Because of the potentially life-threatening compli-cations of Kearns–Sayre syndrome, all patients withCPEO should have screening for heart conductiondefects and a pacemaker implanted if indicated. Foroculopharyngeal muscular dystrophy, managementof swallowing and prevention of aspiration withnasogastric tube or enteral tube feeding is para-mount. Similarly, symptomatic treatment is indicatedfor the other ophthalmoplegia plus syndromes.

—Alvin B. H. Seah and Nancy J. Newman

See also–Migraine, Ophthalmoplegic andRetinal; Mitochondrial Encephalomyopathies,Overview; Ophthalmoplegia

Further Reading

Biousse, V., and Newman, N. J. (2001). Neuro-opthalmology ofmitochondrial diseases. Semin. Neurol. 21, 275–291.

Drachman, D. A. (1968). Ophthalmoplegia plus: The neurode-

generative disorders associated with progressive externalophthalmoplegia. Arch. Neurol. 18, 654–674.

Moraes, C. T., Di Mauro, S., Zeviani, M., et al. (1989).

Mitochondrial DNA deletions in progressive external ophthal-

moplegia and Kearns–Sayre syndrome. N. Engl. J. Med. 320,1293–1299.

Progressive MultifocalLeukoencephalopathy (PML)Encyclopedia of the Neurological Sciences

Copyright 2003, Elsevier Science (USA). All rights reserved.

ALTHOUGH described in earlier literature, progressivemultifocal leukoencephalopathy (PML) was firstclearly defined as a distinct clinical entity in 1958by Astrom, Mancall, and Richardson on the basis ofits unique neuropathological features. The latterincludes demyelination, enlarged nuclei of oligoden-drocytes, and bizarre astrocytes. The etiology of thisentity remained obscure until a decade later whenelectron microscopic appearance of inclusions sug-gested the presence of a polyoma virus. Soonafterward, isolation of a papovavirus in human fetalbrain cultures, referred to as JC virus, confirmed thishypothesis.

ORGANISM

The causative virus, JC virus, belongs to the Poly-omavirus genus in the Papovaviridae family. Poly-omaviruses are double-stranded DNA-containing

viruses with an icosahedral symmetry. JC virus hasa simple DNA genome encapsidated in an icosahe-dral protein structure measuring 40 nm in diameter.The DNA codes for one nonstructural but multi-functional protein (T) and three capsid proteins(VP1–VP3). Although other members of this genus,specifically SV40 and BK virus, have been suggestedas the etiological agent of some cases of PML, it islikely that JC virus is responsible for almost all, if notall, cases. Seroepidemiological studies indicate thatthis virus has a worldwide distribution and that byage 20 approximately 80% of all people have beeninfected. There is no recognized clinical illness thathas been consistently associated with acute JC virusinfection. It is likely that the virus is spread byoropharyngeal or respiratory routes. In latency, thevirus resides in the reticuloendothelial system,including tonsils and other lymphoid tissue as wellas bone marrow.

HOST FACTORS AND UNDERLYINGDISEASES

An underlying immunosuppressive condition hasbeen recognized in 95% of all patients with PML.Typically, the abnormality is one that affects cell-mediated immunity. Until the AIDS pandemic, PMLwas most often associated with underlying lympho-proliferative disorders. A comprehensive review of230 cases published in English up to 1984 found thatlymphoproliferative diseases were associated withmore than 60%. Smaller percentages were associatedwith myeloproliferative diseases, carcinoma, granu-lomatous and inflammatory diseases, and otherimmune deficiency states. In 1984, there were but 2reported cases of PML complicating AIDS. Follow-ing the AIDS pandemic, the incidence of thisformerly rare illness increased quite dramaticallyand AIDS became the most common underlyingpredisposing illness for the development of PML. In astudy from south Florida during the 14-year intervalfrom 1980 to 1994, only 2 of 156 cases of PML wereunrelated to infection with human immunodeficiencyvirus (HIV). During this time period, a 20-foldincrease in the number of PML cases was observedconsequent to the increasing prevalence of HIVinfection. Overall, AIDS has been estimated to bethe underlying cause of immunosuppression in 55%to more than 85% of all current cases of PML.However, in some communities these percentagesmay underestimate the true incidence of AIDS-related PML.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 65

Not unexpectedly, the demographics of PML weresubstantially modified by the substantial increase incases occurring as a consequence of HIV infection.Formerly, the illness was seen in approximately equalproportions of men and women (3:2) and occurred inmiddle to late age when lymphoproliferative diseasesare most common. Currently, the demographics aremore reflective of that of the AIDS population.Therefore, men significantly outnumber women, andthe illnesses are most often observed between theages of 25 and 50 years. Children, regardless of thecause or severity of their underlying immunosuppres-sion, rarely develop PML because they often have yetto be exposed to the causative JC virus. There appearto be geographical differences in the prevalence ofPML in the AIDS population. Despite serologicalevidence of similar rates of JC virus exposure indifferent populations, AIDS-associated PML appearsto be less common in underdeveloped areas of theworld, such as Africa and India. For instance,neuropathological studies from southern India sug-gest an incidence of 1%, in contrast to the 4 or 5%from similar studies performed in the United Statesand Europe. There are several possible explanationsfor this difference, including strain differences in JCvirus in these populations, genetic factors in thepopulation rendering them more or less susceptibleto PML, and earlier mortality of the HIV-infectedpopulation in less developed countries. Following theintroduction of highly active antiretroviral therapy(HAART) in 1996, the incidence of most opportu-nistic infections consequent to HIV infection de-clined; however, the effect of HAART on PMLremains less certain.

CLINICAL FEATURES

The most common symptoms reported by patientswith PML or their caregivers are weakness andspeech disturbances. Also commonly reported arecognitive abnormalities, headaches, gait disorders,visual impairment, and sensory loss. Each of thesesymptoms is seen in more than 15% of patients withAIDS-associated PML. In general, these symptomsare similar to those identified in a series of non-HIV-associated PML cases, although headaches seem tobe more common in the HIV-infected population andvisual disturbances more common in those withother underlying causes of immunosuppression.Although regarded as a disorder of the white matter,seizures can be seen in up to 10% of patients and aretypically focal in onset.

Limb weakness is observed in more than 50% ofpatients with PML, whereas cognitive disturbancesand gait disorders occur in approximately one-fourthto one-third of patients. Extraocular movementdisorders usually due to involvement of the third,fourth, or sixth cranial nerves are seen in up to 10%and may be accompanied by other brainstemfindings. Visual field loss due to involvement of theretrochiasmal visual pathways is significantly morecommon than diplopia or other visual disturbances.Optic nerve disease is not a feature of PML.Similarly, clinical myelopathy due to PML must beextraordinarily rare, despite pathological reports ofPML lesions in the spinal cord. PML is the heraldingAIDS-defining illness in approximately 1% of allHIV-infected persons. Therefore, the occasionalpatient is seen with neurological features antedatingknowledge of HIV infection. This may lead tosignificant diagnostic confusion in the otherwisehealthy individual with unsuspected HIV infection.The treating physician need always maintain a highindex of suspicion for underlying HIV infection whenconfronted with unusual neurological illnesses.

NEUROIMAGING

In the appropriate clinical context, radiographicimaging may strongly support the diagnosis ofPML. Computed tomography (CT) of the brain inPML reveals hypodense lesions of the affected whitematter (Fig. 1). On CT scan, the lesions of PML showno mass effect. Involvement of the subcorticalarcuate fibers results in a ‘‘scalloped’’ appearancebeneath the cortex. Contrast enhancement is rareand, if observed, is typically faint and located in theperiphery of the lesions. Although multiple whitematter lesions are characteristic of PML, isolatedlesions may be observed. Cranial magnetic resonanceimaging (MRI) is far more sensitive to these lesionsthan CT scan. MRI shows hyperintense lesions onT2-weighted imaging in the affected regions (Fig. 2),and, as with CT scan, faint, typically peripheralcontrast enhancement may be observed in up to 10%of cases. These lesions may be seen in virtually anylocation in the brain, with the frontal lobes andparietooccipital regions most commonly affected,presumably as a consequence of their volume.Isolated or associated involvement of the basalganglia and posterior fossa structures (cerebellumand brainstem) may be seen as well and be a sourceof diagnostic confusion. In the setting of HIVinfection, similar white matter lesions may be

66 PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

observed in the absence of PML. These lesions aremost often associated with AIDS dementia or, lesscommonly, other opportunistic infections. Radio-graphic distinctions with respect to AIDS dementiainclude a greater propensity of PML lesions toinvolve the subcortical white matter, its hypointen-sity on T1-weighted images, and its occasionalcontrast enhancement. Among the other HIV-relatedillnesses associated white matter lesions are cyto-megalovirus, varicella-zoster leukoencephalitis, amultiple sclerosis-like illness, acute disseminatedencephalomyelitis, central nervous system vasculitis,and white matter edema associated with primary ormetastatic brain tumors.

Increasingly, newer MRI and other imagingtechnology is being applied to the diagnosis ofPML and other brain disorders. Magnetizationtransfer MRI studies have been suggested as aneffective means of monitoring the degree of demye-lination. Magnetic resonance spectroscopy may beused to assess neuronal loss and myelin breakdownreflected by decreased n-acetylaspartate and creatineand increased choline products, myoinositol andlactate, respectively. In general, thallium-201 singlephoton emission computed tomography reveals nouptake in the lesions of PML but is seldom of

diagnostic utility. Almost always, the clinical fea-tures, laboratory findings, and associated radio-graphic features enable the correct diagnosis.

LABORATORY STUDIES

In the overwhelming majority of patients with PML,cellular immunity is significantly impaired. In thesetting of HIV infection, for instance, 90% ofpatients have CD4 lymphocyte counts of less than200 cells/mm3. However, as many as 5% of allpatients with PML have no observable defect inimmunity despite exhaustive study; therefore, theabsence of a defect in cellular immunity cannot beused as a diagnostic criteria.

Cerebrospinal fluid (CSF) examination is veryhelpful in excluding other diagnoses. However, withthe exception of amplification of JC virus DNA bypolymerase chain reaction (PCR), it is not otherwisediagnostically helpful. CSF cell counts with PML areusually less than 20 cells/mm3, proteins are normal toslightly elevated, and glucose is normal. In the AIDS-associated PML population, it is difficult to distin-guish CSF abnormalities consequent to HIV infection

Figure 1CT scan of brain showing bilateral hypodense areas in the

parietooccipital lobes.

Figure 2MRI of brain showing extensive hypointense areas in both

hemispheres on T1-weighted image due to demyelination fromPML.

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY 67

from that due to PML. CSF PCR for JC virus has asensitivity of approximately 75% and a specificity ofapproximately 100%; therefore, many authoritieshave regarded the demonstration of JC viral DNAcoupled with the appropriate clinical and radiologi-cal features sufficiently suggestive of PML to bediagnostic, obviating the need for brain biopsy.Quantitative PCR techniques for JC virus haverecently been demonstrated to be of some prognosticvalue in PML. Antibody titers in serum or CSF arenot useful because most individuals become seropo-sitive for JC virus before adulthood. Additionally,because PML occurs in the context of immunosup-pression, the individual may not be able to mount anantibody response.

PATHOLOGY

The macroscopic cardinal feature of PML is demye-lination. Typically, as indicated by the name of thedisorder, demyelination is multifocal, with a dis-tribution that suggests a hematological disseminationof the virus. Occasionally, only an isolated lesion ofdemyelination is observed. These lesions may occurin any location in the white matter and range in sizefrom 1mm to several centimeters. The regions ofdemyelination appear to start in a perivenularlocation and subsequently expand. Multiple smalllesions may coalesce into larger lesions. The histo-pathological hallmarks of PML consist of the triad ofdemyelination (Fig. 3), hyperchromatic, enlargedoligodendroglial nuclei, and enlarged bizarre astro-cytes with lobulated hyperchromatic nuclei (Fig. 4).The nonproductively infected (i.e., not replicating

infectious virus) astrocytes may assume malignantappearance. The JC virus may be demonstrated inthe oligodendrocytes by electron microscopic exam-ination, in situ hybridization, or in situ PCR.Electron microscopy reveals virions measuring 28–45 nm in diameter appearing either singly or in densecrystalline arrays. Less frequently, the virions aredetected in reactive astrocytes, and they are uncom-monly observed in macrophages that are engaged inremoving the affected oligodendrocytes.

PROGNOSIS

Regardless of the underlying condition, survival inpopulations of patients with PML is very similar. Themean survival is 6 months. However, the survival isskewed by long-term survivors because the modefrom time of diagnosis is approximately 1 month.The 8–10% of PML patients with survival exceeding1 year shift the mean survival curve inordinately inthe direction of longer survival. In AIDS-associatedPML, recovery of neurological function, improve-ment of PML lesions in radiographic imaging, andsurvival exceeding 12 months have been observed inas many as 10% of patients. Factors that appear tobe associated with prolonged survival include PML

Figure 3Gross pathological specimen showing demyelination in frontalsubcortical region due to PML.

Figure 4Microscopic histopathology showing oligodendroglial cells withenlarged nuclei. This is the classic ‘‘fried egg’’ appearance. These

cells are productively infected with JC virus.

68 PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

as the presenting manifestation of AIDS, higherCD4 lymphocyte counts, and contrast enhance-ment on radiographic imaging, although the latterremains controversial. There is also an inversecorrelation between quantitative levels of JC viralDNA in the CSF and survival. Some patientsexperiencing long-term survival appear to clear JCvirus from the CSF.

TREATMENT

To date, no therapy has demonstrated clinicalefficacy in PML. The therapies that have beenadopted have been based on experiments in whichJC virus replication has been inhibited in vitro or,more commonly, on anecdotal experience and casereports. Clearly, the single most important factor inthe small number of patients experiencing prolongedsurvival and recovery seems to be recovery of theimmune system. In the HIV-infected population,several studies suggest that an aggressive regimenwith HAART may influence the course of PML. Thisimproved survival has been associated with JC virusclearance from CSF and an increase in antibodyresponse to JC virus proteins. A substantial improve-ment in host immunity consequent to HIV inhibitionis likely fundamental because the antiviral agentsused have no effect in vitro on JC viral replication.

A wide variety of therapies have been suggested inthe treatment of PML. Cytosine arabinoside has beenreported to be beneficial in PML in many case reportsand small series. However, a large randomized trialin which cytosine arabinoside administered eitherintravenously or intrathecally to patients with AIDS-associated PML failed to reveal any difference insurvival when compared to antiretroviral therapyalone. Conceivably, failure of this antineoplasticagent clinically in the treatment of PML despiteestablished efficacy in inhibiting JC virus replicationin vitro may be the consequence of levels of the drugthat are too low at sites of infection. Convection-enhanced delivery may overcome this inability toobtain adequate suppressive levels. Other suggestedtherapies include a-interferon, cidofovir, topotecan,and camptothecin; however, none has establishedclinical efficacy.

—Joseph R. Berger

See also–AIDS/HIV and Neurological Disease;HIV Infection, Neurological Complications of;Leukoencephalopathy

Further Reading

Astrom, K. E., Mancall, E. L., and Richardson, E. P., Jr. (1958).Progressive multifocal leukoencephalopathy. Brain 81, 93–127.

Berger, J. R., Pall, L., Lanska, D., et al. (1998). Progressive

multifocal leukoencephalopathy in patients with HIV infection.J. Neurovirol. 4, 59–68.

Berger, J. R., Levy, R. M., Flomenhoft, D., et al. (1998). Predictivefactors for prolonged survival in acquired immunodeficiency

syndrome-associated progressive multifocal leukoencephalopa-thy. Ann. Neurol. 44, 341–349.

Brooks, B. R., and Walker, D. L. (1984). Progressive multifocal

leukoencephalopathy. Neurol. Clin. 2, 299–313.Houff, S. A., Major, E. O., Katz, D., et al. (1988). Involvement of

JC virus-infected mononuclear cells from the bone marrow and

spleen in the pathogenesis of progressive multifocal leukoence-

phalopathy. N. Engl. J. Med. 318, 301–305.Major, E. O., Amemiya, E. E., Tornatore, C. S., et al.

(1992). Pathogenesis and molecular biology of progressive

multifocal leukoencephalopathy, the JV virus-induced

demyelinating disease of the human brain. Clin. Microbiol. 5,49–73.

Progressive SupranuclearPalsy (PSP)Encyclopedia of the Neurological Sciences

Copyright 2003, Elsevier Science (USA). All rights reserved.

BESIDES Parkinson’s disease, several clinical disordershave parkinsonian features that occur in the contextof more extensive central nervous system damage.Progressive supranuclear palsy (PSP) is the mostcommon and best recognized entity among theseparkinsonism-plus syndromes. PSP has no knowncause. Several areas of the nervous system degenerateand chemical systems that involve neurotransmitterssuch as dopamine, acetylcholine, and norepinephrineare affected. Most patients experience initial diseasesymptoms during their sixth and seventh decades. Noclear geographical, occupational, or temporal clus-ters of PSP have been found. Rare familial clustershave been reported in association with a particulartau genetic factor.

Clinically, PSP shares some clinical features withParkinson’s disease, such as bradykinesia or slownessof movement, rigidity or stiffness of the muscles,slurred speech, swallowing difficulties, and imbal-ance. Unlike Parkinson’s disease subjects, PSP pa-tients rarely exhibit prominent tremor and usuallyhave much more profound postural instability andfalling in the early years of disease. In addition, theposture of PSP patients is often erect and the headcan be extended slightly backwards, whereas typical

PROGRESSIVE SUPRANUCLEAR PALSY 69