Translational Neuroscience
115
Communication • DOI: 10.2478/v10134-010-0016-9 • Translational Neuroscience • 1(2) •2010 •115–123
* E-mail: rik.vandenberghe@uz.kuleuven.ac.be
ReveRsible posteRioRleukoencephalopathysyndRome
1
Dimitri Renard and Pierre LabaugeDepartment of Neurology CHU Nîmes, Hôpital CaremeauPlace Pr Debre,30029 Nîmes, France
2
Department of Neurology Universitair Ziekenhuis GasthuisbergHerestraat 49,3000 Leuven, Belgium
Dimitri Renard
1
,Pierre Labauge
1
,
Rik Vandenberghe
2*
ar
Reversible posterior leukoencephalopathy syndrome (RPLS) is characterized by subacute onset of headache,decreased alertness, vomiting, seizures, visuoperceptual disturbances, together with bilateral white matterlesions in posterior brain regions on brain imaging. The most frequently associated conditions related to RPLSare arterial hypertension and the use of immunosuppressive or cytotoxic treatment. T2-, Fluid AttenuationInversion Recovery (FLAIR), and Apparent Diusion Coecient (ADC)- weighted magnetic resonance imaging(MRI) reveal hyperintensities in parietooccipital white matter but grey matter and other regions including frontaland temporal lobes, brainstem, cerebellum, basal ganglia, or even spinal cord may also be involved. According toADC ndings, the underlying pathophysiologic mechanism is probably one of vasogenic (rather than cytotoxic)oedema. These MRI ndings help in dierentiating RPLS from ischaemic events and other diseases resemblingRPLS. Failure of cerebral autoregulation, endothelial dysfunction, disrupted blood-brain barrier, vasospasm, anddirect toxic drug eects may all play a role in the pathophysiology of RPLS. Treatment consists of discontinuationof the causal drug, treatment of high blood pressure, and antiepileptic therapy. Clinical recovery and regression of radiological abnormalities are typically seen after early treatment. However, delay in diagnosis and treatment canresult in irreversible brain damage, often in association with complicating cerebral infarction or haemorrhage.
Received 19 May 2010accepted 15 June 2010
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Drug-induced • Hypertensive • White matter • Cyclosporine • MRI • Brain • Immunosuppression
© Versita Sp. z o.o.
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Reversible posterior leukoencephalopathysyndrome (RPLS) was rst described byHinchey et al in 1996 who reported 15 patientswith a wide variety of diseases presentingwith headache, decreased alertness, vomiting,seizures, and visuoperceptual disturbances
[1
]. Of these 15 patients, 7 had previouslyreceived immunosuppressive treatment, 1was on interferon treatment, 3 had eclampsia,and 4 suered from acute hypertensiveencephalopathy related to renal disease. In 12 of these patients, arterial hypertension was noted.Brain imaging showed bilateral extensive whitematter abnormalities suggestive of oedema inthe posterior cerebral regions. In all 15 patients,neurological abnormalities resolved afterantihypertensive treatment and withdrawalor dose reduction of immunosuppressivetherapy. Prior to this initial description, severalpatients with similar clinical ndings andradiological abnormalities had been described(e.g. associated with malign hypertension,eclampsia, or cyclosporine use) [2-4]. Most
RPLS patients are adults. However, RPLS canalso occur in children and is the most commonabnormality leading to seizures in children withleukaemia[
5
].Most of the literature concerning RPLS is basedon reports of single or multiple cases rather thanconsecutive series of at-risk populations. To thebest of our knowledge no reliable estimates of incidence of RPLS are available. Furthermore,the condition may be underdiagnosed: theclinical syndrome of RPLS is often incomplete,magnetic resonancy imaging (MRI) is not alwaysperformed, and symptoms may be reversible(e.g. after correction of hypertension, change orwithdrawal of immunosuppressive or cytotoxictreatment) even when the diagnosis of RPLS wasoverlooked. It is generally considered a relativelyuncommon disorder. The two most frequentlyassociated conditions related to RPLS are arterialhypertension and the use of immunosuppressiveor cytotoxic treatment. The distinction betweendrug-related RPLS and hypertension-inducedRPLS may be dicult since elevated bloodpressure often complicates RPLS associated withimmunosuppressive and cytotoxic treatment.In principle, RPLS should be distinguished frommore diuse toxic leukoencephalopathiesthat lack any posterior predilection and bydenition aect periventricular white matterand the centrum semiovale relatively evenly [6
]
(see below).Post-mortem studies of RPLS reveal relativelyaspecic changes, such as oedema, reactiveastrocytosis, neuronal loss, demyelination,ischaemic infarction, and haemorrhage.
R r
Drugs associated with RPLS are often - but notlimited to - immunosuppressive and cytotoxicagents (
Table 1
). The exact oending drug is sometimesdicult to identify since oncological patientsundergoing chemotherapy or transplantpatients on immunosuppressive medicationtypically receive multiple drugs that couldcontribute to the development of RPLS. TheRPLS risk associated with specic drugs is hardto quantify since most of the literature consistsof case reports rather than prevalence studiesin at-risk populations. RPLS symptom onset isoften related to the introduction of new drugs,dose increase, or increased blood pressure butcan also occur in patients on stable doses of
116
chronically used drugs [7]. Drug levels abovethe therapeutic range may play a role in thedevelopment of RPLS although in most of thereports drug levels were within the therapeutic
range [
8-9]. Some drugs can indirectly lead to
RPLS because they aect the pharmacodynamicsof immunosuppressant agents. For instance,introduction of omeprazole in a patientchronically treated with methotrexate can leadto RPLS. Drugs that inhibit the cytochromeP450 system, such as steroids, can increasecyclosporine levels. The drug administrationroute inuences the risk and severity of RPLS.For instance, intrathecally administeredmethotrexate and cytarabine are associatedwith a higher risk than intravenousadministration and intravenous administrationof cyclosporine leads to a higher risk thanoral administration [10]. These distinctionshowever are not absolute and long-term oralmethotrexate therapy, for instance, can alsogive rise to RPLS [7]. The risk of developing RPLSalso appears to be higher if chemotherapy iscombined with cranial radiation [
11
].Hypertension seems to play an important rolein the pathophysiology of RPLS since bloodpressure is elevated in the vast majority of reported cases. However, RPLS can occur in theabsence of elevated blood-pressure readings.Elevated blood pressure is a frequent adverseeect of many of the immunosuppressive andcytotoxic drugs described in RPLS. Cases withRPLS primarily related to drugs often presentwith only moderate hypertension. If, however,malignant hypertension is the principal cause,other organs apart from the brain are often alsoaected leading to renal failure, papilloedema,retinal oedema and retinal haemorrhages(Figure 1).Electrolyte imbalance, sepsis, fever, and renalfailure may predispose to RPLS throughdamage of the blood-brain barrier (BBB) leadingto vasogenic oedema at blood pressure levelsthat usually would be well tolerated [12-13].
Hypocholesterolaemia has also been describedas a possible risk factors for RPLS [14-16].
Cyclosporine, one of the most frequentlyreported drugs associated with RPLS, ishighly lipophilic. Fifty to 60% is bound tolipoproteins, especially low density lipoprotein(LDL). Cyclosporine enters the cells throughtransmembrane diusion or can be transportedinto the cell by LDL particles binding to the LDLreceptor. Low cholesterol levels increase theconcentration of cyclosporine in LDL particlesand the density of LDL receptors on the cellmembranes, thereby augmenting cyclosporineuptake. In the brain, the LDL receptor isexpressed primarily by astrocytes and by
R rq rr l rq rr Rr rr
CyclosporineL-asparaginaseErythropoietinMethotrexateInterferon alphaGranulocyte-colony stimulating factor
Tacrolimus
CytarabineAdriamycinPaclitaxelSunitinibAntiretroviral therapy (indinavir)Platinums (cisplatinum, oxaliplatinum)VincristineTNF-alpha inhibitorsBevacizumab
Gemcitabine
Immune globulin therapyAlkylating agents (cyclophosphamide, ifosfamide)
Table 1
.
Non-exhaustive list of drugs that have been associated with RPLSFigure
1.
A. B. Brain MRI showing subcortical and cortical hyperintense signal predominant in posterior regionson FLAIR- (A) and ADC-weighted (B) imaging (vasogenic oedema). Arrows: ADC hyperintense lesion.C. Eye fundus examination showed hypertensive-related retinal exudates (indicated by arrow).
D. CT angiography revealed high grade stenosis of the right renal artery (indicated by arrow), responsiblefor hypertension, with post-stenotic dilatation.
Translational Neuroscience
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arachnoid cells. Under normal conditions theBBB transport of cyclosporine is restricted buta direct toxic eect of cyclosporine on theendothelium or coexisting hypertension mayincrease BBB permeability for cyclosporine.Hypomagnesaemia is also a risk factor forRPLS [17]. Hypomagnesaemia can occur as aside eect of cyclosporine treatment becausecyclosporine causes intracellular migration andrenal wasting of magnesium [18]. Tumor lysis syndrome, most commonlyassociated with Burkitt or other high-gradelymphoma and leukaemia, is another risk factorfor RPLS [19-20]. Massive lysis of malignant cells
can occur spontaneously or after antineoplastictreatment. It can lead to release of intracellularpotassium, phosphorus and uric acid as well asmany other cellular components into the bloodstream leading to vascular endothelial damage.Risk factors for RPLS in children are similarto those described in adults and include,among others, arterial hypertension, with orwithout associated renal involvement (e.g.haemolytic uremic syndrome, nephroticsyndrome, glomerulonephritis), steroids,immunosuppressive and chemotherapy(for bone marrow transplantation, kidneytransplant, systemic lupus erythematosus,acute lymphoblactic leukaemia, and othercancers), Henoch-Schönlein purpura,thrombotic thrombocytopenic purpura (TTP),sickle cell disease, Wegener’s granulomatosis,and haematopoietic stem cell transplantation
[
21-28]. In young children the physiological
myelination process is incomplete makingthem particularly susceptible to permanentleukotoxic eects of radiation therapy.
c r
The common clinical features of RPLS includeheadache, often resistant to simple analgesia,decreased alertness, vomiting, seizures, andvisuoperceptual disturbances. Disease onset isgenerally subacute but thunderclap headachehas been reported as the initial symptomin some cases of RPLS [29-32]. Agitation,
confusion, and restlessness may alternate withapathy.Seizures often precede the other manifestations
[
33-34]. Generalized tonicoclonic seizures may
be preceded by visual auras, consistent withoccipital onset of partial epileptic discharges
[
33-34]. A wide variety of visual abnormalities
may occur, including visual eld defect, blurredvision, visual neglect, visual hallucinations,cortical blindness, visual agnosia, denial of blindness (Anton’s syndrome), simultanagnosia(with or without other components of theBalint syndrome), or alexia without agraphia.Homonymous hemi- or quadrantanopsia (incase of asymmetric involvement of the occipitallobe) and altitudinal visual eld (in case of strictly supra- or infracalcarine lesions) defectsare frequent. Since brain lesions are typicallylocated posterior to the lateral geniculate body,pupillary reexes are preserved and fundusexamination is normal. Plantar responses maybe in extension and deep tendon reexes areoften brisk. If brain lesions extend beyondparieto-occipital regions (e.g. frontal ortemporal zones, brainstem, cerebellum, spinalcord), additional symptoms may be presentdepending on the regions involved.
igg
Brain imaging is essential to the diagnosis of RPLS. Lesions most typically aect occipital andposterior parietal white matter (Figure 2A,B).
Watershed areas between middle and posteriorcerebral artery are frequently involved(Figure 2A). Brain abnormalities in RPLS can
be seen on Computerized Tomography (CT) asbilateral hypodense areas (oedema). CT is alsosensitive for the detection of haemorrhagiccomplications (Figure 3A-C).MRI has the ability to show smaller focalabnormalities at an earlier stage (Figure
3D-E).
Figure
2.
A. Axial FLAIR sequences showing subcortical and cortical multifocal hyperintensities in the bilateral frontal, parietal, and occipital regions in a 24-year-oldwoman with RPLS associated with hypertension and eclampsia. B. Posterior-located, mainly subcortical, hyperintense lesions on coronal FLAIR imaging with anasymmetrical distribution (right hemisphere more involved than the left one) in a 67-year-old patient with RPLS associated with immune globulin therapy andhypertension. Arrows point to the calcarine sulcus (striate cortex) which is relatively spared. The side view of the brain gives an approximate indication of the levelat which the axial and coronal sections are taken.
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