly misdiagnosed as AFP.

METHODS

All available electronic databases, including Medline(1966 to date), Biosis (1969 to date), and CAB Health (1973to date), were systematically reviewed for reports on AFP inany language available. Records in CAB Health areextracted from the Public Health and Tropical MedicineDatabase. Textbooks, monographs, conference proceedings,and other sources were reviewed and searched for cross-references. In addition, experts in the field, including healthofficials in World Health Organization regional offices andindividual countries, were consulted. Our observations fromclinical and epidemiologic field experience were included inthis review.

CLINICAL APPROACH TO PATIENTS WITH AFP

Each case of AFP is a clinical emergency and requiresimmediate examination. The clinical investigation of AFP isoften limited by the existing health infrastructure and avail-able resources. For all cases, a detailed clinical descriptionof the symptoms should be obtained, including fever, myal-gia, distribution, timing, and progression of paralysis. Thesymptoms of paralysis may include gait disturbance, weak-ness, or troubled coordination in one or several extremities.Careful assessment of the patient's personal history (recentillness, exanthem (erythema migrans in Lyme borreliosis),timing, food and water consumption, exposure to chemicals(organic solvents), insect (tick) or snake bites, family his-tory, vaccinations, and psychogenic problems, includingdementia) is crucial in order to narrow the differential diag-nosis. Trauma or spinal cord compression should be kept inmind as an obvious cause of AFP. Depending on the geo-

graphic region, the skin and scalp should be carefullyinspected for ticks, stings from insects, spiders, or scorpi-ons, and snake bites.

Figure 1 shows an algorithm for the clinical evaluation oflimb or respiratory weakness. The signs of AFP should beevaluated clinically by performing a comprehensive neuro-logic examination, including assessment of muscle strengthand tonus, deep tendon reflexes, cranial nerve function, andsensation (tactile sensation, vibration, and kinesthetic per-ception). Particular attention should be paid to the presenceof meningismus, signs of disordered central nervous systemfunction (ataxia), or autonomic nervous system abnormali-ties (bowel and bladder dysfunction, sphincter tonus, neuro-genic reflex bladder) (7). Fasciculation is often cited as asign of anterior horn cell damage, but it may also be presentin demyelinating neuropathies (8). Electrophysiologic stud-ies are very important for determining the diagnosis andprognosis of lower motor neuron disease; nerve conductionvelocity and electromyographic studies, for instance, areused to differentiate demyelinating neuropathies fromaxonal neuropathies (7).

In currently or recently polio-endemic countries, everycase of AFP should be reported, regardless of its presumedetiology. Two stool specimens should be collected within 14days after onset of paralysis, and virus isolation should beperformed by a qualified laboratory (if this is not feasible,stool specimens should still be collected up to 2 monthsfrom the onset of paralysis) (9). If indicated, serologic test-ing, isolation, and immunologic assays should be carried outfor enteroviruses, human immunodeficiency virus (HIV),Herpesviridae (cytomegalovirus, Epstein-Barr virus, herpessimplex virus types 1 and 2, varicella-zoster virus),Mycoplasma pneumoniae, Campylobacter jejuni, andBorrelia species, as well as a VDRL (Venereal DiseaseResearch Laboratory) test. Testing for antinuclear and anti-GMj (glycolipid ganglioside-monosialic acid) glycoconju-gate antibodies may be needed to confirm diagnoses ofimmunologic or autoimmune disorders.

If the necessary infrastructure and resources are available,further laboratory tests may be indicated for differentiating

res

r

MyasthtniaBotuKcm.

Tttanus, Drugs

1Muscle biopsy

r

Polymyo«itte,Toodc mycpathy,

ICU mycpathy

FIGURE 1. Algorithm for the evaluation of patients with limb or respiratory weakness. NMJ, neuromuscular junction; CK, creatine kinase;AMAN, acute motor axonal neuropathy; AIDP, acute inflammatory demyelinating polyneuropathy; ICU, intensive care unit.

Epidemiol Rev Vol. 22, No. 2, 2000


TABLE 1. Differential diagnosis of acute flaccid paralysis: clinical and epidemiologic characteristics COoo

0)

2

Site, condition,factor, or agent

Clinicalfindings

Onset ofparalysis

Progressionof paralysis

Fever S e ^at '" rt

s Pain bladderonset . . . m

a ™ _ . dys-function

andsymptoms

Reducedor Re-

Menin- absent sidualgismus deep paraly-

tendon sisreflexes

Pleocytosisin

cerebro-spinalfluid

Nerveconduction

study

Electro-myogram*

Anterior horn cells ofspinal cord

Poliomyelitis Paralysis in 1% of the Incubation period 24-48 hours to onset Yesinfected; nonspecific 7-14 days of full paralysis;prodrome (abortive (4-35 days) proximal > distal,poliomyelitis) asymmetrical

Iol Rev

Vol. 22, N

o. 2, 2000

Nonpolio entero-virus

Vaccine-associatedparalytic polio-myelitis

Other neurotropicviruses

Rabies virus

Varicella-zostervirus

Japanese enceph-alitis virus

Guillain-Barrdsyndrome

Acute inflamma-tory polyradic-uloneuropathy

Acute motoraxonal neu-ropathy

Cytomegaloviruspolyradiculo-myelopathy

Acute traumaticsciatic neuritis

Intramusculargluteal injection

Hand-foot-and-mouthdisease, asepticmeningitis, AHCt

Exanthematous vesic-ular eruptions

Preceding infection,bilateral facialweakness

Fulminant, widespreadparalysis, bilateralfacial weakness,tongue involvement

Acute, asymmetrical

As in polio-myelitis

As in polio-myelitis

Months to years

Incubation period10-21 days

Incubation period5-15 days

Hours to 10 days

Hours to 10 days

Hours to 4 days

As in poliomyelitis

As in poliomyelitis

Acute, symmetrical,ascending

Acute, symmetrical,ascending

Acute, proximal,asymmetrical

Acute, symmetrical,ascending(days to 4 weeks)

1-6 days

Subacute ascendinghypotonic

Complete, affected Flimb

Yes

Yes

No

Yes

Yes

No

No

+/-

30SSil

No

No

Yes

Yes

Yes Rare +/- Yes Yes Aseptic meningitis(moderatepolymorpho-nuclearleukocytes at2-3 days)

No Yes None +/- Yes Yes As in poliomyelitis

No Yes None +/- Yes Yes As in poliomyelitis

Yes Yes Yes +/- Yes No

Yes Yes No +/- +/- +/-

+/- +/- No Yes +/- +/-

Yes +/- No No Yes +/-

Reduced DenervationCMAPtampli-tude

ReducedCMAPampli-tude

ReducedCMAPampli-tude

Denervation

Denervation

No

Yes No Yes

Yes Yes

Yes

Yes

Yes No No Yes

Yes

Yes

No

No

Yes

No

ReducedCMAP amp.

ReducedCMAPamplitude,demye-lination

ReducedCMAPamplitude,axonal de-generation

Mixed axon-al degen-eration anddemyelina-tion

Axonaldegen-eration

Abnormal

Denervationpoten-tials

Denervationat roots

Sciaticdener-vation


Acute transverse myelitis

&

CD

§̂roN

pro

8o

Acute transversemyelitis

Epidural abscess

Spinal cordcompression;trauma

NeuropathiesExotoxin of

Corynebac-teriumdiphtheriae

Toxin of Clostrid-ium botulinum

Karwinskiahumboldtiana,K. calderoni

Tick bite paralysis

Preceding Mycoplasmapneumoniae,Schistosoma, otherparasitic or viralinfection

Headache, back pain,local spinal tender-ness, meningismus

In severe cases,palatal paralysis,blurred vision

Abdominal pain,diplopia, loss ofaccommodation,mydriasis

Ocular symptoms

Acute, lowerlimbs sym-metrical,hypotonia/lower limbs

Complete

Complete

Incubation period1-8 weeks(paralysis8-12 weeksafter onsetof illness)

Incubation period18-36 hours

Latency period5-10 days

Hours to days

Hours to days

Rapid, descending,symmetrical

Acute, symmetricalascending

Acute, symmetricalascending

Lyme borreliosis Erythema migrans, Weeks to months Subacute, multifocal(relapsing fever) bilateral facial after tick

paralysis, cardiac exposureabnormalities

Diseases of theneuromuscularjunction

Myasthenia gravis

Nondepolarizingdrugs

Disorders of musclePolymyositis

Viral myositis

Trichinosis

Weakness, fatigability,diplopia, ptosis,dysarthria

Neoplasma, auto-immune disease

Preceding gastro-enteritis

Sudden,complete

Subacute, proxi-mal > distal

Subacute myalgiaand weakness

Multifocal

Hours to days:prolongedblockade

Weeks to months

Hours to days

Days

Yes

Yes

No

Yes

No

No

No

Yes

No

No

No

Yes

Yes

Yes Yes No Yes, Yesearly

Yes Normal Normal

Yes Yes Yes Yes Yes +/- Moderate Normal Normal

Yes Severe Yes Yes Yes +/- Moderate Normal Normal

Yes

Yes

No

No

No No

No

No

No

No No

No

No

No No

No

Yes No

Yes

No

Yes

No No No No Yes

Yes +/- +/- +/-

Yes

No Yes No No Yes

No Yes No No No

No Yes No No No

+/- Demyelina- Latetion dener-

vation

No Facilitation Normal orwith re- dener-petitive vationstimuli

No Reduced DenervationCMAPamp.

Yes Yes, increasedprotein

No No

No

No

No

No

No

No

Decrement Normalon rep.stimulus

Normal or MyopathicreducedCMAP



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other viral or bacterial infections. A lumbar puncture andexamination of the cerebrospinal fluid may be indicated toexclude bacterial infection of the nervous system. Bacterialinfections frequently demonstrate large numbers of polymor-phonuclear leukocytes, with low glucose and high proteinlevels. Of course, culture will frequently identify the specificorganism involved. Cultures for bacteria are negative, identi-fying the illness as "aseptic" meningitis. However, cliniciansshould keep in mind that intramuscular injections mayaggravate the risk of paralysis in poliovirus-infected individ-uals (10, 11). Imaging of the spine (radiography, computedtomography, or magnetic resonance imaging (if available))may be indicated to rule out spinal cord compression,trauma, myelopathy, spondylotic polyradiculopathy, or neo-plasm. Laboratory test methods, if feasible, should includered blood cell and white blood cell differentials (e.g., nucle-ated and stippled red blood cells with karyorrhexis in arsenicpoisoning, basophilic stippling of white blood cells in leadpoisoning); determination of red blood cell sedimentationrate; and measurement of serum and urinary levels of sodium,potassium, calcium, magnesium, chloride, carbonate, creati-nine, uric acid, porphyrins (porphobilinogen, 8-aminolev-ulinic acid), and thyroxin. Measurement of enzyme activity(e.g., serum creatine kinase, acetylcholinesterase activity inred blood cells or plasma in case of organophosphate intoxi-cation) may be indicated. An electrocardiogram may be indi-cated to establish the diagnosis of electrolyte metabolism dis-orders, such as hypokalemic periodic paralysis.

Manifestations outside of the nervous system may includeskin ("raindrop" pigmentation) and nail (Mee's lines)changes in arsenic poisoning, or abdominal colic and bluelines in the gums in lead poisoning. More extensive screen-ing for chemical compounds in serum, urine, fingernails(arsenic), or hair (thallium) may be needed at a later time;therefore, clinical specimens should be collected and stored.

DIFFERENTIAL DIAGNOSIS OF AFP

The list of underlying causes of AFP is broad (table 1) andmay vary by age and geographic region. The etiologies ofAFP are often associated with specific pathophysiologicmechanisms or anatomic-morphologic changes, which mayhelp in establishing the correct clinical diagnosis (figure 2).The causes and differential diagnoses of AFP have beenreviewed previously (8, 12-16), including reviews on para-lytic illness in infants (17) and children (18-21) and in trop-ical regions (12, 13,22-24).

LESION OF THE ANTERIOR HORN CELLS OF THESPINAL CORD

Viruses targeting motor neurons

Polioviruses. Poliomyelitis. Poliomyelitis is caused bythree serotypes of poliovirus, a neurotropic RNA virus of thefamily Picornaviridae, genus Enterovirus (25). Poliovirustype 1 has the highest ratio of paralytic infection to subclin-ical infection and is the most frequent cause of epidemics ofparalytic disease. Poliovirus types 2 and 3 are less neurovir-ulent. Type 2 wild poliovirus was the first serotype to be




Acute Transverse Myelitis

Dorsal Root Ganglia:Herpes, CMV, Rabies

Anterior Horn Cell:Poliomyelitis, Enterovirus

Spinal Cord Compression:Space Occuping Lesions

Anterior Spinal ArterySyndrome

Polyradiculomyelopathy:CMV, Carcinomatous

Meningitis

Neuromuscular Junction:Myasthenia, Botulism,

Tetanus, NeuromuscularBlocking Agents,

Plant and Snake Toxins

Myelin:AIDP, Diphtheria

Muscle:Polymyositis,

Toxic Myopathy,ICU Myopathy

FIGURE 2. Pathophysiologic mechanisms and anatomic sites of etiologic factors for acute flaccid paralysis. CMV, cytomegalovirus; AMAN,acute motor axonal neuropathy; AMSAN, acute motor-sensory axonal neuropathy; AIDP, acute inflammatory demyelinating polyneuropathy;ICU, intensive care unit. (Adapted with permission from Ho et al. (99)).

eradicated in the Americas; as of 1999, the only remainingfoci of type 2 wild poliovirus transmission were detected innorthern India (26). Type 3 wild poliovirus caused a majoroutbreak of paralytic disease in Angola in 1999 (27).Poliomyelitis is transmitted by person-to-person spreadthrough fecal-oral and oral-oral routes, or occasionally by acommon vehicle (e.g., water, milk). The incubation period istypically 7-14 days (range, 3-35 days). When nonimmunepersons are exposed to wild poliovirus, inapparent infectionis the most frequent outcome (72 percent) (25). "Abortivepoliomyelitis," also referred to as "minor illness," is themost frequent form (24 percent) of the disease. Nonparalyticpoliomyelitis (including aseptic meningitis) occurs in 4 per-cent of patients. Only 1/1,000 to 1/100 infected individualsdevelop paralytic disease (28-30). Reports of greater ratiosof paralytic infection to subclinical infection inpoliomyelitis are not based on consistent case ascertain-ment, or are not representative of the range in the majorityof literature reports (30, 31). Initial clinical symptoms mayinclude fever, fatigue, headache, vomiting, constipation (orless commonly diarrhea), stiffness in the neck, and pain inthe limbs. A diphasic course featuring these relatively non-specific symptoms with acute onset of paralysis during thesecond phase is seen mostly in young children, and is un-common in individuals over 15 years of age. A monophasiccourse, with more gradual onset of symptoms and some-

times excruciating myalgia, is seen in adults (29).Distinguishing characteristics of paralytic poliomyelitis are1) fever at onset, 2) rapid progression of paralysis within24-48 hours, 3) asymmetrical distribution of limb paralysis,affecting proximal limb muscles more than distal limb mus-cles, 4) preservation of sensory nerve function with (oftensevere) myalgia, and 5) residual paralysis after 60 days (16,25). Paralytic poliomyelitis may show an early cere-brospinal fluid infiltrate of polymorphonuclear leukocytes;however, these are replaced after 2-3 days by moderatenumbers of lymphocytes and monocytes (32). The proteincontent of the cerebrospinal fluid is elevated only slightly,but it rises gradually in paralytic cases until the third week,generally returning to normal by the sixth week. Glucoselevels are usually within the normal range.

Research by Sabin (28), Bodian (33), and Horstmann andPaul (34) laid the foundation for understanding of the patho-physiologic and immunologic mechanisms leading to para-lytic poliomyelitis. Mendelsohn et al. (35) developed theconcept that motor neuron cells expressing a specific recep-tor for poliovirus are susceptible to virus adherence andmultiplication, leading to the subsequent destruction ofmotor neurons responsible for activating muscles. Anteriorhorn cell disease, including the appearance of inflammatorycells and motor neuron loss in the spinal cord, normallyoccurs within the first 2 weeks. Affected nerve cells do not



304 Marx et al.

regenerate, which results in the inability of affected musclesto function; however, axonal sprouting may result in somerecovery of function (7, 25). Poliomyelitis may lead tosevere asymmetrical atrophy and skeletal deformities.

Paralytic poliomyelitis may be associated with significantmortality—die case fatality rate, which is generally 5-10percent among polio patients, was as high as 20-30 percentduring outbreaks in the early 20th century (36, 37), and itincreases with age (38, 39). The case fatality rate was 12percent in a polio outbreak among young adults in Albaniain 1996 (38). Most of these patients died from complicationsof bulbar paralysis, i.e., respiratory failure. Although chil-dren under 5 years of age are most frequently affected, out-breaks of poliomyelitis with high attack rates among adultshave been described (25, 36-38, 40). The greater severityamong older patients is consistent with that observed in out-breaks among susceptible adults (38, 40, 41).

Besides age, being unvaccinated or inadequately vacci-nated (42), and lower socioeconomic status (16, 43), severalfactors have been shown to increase the risk of acquiringparalytic manifestations, including intramuscular injections,infection, stress, strenuous exercise, surgery (e.g., tonsillec-tomy), trauma, and pregnancy. The term "provocationpoliomyelitis" describes the enhanced risk of paralytic man-ifestations that follows intramuscular injection, and it occurswhen inflammation in muscle coincides with poliovirusinfection; entry of poliovirus to nerve endings in die muscleis facilitated, and paralysis occurs 4—30 days later (44).Aggravation occurs when signals from a particular muscle(from physical activity or inflammation) cause increasedblood flow in the relevant segments of the spinal cord whichhave already been invaded by poliovirus; increased severityof paralysis occurs 24-48 hours later (44).

Poliomyelitis changed from a comparatively rare diseaseinto an epidemic disease during the late 19th century andearly 20th century. Epidemics in Sweden in 1887-1911 andin Vermont in 1894 preceded the great New York epidemicof 1916, in which 27,000 children and adults were affectedand 6,000 (22 percent) died (36, 37). Large epidemics con-tinued to occur around the world through the 1950s, until thepoliovirus vaccine was introduced. Endemic spread and out-breaks of poliomyelitis continue to occur among incom-pletely vaccinated populations in Eastern Europe, theMiddle East, Asia, and Africa, particularly in countriesaffected by conflict (6).

Vaccine-associated paralytic poliomyelitis. Inactivated,injectable poliovirus vaccine, which was developed bySalk (45) following the discovery by Enders et al. (46) thatlarge quantities of poliovirus could be grown in tissue cul-ture, was licensed in the United States in 1955. Severalweeks after the introduction of inactivated poliovirus vac-cine in the spring of 1955, cases of vaccine-associatedparalytic poliomyelitis (known as "the Cutter incident")were reported in association with the use of incompletelyinactivated vaccine (47). Oral poliovirus vaccine, devel-oped by Sabin (48), was licensed in the United States in1961. Oral poliovirus vaccine has been effectively used tocontrol poliomyelitis and is the vaccine recommended bythe World Health Organization for interrupting transmis-

sion and eradication of wild poliovirus. Since a live atten-uated strain of the virus is used in oral poliovirus vaccine,the Sabin-derived virus may occasionally revert to aneurovirulent strain, potentially causing paralytic illnessthat is clinically identical to poliomyelitis resulting fromwild-type virus. The overall risk of vaccine-associatedparalytic poliomyelitis in the United States and LatinAmerica is one case per 2.5 million oral poliovirus vaccinedoses; the risk in Romania is one case per 183,000 oralpoliovirus vaccine doses—a 14-fold increased risk (49,50). Three distinct groups are at risk of vaccine-associateddisease: recipients of oral poliovirus vaccine (mostlyinfants receiving their first dose), persons in contact withoral poliovirus vaccine recipients (mostly unvaccinated orinadequately vaccinated adults), and immunocompromisedindividuals (51). However, neither HIV infection nor AIDShas been associated with an increased risk of paralytic dis-ease due to wild-type or Sabin-derived poliovirus (52).There is no long-term carrier state in infected immuno-competent persons, regardless of the clinical course.However, prolonged shedding of Sabin-derived poliovirushas been shown to occur in immunocompromised patientswith B-cell deficiencies (53).

Nonpolio enteroviruses. Nonpolio enteroviruses havebeen associated with polio-like paralytic disease, frequentlyaccompanied by other clinical syndromes, such as asepticmeningitis, hand-foot-and-mouth disease, and acute hemor-rhagic conjunctivitis. Coxsackieviruses A and B, echovirus(54), enterovirus 70 (24, 55), and enterovirus 71 (56-65)have been implicated in polio-like paralytic disease.Outbreaks of acute hemorrhagic conjunctivitis with radicu-lomyelitis and paralytic illness in India, Taiwan, Thailand,and Panama were etiologically linked to enterovirus 70 (24,55). Muscle weakness and wasting associated withenterovirus 70 is usually severe and permanent (24).

Among all known nonpolio enteroviruses, enterovirus 71has been most strongly implicated in outbreaks of centralnervous system disease and AFP, first described inCalifornia during 1969- 1973 (60). Global attention focusedon enterovirus 71 when severe epidemics of central nervoussystem disease occurred in Japan in 1973 (56) and inBulgaria in 1975 (57). Of 705 patients infected withenterovirus 71 in Bulgaria, 149 (21 percent) developedparalysis, and 44 (29 percent) of those persons died. Youngchildren under 5 years of age were most frequently affected.Further outbreaks were reported in Hungary in 1978 (63)and in Philadelphia, Pennsylvania, in 1987 (59). Householdclusters of acute neurologic disease associated withenterovirus 71 were reported among children in Brazil in1988-1990 (62). The most recent outbreaks were reported inMalaysia in 1997 (66) and in Taiwan in 1998 (64, 65).Antecedent illness (7-14 days before onset of AFP) wasgenerally characterized by fever, vomiting, diarrhea,lethargy, nuchal rigidity, irritability, and anorexia; at 60-dayfollow-up, these patients suffered from residual paralysiswith weakness and muscle wasting (67). Although signs ofpolio-like illness were found less frequently in AFP patientswith isolation of nonpolio enterovirus than in poliovirus-positive patients, nonpolio enterovirus infection may be




clinically indistinguishable from paralytic poliomyelitiswithout laboratory studies (55, 67).

Other neurotropic viruses. Rabies and rabies vaccines.Rabies manifests after an incubation period of 1-2 months(or, infrequently, years). Typical rabies includes an "excite-ment" phase characterized by behavioral and autonomicnervous system abnormalities. A minority of cases willprogress directly to a paralytic phase ("dumb" rabies) (68).Following nonspecific prodromal symptoms with paresthe-sia of the bitten area, paralytic rabies manifests as ascendingAFP with sphincter involvement and sensory disturbances.Death from respiratory and bulbar paralysis occurs after alonger illness than is seen in furious rabies. Differentialdiagnoses of paralytic rabies include postvaccinalencephalomyelitis, poliomyelitis, Guillain-Barre syndrome,and other causes of Landry-type ascending paralysis (68).

Neuroparalytic post-rabies vaccine encephalomyelitis,Guillain-Barre syndrome, and allergic neuritis weredescribed after the administration of earlier rabies vaccines,namely the Semple and Hempt types (see sections onGuillain-Barre syndrome and peripheral neuropathiesbelow), and varied in severity from neuritic and dorsolum-bar myelitic paraplegic forms to the ascending Landry-typeparalytic form (69). Nerve tissue cell rabies vaccines pro-duce a rate of one neuroparalytic adverse event per 200 vac-cine recipients, whereas the complication rate is much lowerin vaccines derived from cell culture (69, 70).

Herpesviridae. Herpesviridae (cytomegalovirus, Epstein-Barr virus, varicella-zoster virus) are a group of neurotropicDNA viruses that may cause AFP associated with Guillain-Barre syndrome, opportunistic infections of the nervous sys-tem in individuals with AIDS, and acute transverse myelitis(see sections on Guillain-Barre syndrome, acute transversemyelitis, and neurologic disorders associated with HIV,AIDS, or opportunistic infections below). Herpes simplexvirus encephalitis is the most common form of nonepidemicviral encephalitis in the world, with an annual incidence of1-3 cases per million population; all age groups may beaffected, including newborns infected at birth (usually withherpes genitalis, herpes simplex virus type 2) (71). Bothcytomegalovirus and herpes simplex virus type 2 may causepolyradiculoneuropathies (see section below).

Viral meningoencephalitis. Viral meningoencephalitismay be caused by neurotropic viruses (paramyxovirus (para-influenzavirus, mumps virus), togovirus, arbovirus, Herpes-viridae), parasites (Trichinella spiralis; see section below), orstroke of the spinal cord (71, 72). Meningoencephalitis gen-erally manifests with central nervous system signs such asdisorientation, convulsion, or coma, and transient flacciditymay only precede the classic spasticity of upper motor neuronlesions (71). In the case of Herpesviridae or rabies virus,meningoencephalitis is due to direct invasion of brain cells,but it may be a secondary immunologic response to infectionor immunization (parainfectious or postinfectious encephali-tis) (71, 72).

Japanese encephalitis virus. Japanese encephalitis virus, aflavivirus, is endemic in Southeast Asia, parts of China, andthe Indian Subcontinent; in specific areas, it may be animportant cause of AFP (73). Electrophysiologic studies

suggest that Japanese encephalitis virus myelitis is causedby anterior horn cell damage, and the clinical presentationmimics poliomyelitis in many respects, including weaknessand wasting beyond 60 days after onset of paralysis.

POLYRADICULONEUROPATHIES

Landry-Guillain-Barre-Strohl syndrome

Landry-Guillain-Barre-Strohl syndrome, hereafter calledGuillain-Barre syndrome, is a disorder of peripheral nerves,characterized by subacute (days to weeks) progression ofmotor-sensory dysfunction not associated with meningis-mus or fever. The syndrome was first described by Landryin 1859 and by Guillain, Barre, and Strohl in 1916. Thediagnostic criteria developed by Asbury and Cornblath (74),based on the pathophysiologic and morphologic understand-ing of Guillain-Barre syndrome, correspond to those ofacute inflammatory demyelinating polyradiculoneuropathy(AIDP). There is increasing evidence that what is diagnosedas Guiltem-Barre" syndrome may include conditions origi-nating from a variety of underlying pathogenic mechanisms(75). In the absence of wild virus-induced poliomyelitis,Guillain-Barre syndrome is the most common cause of AFPin many parts of the world, and it accounts for over 50 per-cent of AFP cases in both industrialized and developingcountries (76, 77). The annual incidence globally is 1-2 per100,000 population (78); however, there are differences byregion and ethnicity. Guillain-Barre syndrome is an impor-tant cause of AFP among children (21), but the incidenceincreases with age, and it is most common in the elderly(77). Rarely, cases in infants have been reported (21).

Guillain-Barre syndrome occurs in 50-70 percent of itspatients within 2-28 days after a gastrointestinal or respira-tory infection (21). It is characterized by 1) afebrile onset,2) ascending symmetrical paralysis progressing within daysto weeks (in >90 percent of patients, the nadir occurs by 4weeks), and 3) disturbances of sensory function (74). If re-spiratory muscles become involved, the patient may die ofrespiratory failure. Patients surviving the acute phase fre-quently (>80 percent) recover functionally (74). In severecases, persistent residual paresis occurs; however, themajority of patients in this group ultimately have a goodfunctional recovery (74). The presence of bilateral facialweakness, a normal cell count and elevated protein level inthe cerebrospinal fluid, and electrophysiologic evidence ofabnormal conduction support the diagnosis of Guillain-Barre syndrome.

Preceding infection with C. jejuni has been identified asthe most common etiologic factor of Guillain-Barre syn-drome (79). Infection with M. pneumoniae, Herpesviridae(cytomegalovirus, Epstein-Barr virus, varicella-zostervirus), HIV, measles virus, mumps virus, rubella virus, viralhepatitis, influenza A and B viruses, vaccinia virus, andnonpolio enteroviruses (Coxsackievirus, echovirus) havebeen demonstrated in epidemiologic studies to precedeGuillain-Barre syndrome. Malignant lymphoma, alco-holism, liver cirrhosis, and thyroid disorders (hyperthy-roidism, Hashimoto thyroiditis) have been linked toGuillain-Barre syndrome (80). Preceding vaccination



306 Marx et al.

against rabies (especially with the Semple-type vaccine(69); see section on rabies vaccines above), influenza,typhoid fever, rubella, or cholera and administration of vac-cines containing tetanus toxoid (Td, DT), anti-tetanus toxinserum, or plasma-derived hepatitis B virus have been asso-ciated with Guillain-Barre syndrome. A causal associationbetween use of oral poliovirus vaccine and Guillain-Barresyndrome has been suggested but has been ruled out bymore recent studies (81, 82).

Outbreaks of Guillain-Barre syndrome were reported inColombia in 1968 and in Jordan in 1976 (83). In the UnitedStates, during 1976-1977, 516 individuals aged 18 years orolder who had received the influenza A/New Jersey vaccineand 432 unvaccinated individuals developed Guillain-Barresyndrome; the swine influenza component was not added tothe vaccine after 1977, and there were no further cases ofGuillain-Barre syndrome (84, 85).

Understanding of the immunopathogenesis of Guillain-Barre syndrome, including the primarily demyelinating andaxonal forms, is based mainly on the following: 1) preced-ing infection with specific organisms, most notably C. jejuniand M. pneumoniae; 2) the contribution of antibody- andcomplement-mediated mechanisms of immune injury;3) glycoconjugate antigens' being likely targets of immuneattack, and expression of anti-GM! glycoconjugate antibod-ies' possibly being associated with C. jejuni infection (86);4) heterogeneity of immunologic targets on nerve fibers;5) the presence of Ranvier nodes as immunologic targets;and 6) "molecular mimicry," a host-generated immuneresponse to infectious organisms or tumor cells that shareantigenic determinants with the host's tissue. C. jejuni maycontain GM^like epitopes inducing the expression of anti-GM| antibodies, which cross-react with antigenic determi-nants on nerve fibers. High titers of immunoglobulin G andimmunoglobulin M anti-GM! antibodies have been found in5-85 percent of patients with Guillain-Barre syndrome, aswell as acute motor axonal neuropathy and autoimmune dis-ease, including myasthenia gravis and polymyositis (86).

AIDP with acute lymphocytic infiltration andmacrophage-mediated demyelination reproduces the clinicaland pathologic features of Guillain-Barre syndrome mostoften reported in North America, Europe, and Australia (87).In other parts of the world, it has recently become clear thatsome cases of Guillain-Barre syndrome have extensiveaxonal degeneration with only minimal evidence of demyeli-nation (88, 89).

Subacute and chronic inflammatory demyelinatingpolyradiculoneuropathy

Subacute inflammatory demyelinating polyradiculoneu-ropathy (SIDP) and chronic inflammatory demyelinatingpolyradiculoneuropathy (CIDP) may be considered variantsof AIDP (90). CIDP is defined as an acquired demyelinatingneuropathy with insidious onset and progression over atleast 8 weeks (as opposed to AIDP, which progresses over aperiod of up to 4 weeks, and SIDP, which progresses over4—8 weeks) (90). All of the clinical features reported forAIDP have been seen in CIDP, including ascending, sym-

metrical AFP, disturbances of sensory function, cranialnerve involvement, respiratory failure, autonomic distur-bances, and albuminocytologic dissociation and dys-immunoglobulinemia in the cerebrospinal fluid (90).Electrophysiologic studies allow one to distinguish CIDPfrom inherited demyelinating or axonal neuropathy (91).

Acute motor axonal neuropathy

Acute motor axonal neuropathy (AMAN), also referred toas "Chinese paralytic syndrome," is a distinct disease entitythat appears different from AIDP and poliomyelitis becauseof its primarily axonal involvement (88, 89, 92). Recentresearch documented excessive axonal degeneration withoutpreceding demyelination and suggested that the target anti-gen may lie on the axon (92). AMAN has been described,particularly during the summer months, among children andyoung adults in northern China (88) and has also beenreported in Mexico (93), Spain (94), India (recentlydescribed as "Asian paralysis syndrome") (95, 96), Pakistan(97), and South Korea (80). Characteristic features ofAMAN include fulminant and widespread paralysis withslow and usually incomplete recovery, bilateral facial weak-ness, frequent involvement of the tongue, normal sensoryperception, and normal cerebrospinal fluid cell count (88,98). Early symptoms of this disease include leg weaknessand resistance to neck flexion. The weakness ascendsrapidly, affects symmetrically the arms and respiratory mus-cles, and progresses to the maximum extent of weaknesswithin 6 days, on average. Electromyographic studies indi-cate denervation potentials in weak muscles and suggest thatthis entity may be a reversible distal motor nerve terminal oranterior horn lesion. Serum antibodies to C. jejuni are fre-quently elevated (88, 99). Acute motor-sensory axonal neu-ropathy (89) is seen throughout the world, is rarer thanAIDP and AMAN, and probably does not have a seasonalvariation.

Neurologic disorders associated with HIV infection,AIDS, or opportunistic infections

Neurologic disorders, including AFP, may complicate HIVinfection and AIDS (100). Such disorders may be caused by1) HIV infection or AIDS; 2) opportunistic infections (e.g.,Herpesviridae (cytomegalovirus, Epstein-Barr virus, herpessimplex virus, varicella-zoster virus), Giardia lamblia,Toxoplasma gondii, Mycobacterium tuberculosis, orTreponema pallidum (syphilis)); or 3) vitamin B12 deficiencyand other deficiencies of AIDS cachexia contributing to theneuropathic process in terminal AIDS. Nucleoside antiretro-viral agents and prophylactic and therapeutic drugs used totreat HTV-associated complications may cause motor-sensoryneuropathies and myopathies but are generally not associatedwith AFP. In the early stages of AIDS, AIDP, CIDP, isolatedcranial or other mononeuropathies, and brachial plexopathycan occur. In later stages, opportunistic infection of peripheralnerves by cytomegalovirus can cause syndromes of subacuteprogressive polyradiculomyelopathy (cytomegalovirus-polyradiculomyelopathy) (101).




Cytomegalovirus causes meningoencephalitis, myelitis,and cytomegalovirus-polyradiculomyelopathy (101) (seesection on neurotropic viruses above). Cytomegalovirus-polyradiculomyelopathy is a rare but distinctive clinicalsyndrome causing subacute ascending hypotonic lowerextremity weakness, often preceded or accompanied bypain and paresthesia in the legs and perineum, with are-flexia, urinary retention, and loss of sphincter control(101). Tactile, vibratory, and kinesthetic impairments andsensory levels are noted in certain patients. The cere-brospinal fluid typically shows prominent representationof polymorphonuclear leukocytes, elevated protein levels,and low glucose levels. Electrophysiologic studies typi-cally demonstrate features of axonal neuropathy associ-ated with varying degrees of demyelination. The differen-tial diagnosis of cytomegalovirus-polyradiculomyelopathyincludes the following opportunistic conditions affectingthe lumbosacral nerve roots and spinal cord: herpes sim-plex virus type 2, varicella-zoster virus, T. gondii, T. pal-lidum, and other bacterial infections (101).

Varicella-zoster virus infection may cause symmetricalascending AFP, mimicking or potentially causing Guillain-Barre syndrome (102). Frequently in zoster patients, painand paresthesia precede the belt-like vesicular eruption fol-lowing sensory dermatomes. Rarely, a somewhat similarclinical picture may be seen in patients suffering fromHerpesvirus simiae infection of the central nervous systemfollowing a monkey bite (19). Varicella also has been asso-ciated with AMAN (103).

ACUTE MYELOPATHIES

Acute transverse myelitis

As a cause of AFP, acute transverse myelitis is less fre-quent than Guillain-Barre syndrome or paralytic nonpolioenterovirus infection; the reported annual incidence is lessthan one case per 2 million population (104). The com-mon presentation includes, in the initial phase of spinalshock, weakness of the lower extremities, AFP, urinarydistention (neurogenic bladder), constipation, hypo-reflexia, sensory impairment (sensory level), severe pain,and paresthesia. After 2-3 weeks, hyperreflexia and spas-ticity appear. Among patients with acute transversemyelitis, approximately one third fully recover, one thirdpartially recover, and the rest remain disabled or die(105).

Acute transverse myelitis has been associated with M.pneumoniae, Herpesviridae (cytomegalovirus, Epstein-Barrvirus, varicella-zoster virus), rabies virus, hepatitis A virus,and enteric fever. Parasitic infection may involve the spinalcord or brain stem, including Schistosoma mansoni andSchistosoma haematobium, Cysticercus cellulosae, Taeniasolium and Taenia multiceps, Echinococcus granulosus(cystic hydatid disease) and Echinococcus multilocularis,and paragonimiasis (104). Cases of acute transverse myelitishave been documented following administration of oralpoliovirus vaccine, tetanus toxoid (DT, Td), and cholera,typhoid fever, and plasma-derived hepatitis B virus vaccine,but the evidence has been considered inadequate to confirm

a causal relation (106). The illness may be suggestive ofencephalomyelopathy or a tumor rather than poliomyelitis-like paralysis. Diagnostic testing (eosinophilia, positiveparasite-specific complement fixation tests) or empiricaltreatment (antiparasitic agents) may provide clinical leads asto the etiology.

Acute myelopathy due to spinal cord compression(space-occupying lesions, spinal block, epiduralabscess) or anterior spinal artery syndrome

Acute myelopathy may occur because of the presence ofspace-occupying lesions or spinal block—e.g., paraspinalor epidural abscess, tumor or hematoma, or anterior spinalartery syndrome (107). The common presentations includeweakness of the lower extremities, AFP, urinary distention,constipation, hyporeflexia, sensory impairment, and pares-thesia. A slightly elevated protein level in cerebrospinalfluid may be found. There have been reports of acute trans-verse myelitis with sensory disturbances and AFP of bothlower limbs following intragluteal penicillin injection(108). These accidents were probably due to mistakenintraarterial injection of the drug, with retrograde progres-sion through branches of the internal iliac artery up to thespinal cord.

TRAUMA

Acute traumatic sciatic neuritis associated withintramuscular gluteal injection

Administration of intramuscular injections in the glutealregion is still common practice, despite the potential risk ofdirect trauma or postinjection neuritis. The World HealthOrganization recommends that diphtheria-tetanus-pertussisvaccines and other intramuscular injections be given at theanterolateral aspect of the upper thigh (109). A history ofrecent injections in paralyzed limbs—for the treatment offebrile infections, for instance—provides a characteristiclead for diagnosing traumatic neuritis. Traumatic neuritisneeds to be differentiated from aggravation poliomyelitis(see section on poliomyelitis above).

Spinal cord injury

Trauma should always be considered clinically as a causeof AFP. However, paralysis that is clearly associated withtrauma should not be included in the AFP reporting system.

Cardiovascular disorders, surgical complications

Postoperative spinal cord damage due to ischemia mayoccur because of the interruption of critical radicular arter-ies at the lower thoracic or high lumbar vertebral levels, andmay result in total paraplegia orparaparesis (107). High aor-tic clamping and hypotension increase the probability of thisoccurrence. The clinical examination in such cases revealsAFP, areflexia, sensory loss, patulous sphincter, and reflexneurogenic bladder (107).



308 Marx et al.

PERIPHERAL NEUROPATHIES

Anatomically, two broad categories of peripheral neuropa-thy can be distinguished in terms of the pattern of involve-ment of the peripheral nervous system: 1) polyradiculoneu-ropathies involve the spinal roots and peripheral nerve trunks,and 2) poly neuropathies, which result in bilaterally symmet-rical disturbance of function, tend to be associated with agentsthat act diffusely on the peripheral nervous system, such astoxic substances, deficiency states, systemic metabolic disor-ders, and certain types of autoimmune reactions.

Toxic neuropathies are an important group of disorders inneurologic practice in the tropics. Distal axonal degenera-tion ("dying back phenomenon") is the neuronal dysfunc-tion in most toxic neuropathies (13). Neuropathies mayoccur in the course of infectious diseases, such as diphthe-ria, borreliosis, and rabies. Acute peripheral neuropathywith features similar to those of Guillain-Barre syndromecan occur in acute beriberi, acute intermittent porphyria,AIDS, paralytic rabies, cytomegalovirus infection, Epstein-Barr virus infection (110), and hepatitis B virus infection,and following the administration of Semple-type rabies vac-cine (69) (see section on rabies vaccines above).

Toxic neuropathies

Diphtheria neuropathy is an infrequent complication (-10percent) among patients infected with Corynebacteriumdiphtheriae. Patients with more severe manifestations ofdiphtheria (toxic forms) are at greater risk of developingcranial and peripheral neuropathy, which makes its appear-ance during the initial acute phase of illness or 8-12 weekslater. The neuropathy is mostly distal and mixed motor-sensory disease (111), characterized by palatal palsy, earlysensory signs and symptoms, fever, and reduced or absentdeep tendon reflexes. Studies of nerve conduction velocitydemonstrate prominent demyelination with signs of dener-vation upon electromyography.

Tick bite paralysis manifests 5-10 days after a tickattaches itself. The onset of the illness is rapid, with prodro-mal symptoms including irritability, anorexia, pain andparesthesia in the extremities, and ataxia and being followedby symmetrical, ascending AFT within 12-36 hours. If thetick is not removed, the illness will eventually involve bul-bar musculature and will lead to a fatal outcome in up to 12percent of patients. Paralysis usually (but not always)resolves rapidly after tick removal (13). Ocular symptoms,if present, may provide clues with which to differentiate tickparalysis from Guillain-Barr6 syndrome, myasthenia gravis,or botulism (112). Various Dermacentor and Ixodes species,mainly in North America and Australia but also in tropicalareas, are known to produce paralysis in humans and indomestic and wild animals (13). While tick toxin wasthought to block neuromuscular transmission, recent reportsindicate that ticks elaborate a toxin directed at the large-diameter motor or sensory nerves, particularly the motornerve terminals (112).

Neuropathy associated with Lyme borreliosis (113) maymanifest as cranial neuropathy, most commonly facial palsy,

radiculoneuropathy, or symmetrical distal neuropathy. Lymedisease, caused by the spirochete bacterium Borreliaburgdorferi, is characterized by erythema migrans, highacute-phase serum titers of immunoglobulin M andimmunoglobulin G Borrelia antibodies, and lymphocytosisand increased total protein levels in the cerebrospinal fluid(113). Ixodes ticks, the vector of Lyme disease, are prevalentmainly in North America, Europe, Eastern Europe, andnortheastern China. The incubation period between tickexposure and erythema migrans is 3-32 days; within weeksor months after the appearance of erythema migrans, a vari-ety of neurologic abnormalities may occur. Lyme meningi-tis affects nerve roots as the spirochete bacteria pass throughthe subarachnoid space. AFP due to Lyme polyradiculoneu-ropathy may develop 6—8 weeks after the tick bite and ispainful and asymmetrical. Weakness that may affect boththe lower and upper limbs develops within 4 weeks afteronset, much more slowly than in poliomyelitis. Deep tendonreflexes are usually depressed, and sensory loss is der-matomal (72). Lyme borreliosis also may cause facial paral-ysis, which is bilateral in 50 percent of cases; in the absenceof other clinical systemic features, it may be indistinguish-able from idiopathic facial paralysis (Bell's palsy; see sec-tion below).

Louse- or tickborne relapsing fever caused by severalBorrelia species occurs worldwide and may cause AFP(114). Borreliae in tick-borne relapsing fever more fre-quently cause neuroparalytic complications, while louse-borne borreliae cause more severe systemic illness andgreater mortality.

The ingestion of the ripe fruit of Karwinskia humbold-tiana (tullidora, coyotillo, buckthorn, wild cherry), whichgrows in northern Mexico, Central America, and the USstates of Texas and New Mexico, produces a progressiveascendent symmetrical AFP resembling Guillain-Barr6 syn-drome that in severe cases may cause bulbar paralysis anddeath (115, 116). K. humboldtiana has caused outbreaks ofAFP in Nicaragua (117). Wild berries of Karwinskiacalderoni in El Salvador may contribute to the elevated rateof AFP (erroneously attributed to Guillain-Barre syndrome)seen among children in the Americas.

Gloriosa superba (climbing lily, glory lily), found inAfrica and Asia, contains colchicine, which impairs rapidaxonal transport in peripheral nerves, resulting in axonalneuropathy; it also causes myopathy (22). Other poisonousplants implicated in paralytic illness include Aconitumnapellus (monkshood); Callilepsis species (daisy);Gelsemium (jasmine—blossoms); Heliotropum (bush teashrub); Melochia species (stems); and Oenanthe species(parsnip) (19).

A variety of chemicals, metals, and drugs have been asso-ciated with motor-sensory neuropathies. Exposure (oftenagricultural or industrial) to chemicals such as lead, arsenic(118), and thallium, as well as glue-sniffing (119), maycause peripheral motor neuropathy. Historically, epidemicneuropathies in Jamaica and England could be linked tochronic arsenic intoxication rather than nutritional defi-ciency. Arsenic-containing compounds such as melarsoprolare still being used in developing countries for the treatment




of African trypanosomiasis (sleeping sickness) and maycause Guillain-Barre syndrome-like AFP (120).

Many antimicrobial or chemotherapeutic agents maycause peripheral neuropathy. Symptoms are mainly sensory,but distal weakness can occur. Antirheumatic drugs (gold,colchicine) have been associated with peripheral neuropathy(22). The number of cases involved is relatively small, andcessation of treatment with these compounds results inregression of the neurologic symptoms. This observationalso applies to chemotherapeutic agents (Vmca alkaloidsand platinum-containing compounds).

DISEASES OF THE NEUROMUSCULAR JUNCTION

The skeletal neuromuscular junction, the most exposedand most vulnerable synapse known, is the site of primarypathology in disorders such as myasthenia gravis andLambert-Eaton myasthenic syndrome (121). Both syn-dromes are rare, characterized by weakness and fatigabilityof skeletal muscles. High titers of anti-GM, glycoconjugateantibodies in patients with myasthenia suggest an autoim-mune disorder (86). Endogenous chemicals such as calciumand magnesium, when in excess or deficit, will affect theneuromuscular junction (122). Exogenous chemicals suchas organophosphates inhibit acetylcholinesterase activity,leading to neuromuscular blockage and muscle paralysis. Alarge number of drugs also alter neuromuscular transmis-sion, acting either directly in nondepolarizing neuromuscu-lar blocking agents or through adverse effects (e.g., amino-glycosides, phenytoin) (23).

A variety of naturally occurring toxins of animal, plant,and bacterial origin are capable of causing disorders of neu-romuscular transmission.

Botulism is caused by the exotoxin of Clostridium botu-linum. Botulism toxin can cause descending paralysis—characterized by symmetrical impairment of cranial nerves,followed by a descending pattern of weakness or paralysisof the extremities and trunk (123).

Tetanus exotoxin from the spores of Clostridium tetani isa major cause of perinatal mortality, and it may also causeAFP of the muscles innervated by the affected cranial nerves(i.e., cephalic tetanus) (124). The latent period for the neu-rologic syndrome is 14 days in neonates and 6-10 days inadults (range, 3-21 days). Tetanus toxin is carried intra-axonally within membrane-bound vesicles to spinal motorneurons, where it causes presynaptic inhibition of spinalglycinergic neurons (22). Subclinical axonopathy has alsobeen described in patients recovering from tetanus.

Animal toxins leading to neuroparalytic syndromesinclude those derived from the venom of various snakes,arthropods, and marine creatures and those derived from theskin excretions of "dart-poison" frogs, poisonous fish, shell-fish, and crabs (producing the active agents ciguatoxin,tetrodotoxin, saxitoxin, and domoic acid). Neurotoxins pro-duced by elapid snakes, particularly the African and Asiancobra (Naja) and the krait of southern Asia (Bungaris), maycause acute neuroparalytic syndromes in 30-50 percent ofvictims, including AFP, ophthalmoplegia, and bulbar andrespiratory palsy. Many elapid snakes, including the mam-

bas of Africa, Vipiridae (including rattlesnakes), and thecoral snakes of America, produce neurotoxins; however,only cobra and krait bites have been associated with neu-roparalytic syndromes in the absence of any other symptomexcept local pain. An interesting early morning syndrome ofacute oculobulbar palsy with flaccid paralysis, resemblingthe clinical picture seen with elapid snake bite but withoutevidence of snake bite, has been reported in India (12, 125).The features of acute onset of ptosis, external ophthalmo-plegia, and bulbar paralysis with mild to moderate weak-ness, in the absence of a history of snake bite, could be con-founded with myasthenia gravis, acute infectivepolyneuritis, or poisoning because of numerous agents' act-ing at the neuromuscular junction, but they should be dis-tinctive enough to differentiate this syndrome from paralyticpoliomyelitis.

Tetrodotoxin poisoning from consumption of puffer fish(fugu, Sphaeroides maculatus) results in a fatality rate of upto 60 percent (126). Within several hours after consumption,individuals develop circumoral paresthesia spreading to thelimbs and trunk, with AFP and difficulty in breathing (126).Tetrodotoxin may act at the motor end plate as well as onaxon and muscle membranes, and patients clinicallyrespond to treatment with anticholinesterase drugs (126).

The known plant toxins most commonly implicated inparalytic illness due to neuromuscular blockade are curare,camethonium, and hemlock extract (127).

Organophosphorus esters are used mainly as insecticides,petroleum additives, and modifiers of plastics (128). Mostinhibit acetylcholinesterase activity; some, used as pesti-cides, helminthicides, or war gases, are extremely potent.The main symptoms include acute weakness of the hands,calf pain preceding paresthesia and weakness of the limbs,absent ankle jerks, foot-drop, and claw-hand (13). The mus-cle paralysis caused by delayed neuropathy (2-3 weeks afterorganophosphorus exposure) should be differentiated fromthe intermediate syndrome (3-4 days postexposure), whichaffects the neuromuscular junction and carries the risk ofrespiratory paralysis and death (13, 22, 129).

Outbreaks of neuropathy resulting from exposure to tri-orthocresyl phosphate, a potent organophosphate, haveoccurred in Morocco, Jamaica, the United States, SouthAfrica ("Durban mystery disease"; see "Other ClinicalSyndromes Causing AFP" below) (19), India (13), and SriLanka (13). The consumption of accidentally contaminatedor adulterated food products (Jamaican ginger tonic,Romanian liquor, or contaminated cooking oil, mustard oil,or flour) may lead to paralytic disease (130). Outbreaks inSri Lanka were linked to sesame-derived gingili oil given toteenage girls at menarche and to adult women after child-birth; these women exhibited the characteristic wrist-dropand claw-hand (13). Triorthocresyl phosphate intoxicationtypically begins with aching pain in the calves, followed byparesthesia, numbness, and weakness distally in the lowerextremities, along with a high incidence of pyramidal signs(13). Upon examination, ankle jerks are diminished orabsent; knee jerks, however, are usually exaggerated, sug-gesting upper motor neuron involvement (destruction ofcorticospinal tracts and the spinal cord, including anterior



310 Marxetal.

horn cell damage) rather than peripheral axonal neuropathyor neuromuscular blockade (1, 13).

WEAKNESS ASSOCIATED WITH CRITICAL ILLNESS

Acute weakness syndromes in critically ill patients can becategorized into three major groups with different etiolo-gies: 1) critical illness polyneuropathy; 2) neuromuscularjunction abnormalities, subdivided into myasthenia-likesyndromes and prolonged neuromuscular blockade; and3) myopathy, including acute disuse (cachectic), necrotizing,and thick filament (myosin) loss myopathy (131). Recentdata also suggest that physiologic muscular inexcitabilitydue to sodium channel dysfunction, rather than morphologicchanges of the muscle, may contribute to weakness in criti-cally ill patients (132).

Nondepolarizing neuromuscular blocking agents, usedwith increasing frequency in critically ill patients, have beenassociated with prolonged muscle weakness (133).Individuals with status asthmaticus treated with bron-chodilators, antibiotics, and high dose corticosteroids andparalyzed with vecuronium to facilitate mechanical ventila-tion have developed flaccid quadriplegia with areflexia.Brief weakness lasting for several hours to several days isprobably the result of prolonged neuromuscular blockade,while more prolonged weakness lasting for several weeks tomonths is probably caused by myopathy. Clinically, patientsdevelop AFP with intact sensation and cognition.

Neuromuscular dysfunction in patients with sepsis isincreasingly being reported (131, 134). The common under-lying pathogenic process in these syndromes appears to besystemic inflammatory response syndrome, induced byinfection or trauma and accentuated by the administration ofsteroids or neuromuscular blocking agents (131). Flaccidquadriplegia with the inability to wean from ventilatory sup-port despite full cardiopulmonary recovery is the typicalpresentation. Electrophysiologic studies often demonstratethe presence of axonal polyneuropathies, abnormalities ofneuromuscular transmission, or acute myopathies. Recoveryin strength usually occurs over a period of weeks to months.Variants of critical illness polyneuropathy may affect end-stage uremic or diabetic patients developing axonal, pre-dominantly motor polyneuropathy.

First described by Hopkins and Shield in 1974 (135), acutepostasthmatic amyotrophy (Hopkins syndrome) is character-ized by sudden onset of AFP of an arm or a leg with com-pletely preserved sensibility approximately 1 week after anasthma attack. All children in the initial case description wereunder 10 years of age, and most were male. To date, fewerthan 30 cases have been described in the literature. The AFPis probably due to a lesion of the anterior horn cells of thespinal cord, but evidence indicates a more widespread patho-logic process. The etiology is unknown, but infectious orimmunologic mechanisms are likely. It has been suggestedthat a combination of immune suppression with the stress ofan acute asthma attack, concurrent infection, or corticosteroidtherapy renders patients susceptible to viral invasion of ante-rior horn cells. Infections with M. pneumoniae and otheragents have been associated with Hopkins syndrome (136).

DISORDERS OF THE MUSCLE

Idiopathic inflammatory myopathy (polymyositis) rarelymay cause Guillain-Barre' syndrome-like AFP (137). Theonset more frequently is subacute and insidiously progres-sive over weeks, months, or even years. Proximal limb mus-cles are mostly affected, but respiratory weakness, cardiacproblems, or dysphagia may occur. The diagnosis is basedon electromyographic abnormalities, elevated serum crea-tine kinase levels, and muscle biopsy. As in other autoim-mune disorders, high titers of anti-GM, glycoconjugate anti-bodies are found in polymyositis patients as well (86).Polymyositis is primarily found among females aged 20-40years. Associated conditions often include lung cancer andautoimmune disease (systemic lupus erythematosus andmixed connective tissue disorder). Inflammatorypolymyositis may also be associated with viral (HIV, humanT-lymphotropic virus type 1, nonpolio enterovirus), para-sitic {Toxoplasma), or bacterial (Lyme disease) infections(137).

Hereditary motor and sensory neuropathies, historicallycalled spinal muscular atrophies or muscular dystrophies,may affect the anterior horn cells of the spinal cord.Werdnig-Hoffmann disease is a rapidly progressing, oftenfatal disorder with onset during the first year of life;Wohlfart-Kugelberg-Welander disease is a more benign dis-order with onset in late childhood or early adolescence(138). The etiology and pathogenesis of hereditary motorand sensory neuropathies are still incompletely understood(139).

Trichinosis is characterized by painful myopathic weak-ness potentially mimicking poliomyelitis, periorbitalswelling, splinter hemorrhages, and fever, and it also maymanifest as meningoencephalitis, mononeuropathies,polyneuropathies, and radiculitis (140). Signs of spinal corddamage have included paraparesis, hyperalgesia anddecreased deep tendon reflexes of the lower extremities, uri-nary retention, and bladder anesthesia. The diagnosis isbased on eosinophilia, serologic testing, history of preced-ing gastrointestinal illness, consumption of contaminatedpork or walrus meat, and the presence of larvae of the nema-tode helminth Trichinella spiralis upon muscle biopsy(141). Although it is prevalent in tropical and temperateareas, trichinosis is also a serious medical problem amongNative populations in Arctic regions.

NEUROPATHIES OCCURRING IN SYSTEMIC ORMETABOLIC DISORDERS

Acute hypokalemic periodic paralysis is a rare cause ofAFP (142). Two thirds of cases are due to hypokalemicfamilial periodic paralysis, a disease that exhibits auto-somal-dominant inheritance and mostly affects Caucasianmale children and adolescents (142). Familial periodicparalyses have been divided into three main forms accord-ing to precipitating factors and the patient's potassium levelat the time of an attack: 1) Hypokalemic familial periodicparalysis is usually precipitated by a meal rich in carbohy-drates, and it has the tendency to manifest in the morning




hours after rest. 2) Potassium-sensitive familial periodicparalysis usually has its onset before the age of 10 years; theattacks are less severe than those of the hypokalemic formand tend to occur during the daytime. 3) In familial ady-namia episodica hereditaria, first described by Gamstorp(143), glucose prevents potassium-induced attacks of AFP.Familial periodic paralysis and other muscle disorders lead-ing to attacks of weakness that occur intermittently in other-wise normal people have been linked to disturbed functionof skeletal muscle ion channels ("channelopathies") (144).Depending on the type of familial periodic paralysis, thediagnosis is established by the demonstration of changes inserum potassium levels during the attack, the presence ofelectromyographic and electrocardiographic abnormalities,and the use of muscle biopsy and potassium-, glucose-, orinsulin-loading tests.

Thyrotoxic periodic paralysis is a syndrome defined bycharacteristic clinical, electromyographic, biochemical, andmicroscopic features. Asian, Hispanic, and Native Americanmales aged 30-60 years are most commonly affected.Clinical manifestations include acute-onset progressivesymmetrical weakness leading to AFP of the extremities andother muscle groups (acute episodes of flaccid paraplegia ortetraplegia) which is induced by excess levels of exogenousor endogenous (Graves' disease) thyroid hormones and afterhigh carbohydrate ingestion or heavy exertion. This syn-drome is distinct from thyrotoxic myopathy and familialperiodic paralysis. Because of its association with use ofdiuretics, the syndrome is found in older individuals andneeds to be differentiated clinically from Guillain-Barre'syndrome.

Acute intermittent porphyria may cause a rapidly pro-gressing peripheral neuropathy with motor-sensory signsand symptoms and consequent AFP (145). Acute intermit-tent porphyria may include abdominal pain and psychologi-cal and neurologic signs (disturbances of consciousness andmentation, convulsions), but not all attacks progress to theneurologic stage. The initial episode often occurs in earlyadolescence. The classic ruby-red coloration or measure-ment of porphyrins (porphobilinogen, 8-aminolevulinicacid) in the urine helps confirm the diagnosis.

Sporadic cases of hypokalemic paralysis are associatedwith various underlying disorders, such as renal tubularacidosis, primary hyperaldosteronism (Conn's disease)(146), and secondary hyperaldosteronism due to licorice(Glycyrrhiza glabra) ingestion (22). Barium salts contam-inating table salt or flour have been associated withChinese outbreaks of hypokalemic paralytic diseaseknown as "Pa Ping" or "Kiating" paralysis (147) (Pa Pingand Kiating are areas in China's Szechwan Province).Gossypol, a phenolic compound present in the seeds androot barks of cotton plants (Gossypium, family Malvaceae)and used in cottonseed oil for domestic cooking, is proba-bly also responsible for epidemics of hypokalemic paraly-sis in China (22). Paralysis develops within 24 hours,along with dysarthria, areflexia, and dysphagia. Disordersof muscle energy metabolism causing AFP (Leigh's andMcArdle's disease) may be confounded with Guillain-Barre' syndrome.

OTHER CLINICAL SYNDROMES CAUSING AFP

Other entities that have been misdiagnosed aspoliomyelitis include osteoarticular trauma, acute cerebelli-tis, retroperitoneal tumors, infection of an intervertebraldisc, scurvy, Caffey's disease (infantile cortical hyperosto-sis), postictal hemiparesis (Todd's paralysis), and "floppyinfant" syndrome (18, 20).

An important psychological element was observed in acondition known as epidemic neuromyasthenia, alsoreferred to as "the summer grippe," "Iceland disease," or"Durban mystery disease," which has been reported in vari-ous parts of the United States, Iceland, South Africa, andEngland (19). Reports from South Africa suggest an associ-ation with the organic compound triorthocresyl phosphate(19) (see "Diseases of the Neuromuscular Junction"), whilerecent reports suggest that neuromyasthenia may be causedby a low-virulence but neuropathic type 2 poliovirus (148).

Although it is not included in the surveillance case defin-ition of AFP, facial paralysis may be associated withpoliovirus infection, Guillain-Barr6 syndrome, or AMAN(149). The most common form of facial paralysis, idiopathicBell's palsy (150), is characterized by complete flaccidfacial paralysis. Eighty percent of affected individualsrecover within a few months. A rather typical clinical courseof Bell's palsy allows one to focus differential diagnosticinvestigation predominantly on the rapid identification oftreatable infections such as those caused by varicella-zostervirus or borreliae (149). Other causes of facial paralysisinclude enterovirus infection, HIV infection, Ramsay-Huntsyndrome (presumably due to varicella-zoster virus infec-tion of the geniculate ganglion), Guillain-Barre syndrome(mainly affecting cranial nerves VII and IX-XII), AMAN,and sarcoidosis (uveoparotid fever or sarcoidosis, Heerfordtsyndrome).

PARALYTIC SYNDROMES COMMONLY MISDIAGNOSEDAS AFP

Conditions commonly misdiagnosed as AFP can begrouped into two broad etiologic categories: paralytic illnessassociated with nutritional toxins (151) and chronic centralnervous system disease, frequently with dementia. The linksbetween these two etiologic categories are influenced bypostinfective tropical malabsorption and micronutrient andmineral deficiency from food and water. Cobalamin (vita-min B)2) deficiency causes pernicious anemia and can alsoresult in severe polyneuropathy with symmetrical paralysisand atrophy (152). Chronic cycad poisoning (evergreens,seeds), in conjunction with deficiency syndromes, has beenimplicated in the etiology of these clusters of paralytic ill-ness.

Clusters of amyotrophic lateral sclerosis, Parkinsondementia, and a subacute paralytic condition reminiscent ofGuillain-Barre' syndrome, referred to as "poliomyeloradic-ulitis" because of the asymmetrical distribution of paralysis(152), must be differentiated from poliomyelitis, other non-polio enterovirus infections, and micronutrient deficiencysyndromes.



312 Marxetal.

Tropical myeloneuropathies, a serious health problem intropical regions, include tropical spastic paraparesis andtropical ataxic neuropathy. Although tropical myeloneu-ropathies are multifactorial, specific etiologic agents—e.g.,cyanogenic glycosides from cassava (129), lathyrism (153),postinfective tropical malabsorption, and human T-cell lym-photropic virus (154)—have been implicated. Toxicity fromcyanide or cyanoglycosides in cassava can be exacerbatedby relative deficiencies of B vitamins (thiamine (vitaminBj), riboflavin (vitamin B2), and cobalamin (vitamin B12))and sulfur-containing amino acids, which are necessary forthe detoxification of these compounds. Nutritionalmyelopathies have been documented in Sub-Saharan Africa.

Isolated nonprogressive spastic paraparesis of acute onsethas been reported as "konzo" in the Democratic Republic ofthe Congo and the Central African Republic and as "man-takassa" in Mozambique and Tanzania (22, 155). Seasonaloutbreaks have been linked epidemiologically to consump-tion of bitter cassava (Manihot esculenta, Manihot utilis-sima) (13). Cassava roots contain naturally occurringcyanogens, and the plant's toxicity is enhanced withdecreased intake of foods with sulfur-containing aminoacids, which promote cyanide detoxification. Acute hydro-cyanide poisoning may result from consuming toxic wingedbeans, and chronic cyanide acid poisoning may result fromconsuming poorly washed manioc.

Lathyrism is the classic cause of epidemic outbreaks oftropical spastic paraparesis associated with excessive inges-tion of certain flowering peas in times of famine (Lathyrussativus (chickling pea), Lathyrus clymenwn (Spanish vetch),Lathyrus cicera (flat-podded pea)), Phascolus, and severalgrasses (156). Lathyrism is still endemic in regions of India,Bangladesh, and Ethiopia and continues to be a publichealth problem. Lathyrism has been associated with out-breaks of paralytic illness in Myanmar (World HealthOrganization, unpublished data).

GEOGRAPHIC DISTRIBUTION OF PARALYTICILLNESSES

Host or environmental factors may considerably influ-ence the occurrence and frequency of AFP. For instance, theability to metabolize certain drugs or compounds may varybetween certain populations (isoniazid toxicity in Japan;thyrotoxic periodic paralysis mostly among Asian, Latin,and Native American men). The spread of C. jejuni infec-tions, in conjunction with host, dietary, and sanitary factors,may account for summertime epidemics of AMAN withoutgeographic clustering in northern China. The spread ofpotential vectors determines the occurrence of tickborneparalysis or borreliosis (Lyme disease, relapsing fever)causing GuiUain-Barre syndrome-like AFP. The geographicdistribution of genetically determined neuromuscular dis-eases may be influenced by genetic factors, while environ-mental factors may be associated with nonhereditaryimmunologic myopathies and neuropathies. Exposure tomanmade or naturally occurring toxins, such as those foundin toxic plants (e.g., K. humboldtiana, K. calderoni), ven-omous animals (e.g., snakes, scorpions, frogs), contami-

nated water or food, or infectious agents, combined withdeficiency syndromes, may lead to a wide array of toxicneuropathies, mostly in tropical areas (13).

CONCLUSIONS

AFP is a complex clinical syndrome that requires imme-diate and careful evaluation of the differential diagnoses.Each case of AFP is an emergency, from both a clinical per-spective and a public health perspective, and precise knowl-edge of the etiology, underlying pathophysiologic mecha-nisms, and anatomic-morphologic changes involved hasprofound implications for prognosis and treatment. Theunderlying pathology, precise cellular basis, or pathophysi-ologic mechanisms for certain causes of AFP are not yetunderstood. The examples of Guillain-Barre' syndrome, neu-rologic complications in AIDS, acute transverse myelitis,and Hopkins syndrome illustrate the complex and multifac-torial interaction between different pathogenic factors,including preceding or concurrent infection with neu-rotropic agents, along with inadequate immune or autoim-mune responses of the nervous system. Infections with neu-rotropic viruses and other infectious agents may set inmotion a pathologic immune process that inappropriatelytargets central or peripheral myelin or peripheral axons (8,99). The association between infection with C. jejuni, M.pneumoniae, S. mansoni, or 5. haematobium and a variety ofcauses of AFP, such as AIDP, AMAN, Hopkins syndrome,and acute transverse myelitis, is intriguing and has drawnconsiderable research interest. The role of infectious agentsand immune processes as significant causes of AFP may becomplemented by a variety of naturally occurring or man-made toxins.

The list of underlying causes of AFP is broad, and there issubstantial variation by age, ethnicity, and geographic area.In the absence of wild virus-induced poliomyelitis, the acutedemyelinating form of Guillain-Barr6 syndrome (AIDP)accounts for at least 50 percent of AFP cases globally (16,77), followed in frequency by paralytic nonpolio enterovirusinfection, the motor axonal form of Guillain-Barre syn-drome (AMAN), traumatic neuritis, and acute transversemyelitis.

The campaign to eradicate poliomyelitis is at a criticalstage. The smallpox eradication program demonstrated theneed for accurate surveillance, while a factor contributing tothe failure of earlier eradication programs was the absenceof the capacity to establish surveillance meeting these highstandards. Without accurate disease surveillance, it isimpossible to conduct an effective disease control or eradi-cation program or to measure the disease burden and theeffect of intervention measures.

Because poliomyelitis is on the verge of eradication,accurate surveillance for AFP must be intensified. Theglobal incidence rate of nonpolio AFP would be expected tobe 1 per 100,000 among children under 15 years of ageunder conditions of optimal surveillance with complete caseascertainment (78). Achieving and maintaining this detec-tion rate is considered the most sensitive performance crite-rion for any AFP surveillance system. Epidemiologic and




clinical surveillance require detailed knowledge of thepotential differential diagnoses of AFP. It is therefore crucialthat sensitive AFP surveillance be conducted, even in theabsence of wild poliovirus transmission. Clinicians must beaware of the causes of AFP and of the need to report andcontinuously investigate AFP cases. Virologic and case-based AFP surveillance provides a tool for identifying prob-lem areas where previous immunization strategies havefailed or wild poliovirus transmission continues, and forguiding supplementary activities.

For the eradication of poliomyelitis, a highly sensitive butrelatively nonspecific case definition was selected by theWorld Health Organization. Officials in nationalpoliomyelitis eradication programs first introduced highlysensitive case definitions to avoid missing true cases of thedisease, though false-positive diagnostic errors could stilloccur because of low specificity. No single practical clinicalcase definition combining both high sensitivity and highspecificity has become available (2—4); however, virologicisolation of poliovirus from stools of patients with AFP pro-vides the necessary specificity for confirming poliomyelitis.An internationally concerted effort is needed to develop aglobal registry for the nonpoliomyelitis causes of AFP, inorder to supplement poliomyelitis data banks. Such a reg-istry has been partly established in the Americas (77).

In conclusion, health workers need to be aware of theimportance of comprehensively evaluating and reporting allAFP cases, collecting stool specimens immediately, andtesting for neurotropic agents, including poliovirus.

ACKNOWLEDGMENTS

The authors thank Dr. Peter Strebel, Dr. MuireannBrennan, Dr. Bernard Moriniere, and Dr. Gina Tambini fortechnical advice; Jeff Colby and Patricia Smith for graphicassistance; and Jessie Aukes, Onnalee Henneberry, PamMartin, Matthew Nwosu, and Katherine Tucker for assis-tance in searching the literature.

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