Tropical Neurology - part 6 pptx

Further studies, however, have shown that at similar doses, the duration of therapy could be shortened to one week without compromising the results.Albendazole destroys 75-90% of parench

ab-Stool Examination for Taenia solium Eggs

Eggs of T solium are detected in the stool of 3-27% patients with NCC It is more important to search for T solium carriers in the patients’ close environment

than to determine the prevalence of taeniasis.2 Recognition of Taenia eggs is not easy

and many patients may remain undiagnosed if a single sample study is performed.Serial stool specimens, therefore, must be examined before the patient is considerednegative Two recent advances have been made for the diagnosis of human taeniasis:ELISA for coproantigen detection and DNA hybridization for egg identification

These new tests will greatly improve the screening for T solium carriers among healthy

individuals in the endemic areas

Cytochemical Analysis of CSF

CSF abnormalities have been reported in about 80% of patients with NCC(Table 15.2) These abnormalities correlate with the activity of the disease and sub-arachnoid location of the parasite.9,10 A normal CSF examination, therefore, doesnot rule out the diagnosis of NCC The most consistent CSF finding is a moderatemononuclear pleocytosis, with an increase in the number of eosinophils The cellcount rarely exceeds 300 per mm3; however, in severe cysticercus meningitis CSFcell count may rise up to 5000/mm3 CSF glucose levels are usually within the nor-mal range despite active meningeal disease Hypoglycorrhachia (<40 mg/dl) has beenassociated with poor prognosis Elevated CSF protein is common in patients withpleocytosis Protein usually ranges from 50 to 300 mg/dl, although it may be as high

as 1,600 mg/dl

Immunologic Diagnosis

Immunologic diagnostic tests have been used to assess the prevalence of cosis in a population and to exclude or confirm the diagnosis of NCC.2 As theaccuracy of these tests depends on the complex humoral immune response of thehost against cysticerci, these tests have limitation of suboptimal sensitivity and speci-ficity False-negative results are related to local production of antibodies within theCNS without a parallel increase of antibodies in peripheral blood, or to immunetolerance to the parasite without production of anticysticercal antibodies The

cysticer-false-positive results are due to previous contact with adult T solium or to

cross-reactivity with other helminths We are still far from a reliable test that serves

as a “gold standard” for the diagnosis of human cysticercosis

Complement Fixation Test

Complement fixation test has been used for the diagnosis of cysticercosis formore than 80 years Initially this test was developed to determine the presence ofanticysticercal antibodies in serum but later it has been found to be more useful

when used in CSF The complement fixation test is positive in 83% of patients withNCC who also had inflammatory changes in the CSF but only in 22% of patientswith normal CSF The complement fixation test is less sensitive in ventricular thansubarachnoid CSF; therefore, a negative result in a CSF sample obtained at the time

of shunt surgery does not exclude the diagnosis of NCC

Enzyme-Linked Immunosorbent Assay (ELISA)

ELISA has been one of the most widely evaluated immunologic diagnostic testsfor human cysticercosis Preliminary experience with the ELISA postulated that apositive result “strongly suggests” cysticercosis and a negative result indicates thatthe diagnosis is “highly unlikely” Subsequent studies, however, showed that up to30% of patients with NCC may have a false-negative ELISA, particularly if the test

is performed in serum A similar percentage of individuals may have a false-positiveresult due to cross-reactivity with other infectious diseases Detection of anticysticercalantibodies in CSF by ELISA is more accurate than in serum Some authors havefound 87% sensitivity and 95% specificity of ELISA in CSF These results, however,depend on the presence of active disease, since many patients with parenchymalbrain calcifications or granulomas have a negative ELISA, even if the test is per-formed in CSF.12

Enzyme-Linked Immunoelectrotransfer Blot (EITB) Assay

The demonstration that antibodies to species-specific antigens of T solium can

be detected by EITB stimulated investigators to develop highly purifiedantigens of cysticercus to be used in a new immunologic diagnostic test for cysticer-cosis Seven antigenic bands are usually recognized by antibodies of patients withcysticercosis Among these GP13, GP14, GP24 and GP39-42 are the most fre-quently recognized antigens The EITB has been extensively evaluated Some re-ports suggest that serum EITB is 94-98% sensitive and 100% specific for the diagnosis

of human cysticercosis, while results from other studies have been disappointing Inpatients with a single cyst, a high frequency of false negative results has been

Table 15.2 Cerebrospinal fluid findings in neurocysticercosis

Finding Range of Abnormality Prevalence

π Pleocytosis may be up to 5,000 per mm3

β Protein count may be as high as 6,000 mg/dl

ξ Glucose levels<10 mg/dl carry a poor prognosis

+ The percentage is higher when only patients with arachnoiditis are considered

reported, reducing the sensitivity of EITB to 30% Patients with calcified lesionsare less likely to have positive EITB compared to those with active disease Anotherlimitation is that EITB assay may be positive in patients with taeniasis, which isespecially important in endemic areas since many patients who had been exposed tothe adult parasite without developing cysticercosis may test positive The EITB re-sults, therefore, must be interpreted with caution in light of the clinical manifesta-tions, neuroimaging findings and, more importantly, the habitat of the patient Apositive EITB in serum is of lesser value in patients coming from areas where cys-ticercosis is endemic than in those living in areas where it is rare A negative EITBdoes not exclude NCC in patients with a single cerebral lesion or in those withparenchymal brain calcifications.13

Computed Tomography

With computed tomography (CT) cysticerci can be easily visualized Computedtomography also allows assessment of the topography, number and stage of cys-ticerci In addition, CT studies are important for determining the rational thera-peutic approach

Parenchymal Neurocysticercosis

CT findings in parenchymal NCC depend on the stage of development of theparasites (Fig 15.5) Vesicular cysticerci appear as small and rounded low-densityareas that are well demarcated from the surrounding brain parenchyma These cystslack perilesional edema and do not enhance after contrast administration Most ofthese lesions contain an eccentric hyperdense nodule representing the scolex Some-times cysts are so numerous that the brain resembles “Swiss cheese”.11 Colloidalcysticerci appear on CT scan as ill-defined hypodense or isodense lesions surrounded

by edema Most of these show a ring pattern of enhancement after contrast istration Colloidal cysticerci represent the so-called “acute encephalitic phase” ofNCC in which the host’s immune system is actively reacting against the parasite.Parenchymal brain cysticerci may also appear on CT scan as hyperdense lesionssurrounded by edema with nodular enhancement after contrast administration This

admin-CT scan picture corresponds to the granular stage of cysticerci and is commonlyreferred as to “cysticercus granuloma.” Finally, calcified cysticerci appear as smallhyperdense nodules without perilesional edema or enhancement after contrast ad-ministration Another CT scan pattern of parenchymal NCC is observed in patientswith cysticercous encephalitis In these patients, CT shows diffuse brain edema andsinking of the ventricular system without midline shift Following contrast adminis-tration, multiple small ring-like or nodular lesions appear disseminated within thebrain parenchyma (Fig 15.6)

Most of the described CT patterns are characteristic of parenchymal NCC Thedifferential diagnosis, however, with other infectious or neoplastic diseases of theCNS may be difficult in some cases The main problem arises with single or multiplering enhancing lesions, since pyogenic brain abscess, toxoplasma, tuberculoma,mycotic granuloma and primary or metastatic brain tumors may present with simi-lar findings on CT scan In such situations, the presence of different stages of thecyst on CT, clinical findings, immunodiagnostic tests and epidemiological data, aswell as the empirical administration of anticysticercal drugs, help in the diagnosis.13

on CT scan as areas of abnormal leptomeningeal enhancement at the base of thebrain after contrast administration Some patients with hydrocephalus due to

cysticercus arachnoiditis also have single or multiple subarachnoid and mal brain cysts or calcifications, a finding that facilitates the diagnosis of NCC(Fig 15.7) Cystic subarachnoid lesion may be small when located within the corti-cal sulci or may reach a large size if these are located in the Sylvian fissure or withinthe basal CSF cisterns The latter usually have a multilobulated appearance, displaceneighboring structures and behave like space occupying lesions

parenchy-Fig 15.5b Computed tomographic appearance of parenchymal brain cysticercus: loidal cyst appearing as ring-enhancing lesion surrounded by edema.

Ischemic stroke in subarachnoid NCC can be seen on CT scan These findingsare nonspecific since the CT appearance of cysticercus-related cerebral infarctionsare similar to cerebral infarctions from other causes In some patients, the association

of subarachnoid cysts or the presence of abnormal enhancement of basal eninges in the opticochiasmatic region suggests the correct diagnosis The differen-tial diagnosis should include fungal, tuberculous and carcinomatous meningitis sincethese conditions are also associated with cerebral infarctions and abnormal enhance-ment of the leptomeninges

leptom-Fig 15.5c Computed tomographic appearance of parenchymal brain cysticercus: granular cysticercus appearing as nodular lesion.

Ventricular Neurocysticercosis

Ventricular cysticerci appear on CT scan as hypodense lesions that cause metric or obstructive hydrocephalus Ventricular cysts are usually isodense with theCSF; therefore, these can only be inferred on the basis of distortion of the ventricu-lar system (Fig 15.8) The administration of positive intraventricular contrast al-lows precise localization of intraventricular cysticerci This is usually performed by

asym-Fig 15.5d Computed tomographic appearance of parenchymal brain cysticercus: cified cysticerci.

Fig.15.6 Computed tomography of a patient with cysticercus encephalitis There is fuse brain edema, collapse of the ventricular system and multiple small areas of nodular enhancement disseminated throughout the brain parenchyma (with permission from Del Brutto OH, Sotelo J, Roman GC Neurocysticercosis: A Clinical Handbook © Lisse: Swets & Zeitlinger).

dif-transcutaneous puncture of the antechamber of a ventricular shunt previously placedfor the hydrocephalus or through a ventriculostomy tube The contrast may also beadministered through a lumbar puncture; however, this procedure should be con-ducted cautiously since this may result in brain herniation in patients with hydro-cephalus or intraventricular cysts

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) has the advantage of multiplanar (axial, nal and sagittal) reconstruction of images and the capacity to visualize the posteriorfossa without bone artifacts and high contrast resolution By MRI it is possible torecognize forms of cysticerci that were not seen on CT scan The main shortcoming

coro-of MRI, however, is failure to detect small calcifications Parenchymal brain cations are the most common CT finding in patients with NCC and, in manypatients, these may be the only radiological evidence Because of this limitation ofMRI, CT still remains the best screening neuroimaging procedure for patients withsuspected NCC.1

calcifi-Parenchymal Neurocysticercosis

MRI appearance of parenchymal brain cysticerci depends on their stage of opment Vesicular cysts appear as rounded lesions with signal properties similar tothat of CSF in both T1- and T2- weighted images The scolex is usually seen withinthe cyst as a high intensity nodule giving the lesion a “hole-with-dot” image which

devel-is pathognomonic of vesicular cysts (Fig 15.9) The appearance of colloidal cysts devel-is

quite different because as the parasite begins to degenerate, proteins from the scolexcombine with the vesicular fluid, and the whole cysticercus becomes discretelyhypointense with the surrounding brain parenchyma The wall of the cyst becomesthick and hypointense and there is marked perilesional edema; these findings arebetter visualized on T2-weighted images Administration of gadolinium results in aring-like pattern of enhancement (Fig 15.10) Granular cysticerci are visualized asareas of signal void on both T1- and T2-weighted images surrounded by edema orgliosis with hyperintense rims around the area of signal void MRI findings incysticercus encephalitis consist of multiple small rounded areas of decreased signalintensity on a T1-weighted sequence; these lesions become hyperintense on T2 and

Fig 15.7 Computed tomography showing hydrocephalus, subarachnoid cysticercus in Sylvian fissure and lacunar infarction in genu of internal capsule.

most of these are surrounded by edema Due to the small size of the cysts and theirstage of development, some cysts are only discernible on proton-density andT2-weighted sequences

Fig.15.8 Computed tomography showing distortion of ventricular system caused by ventricular cysticercus.

Subarachnoid Neurocysticercosis

MRI provides an excellent opportunity to visualize subarachnoid cysticerci cated over the convexity of cerebral hemispheres (Fig 15.11) Likewise, large cys-ticerci within the Sylvian fissure or the basal CSF cisterns are seen on MRI asmultilobulated hypointense lesions that may not show gadolinium enhancement.Sometimes the cysts have the same signal properties as CSF and may only be in-ferred by the distortion of CSF cisterns The diagnosis is difficult because cystsusually lack a scolex as these are of racemose type In cysticerus arachnoiditis, MRI

lo-Fig 15.9 T1-weighted magnetic resonance imaging showing characteristic

“hole-with-dot” imaging of vesicular cysticercus in cerebellum in axial section.

shows hydrocephalus and signal changes in the basal leptomeninges, with ment of cranial nerves and blood vessels at the circle of Willis Gadolinium en-hancement usually increases the sensitivity for detection of areas of meningealinflammation

entrap-Fig 15.10 T2-weighted magnetic resonance imaging of colloidal cysticercus Cystic fluid appears hyperintense and cyst’s capsule is visualized as a hypointense rim Marked edema is seen surrounding the lesion.

Ventricular Neurocysticercosis

Noninvasive diagnosis of intraventricular cysticerci represents one of the greateradvantages of MRI Most ventricular cysts are readily seen on MRI because thesignal properties of the cystic fluid or the scolex differ from those of the CSF (Fig.15.12) Cyst mobility within the ventricular cavities in response to movements of

Fig 15.11 Gadolinium-enhanced T1-weighted magnetic resonance imaging showing multiple cysticerci located over a convexity of cerebral hemispheres and Sylvian fis- sures.

Other Diagnostic Imaging Tests

Myelography

In patients with spinal leptomeningeal cysticercosis, multiple filling defects areseen in the contrast column on myelography (Fig 15.13) Leptomeningeal cystsmay be freely mobile within the spinal subarachnoid space and may change theirposition during myelography On the other hand, myelography is not specific inpatients with intramedullary cysts since it produces partial or complete block at thelevel of the lesion This finding may also be observed in other intramedullary spinalcord lesions

Cerebral Angiography

During the past decade, a number of reports dealing with the cerebrovascularcomplications of NCC have described in detail the full spectrum of angiographicchanges Angiographic findings in NCC include segmental narrowing of anterior ormiddle cerebral arteries in patients with lacunar infarctions, occlusion of the ante-rior or middle cerebral arteries or even the internal carotid artery in patients withlarge cerebral infarctions and mycotic aneurysms in patients with subarachnoid hem-orrhages The prevalence of angiographic abnormalities in patients with NCC isunknown; however, some studies suggest that angiographically documented arteri-tis is a common finding in patients with subarachnoid NCC, even in patients lack-ing clinical or neuroimaging evidence of a cerebral infarction

Treatment

Neurocysticercosis is a pleomorphic disease that causes several neurological dromes and patholgical lesions; therefore, uniform therapeutic scheme is not practi-cal in every patient Characterization of the disease in terms of cysts’ viability, degree

syn-of the host’s immune response to the parasites and location syn-of the lesions are syn-ofimportance for rational management Therapy of NCC includes a combination ofsymptomatic drugs, specific cysticidal drugs, surgical resection of the lesion andplacement of ventricular shunts.14

Cysticidal Therapy

Praziquantel is an isoquinoline with proven cysticidal properties that have beenused to treat human NCC since 1979 Subsequent studies showed that praziquanteldestroys up to 70% of parenchymal brain cysticerci after a 15 day treatment withdaily doses of 50 mg/kg Albendazole is an imidazole derivative that also has cysticidalproperties This drug was initially administered at a dose of 15 mg/kg per day for

one month Further studies, however, have shown that at similar doses, the duration

of therapy could be shortened to one week without compromising the results.Albendazole destroys 75-90% of parenchymal brain cysts and has been consideredsuperior to praziquantel in several trials comparing the efficacy of these drugs (Table15.3) Another advantage of albendazole over praziquantel is that the former alsodestroys subarachnoid and ventricular cysts due to its better CSF penetration Theinitial regimen of praziquantel at a daily dose of 50 mg/kg for 15 days was arbitrarily

Fig 15.12 T1-weighted magnetic resonance imaging showing cysticercus in the lateral ventricle The capsule and scolex of the cyst are clearly differentiated from cerebrospi- nal fluid.

Fig 15.13 Myelogram showing multiple filling defects in contrast column ing to small spinal leptomeningeal cysticerci (With permission from: Del brutto OH, Sotelo J, Roman GC Neurocysticercosis: A Clinical Handbook © Lisse: Swets & Zeitlinger).

chosen Since then, recommended doses of praziquantel have ranged from 10-100mg/kg for 3-21 days In these studies, praziquantel has been administered eighttimes hourly Since plasma levels of praziquantel decline within three hours of ad-ministration, it seems that the cysticidal effect has been reached by exposing theparasites to several intermittent peaks of the drug On this basis, it was suggestedthat if parenchymal brain cysticerci are exposed to high concentrations of praziquantelwhich are maintained for six hours by giving three individual doses of 25 mg/kg attwo-hour intervals, it might be sufficient to destroy the parasites Preliminary resultswere encouraging since the percentage of cyst disappearance on neuroimaging stud-ies was similar to that observed in patients receiving larger doses

The introduction of praziquantel and albendazole has radically changed the nosis of most patients with NCC; however, the anecdotal nature of initial studies onthese drugs generated doubts about their usefulness Some authors claim that cysticidaldrugs only improved the CT scans without improving the patients Nevertheless,more recent studies have focused on the clinical outcome of the patients followingcysticidal therapy and have shown that such therapy also produces significant clini-cal improvement The control of seizures in patients with NCC is better after treat-ment with anticysticidal therapy compared to those who don’t receive anticysticidaltreatment.15 Moreover, some studies have shown that patients with focal neurologi-cal deficits also have recovered after a trial of cysticidal drugs because the pressureeffects exerted by parasites regress following cysticidal therapy Cysticidal drugs have

prog-a diprog-agnostic role in epileptic pprog-atients with single enhprog-ancing lesions on CT or MRI.11

While most of these lesions are dying cysticerci in the acute encephalitic phase,some single enhancing lesions are, however, due to tuberculoma, mycotic granu-loma or low-grade gliomas and may require a follow-up study Therapeutic trialwith cysticidal drugs, if it results in prompt resolution of an intracranial lesion, maysuggest the diagnosis of cysticercosis and obviate expensive and hazardous investiga-tion and treatment

Patients with cysticercus encephalitis should not receive cysticidal drugs becausethese may aggravate intracranial hypertension In patients with both hydrocephalusand parenchymal brain cysts, cysticidal drugs may be used only after a ventricularshunt has been placed to avoid further increases in the intracranial pressure follow-ing cysticidal therapy Cysticidal drugs must be used with caution in patients withgiant subarachnoid cysticerci because the inflammatory reaction developed by thehost in response to the acute destruction of the parasite within the subarachnoidspace may occlude small leptomeningeal vessels surrounding the cyst In such pa-tients, concomitant steroid administration is mandatory to avoid cerebral infarc-tion In patients with ventricular cysts, the therapeutic approach with cysticidaldrugs should be individualized Albendazole therapy successfully destroys many ven-tricular cysts; however, the inflammatory reaction surrounding those cysts may causeacute hydrocephalus if these are located within the fourth ventricle or near theforaminae of Monro Patients with calcifications alone should not receive cysticidaldrugs since these lesions represent already dead parasites.10

In two large series of patients with epilepsy due to NCC, a statistically significantcorrelation between the use of praziquantel or albendazole and the rate of seizurecontrol was demonstrated The optimal duration of antiepileptic drug therapy inpatients with NCC has not been decided A recent prospective study showed that

up to 50% of these patients had relapses after withdrawal of antiepileptic drugs.Such patients had been free of seizures for two years, and their parenchymal braincysts had been successfully destroyed with albendazole Prognostic factors associatedwith seizure recurrence included the development of parenchymal brain calcifica-tions as the result of albendazole therapy and presence of recurrent seizures andmultiple brain cysts before the institution of cysticidal therapy

Corticosteroids are frequently used in patients with NCC and are the primaryform of therapy for cysticercus encephalitis, and arachnoiditis causing hydroceph-alus and progressive entrapment of cranial nerves According to the severity of thedisease, up to 32 mg per day of dexamethasone may be needed for the control ofsymptoms In patients with cysticercus encephalitis, corticosteroids may be usedalone or in combination with mannitol 2 mg/kg per day The initial trial with highdoses of intravenous dexamethasone may be followed by oral therapy with pred-nisone (50 mg/day) or dexamethasone (10 mg/day) The simultaneous administra-tion of corticosteroids and cysticidal drugs is controversial This combination hasbeen recommended to ameliorate the features of raised intracranial tension that mayoccur during praziquantel or albendazole therapy Such manifestations are not re-lated to toxic effects of cysticidal therapy but to the acute destruction of parasiteswithin the brain and are reliable indicators of drug efficacy Common analgesics andantiemetics may be used to ameliorate such complaints, avoiding the routine use ofcorticosteroids in every patient Absolute indications for corticosteroid administra-

Table 15.3 Results of controlled clinical trials comparing efficacy of

praziquantel and albendazole in treatment of parenchymal brain cysts

Reference Drug Regimen No % of Cyst

PZQ-praziquantal, ALB-albendazole, Pts –Patients

Used with permission from Del Brutto OH, Sotelo J, Roman GC

Neurocysticercosis: A Clinical Handbook Lisse: Swets & Zeitlinger Publishers

tion during cysticidal drug therapy include patients with giant subarachnoid ticerci, ventricular cysts, spinal cysts, and multiple parenchymal brain cysts In suchpatients, corticosteroids must be administered before, during and even a few daysafter the course of cysticidal drugs to avoid the risk of cerebral infarctions, acutehydrocephalus, spinal cord swelling and massive brain edema

cys-Surgery

Patients with hydrocephalus secondary to cysticercus arachnoiditis require tricular shunt surgery The main problem in these patients is the high prevalence ofshunt dysfunction The protracted course of these patients and their high mortalityrates (up to 50% in two years) is directly related to the number of surgical interven-tions for shunt revision A new shunt device functioning at a constant flow without

va vvalve mechvanism hvas been recently developed This shunt does not vallow the trance of spinal CSF into the ventricular system In patients with NCC, this inver-sion of CSF transit is the most common cause of shunt dysfunction as it allows theentrance of subarachnoid inflammatory cells and parasitic debris into ventricularcavities

en-Ventricular cysts may be removed by surgical excision or by endoscopic tion However, the possibility of cyst migration between the time of diagnosis andthe surgical procedure, must be ruled out by a control CT or MRI immediatelybefore surgery to avoid unnecessary craniotomies Permanent shunt placement isusually not necessary after removal of a ventricular cyst in the absence of ependymi-tis In contrast, shunt placement should follow or even precede the excision of aventricular cysts associated with ependymitis For a rare patient with double com-partment hydrocephalus related to both granular ependymitis of the cerebral aque-duct and occlusion of the foraminae of Luschka and Magendie, two independentshunt devices may be needed; one draining the supratentorial ventricular systemand the other draining the isolated fourth ventricle

aspira-Summary

Cysticercosis is the most common parasitic disease of the nervous system The

disease occurs when humans become the intermediate host in the life cycle of Taenia solium by ingesting its eggs from contaminated food Cysticercosis is endemic in

developing countries of Latin America, Asia and Africa Massive immigration ofpeople to industrialized nations has caused a recent increase in the number of pa-tients with cysticercosis in the United States and in some European countries aswell Neurocysticercosis is a pleomorphic disease due to individual differences in thenumber, size and location of the parasites within the nervous system, as well as todifferences in the severity of the host’s immune reaction Epilepsy, focal neurologicalsigns and intracranial hypertension are the most common clinical manifestations ofNCC Since the diagnosis is not possible on clinical grounds, it is necessary to un-dertake radiological and immunological investigations Neuroimaging studies (CT

or MRI) usually permit the diagnosis as these show objective evidences of the sites and the inflammatory changes induced in the surrounding nervous tissue Im-munological tests developed to detect anticysticercal antibodies in serum or CSFhave many problems due to inherent lack of specificity or sensibility The immuno-logical tests, therefore, should not be the sole basis for confirming or excluding thediagnosis of NCC The development of potent cestocidal drugs, albendazole andpraziquantel, have greatly improved the prognosis of NCC Nevertheless, some pa-

tients still have torpid clinical courses despite proper therapy Surgery has a role inthe management of selected patients, particularly in patients with hydrocephalusand intraventricular cysts

References

1 Del Brutto OH, Sotelo J Neurocysticercosis: An update Rev Infect Dis 1988;10:1075-1087

2 Garcia HH, Gilman R, Tovar MA et al Factors associated with Taenia solium

cys-ticercosis: Analysis of nine hundred forty-six Peruvian neurologic patients Am JTrop Med Hyg 1995; 52:145-148

3 Flisser A Taeniasis and cysticercois due to Taenia solium In: Sun T, ed Progress in

Clinical Parasitology Boca Raton: CRC Press, 1994:77-116

4 Trelles JO, Trelles L Cysticercosis of the nervous system In: Vinken PJ, Bruyn

GW, eds Handbook of Clinical Neurology Vol 35 Amsterdam: North Holland,1978:2910-320

5 Escobar A The pathology of neurocysticercosis In: Palacios E, Rodriguez-Carbajal

J, Taveras JM, eds Cysticercosis of the Central Nervous System Springfield: Charles

C Thomas Publisher, 1983:27-54

6 Pittella JEH Neurocysticercosis Brain Pathol 1997; 7:681-693

7 Sotelo J, Del Brutto OH, Roman GC Cysticercosis In: Remington JS, Swartz

MN, eds Current Clinical Topics in Infectious Diseases, 16 Cambridge: BlackwellScience, 1996:240-259

8 White Jr AC, Tato P, Molinari JL Host-parasite interactions in Taenia solium

cys-ticercosis Infect Ag Dis 1992; 1:185-193

9 Sotelo J, Guerrero V, Rubio F Neurocysticercosis: A new classification based onactive and inactive forms Arch Intern Med 1985; 145:442-445

10 Dixon HBF, Lipscomb FM Cysticercosis: An analysis and follow-up of 450 cases.Medical Research Council Special Report Series No 299 London: Her Majesty’sStationary Office, 1961:1-58

11 Wadia NH Neurocysticercosis In: Shakir RA, Newman PK, Poser CM, eds cal Neurology London: W.B Saunders Co., 1996:247-274

Tropi-12 Del Brutto OH, Sotelo J, Roman G Neurocysticercosis: A clinical handbook.Lisse: Swets & Zeitlinger Publishers, 1998

13 Del Brutto OH, Wadia NH, Dumas M, Tsang VCW, Schantz PM Proposal ofdiagnostic criteria of human cysticercosis and neurocysticercosis J Neurol Sci 1996;142:1-6

14 Del Brutto OH, Sotelo J, Roman GC Therapy for neurocysticercosis: A praisal Clin Infect Dis 1993; 17:730-735

reap-15 Vazquex V, Sotelo J The course of seizures after treatment for cerebral sis N Engl J Med 1992; 327:696-701

cysticerco-Tropical Neurology, edited by U K Misra, J Kalita and R A Shakir.

©2003 Landes Bioscience

Cerebral Malaria

J E Touze, L Fourcade, P Heno, P Riviere and P Paule

Cerebral malaria, mostly caused by Plasmodium falciparum, remains a major health

problem in the endemic areas The last report of the World Health Organizationindicates an increasing incidence of malaria Over three billion people are poten-tially exposed to malaria each year with an estimated death rate of two million everyyear, mainly among African children and nonimmune adults, such as travellers.Failure to provide appropriate chemoprophylaxis, lack of convenient methods forscreening high-risk populations, delay in the diagnosis, use of inappropriate therapyand widespread falciparum resistance to chloroquine have contributed to high mor-bidity and mortality Most patients with falciparum malaria do not have CNS mani-festations Cerebral malaria, however, is one of the manifestations of severe falciparuminfection and should be considered a medical emergency as it may rapidly progress

to a fatal multisystem disease Cerebral malaria is a major cause of death, accountingfor more than 80% of patients dying of falciparum infection The last two decadeshave witnessed better understanding in the pathophysiology of cerebral malaria.Sequestration of parasitized erythrocytes in deep capillaries and host response arebetter approached with new mechanisms such as rosetting, cytoadherence andcytokine secretion The clinical presentation of cerebral malaria is now better de-fined It may be associated with other complications such as pulmonary edema,hemodynamic failure, renal insufficiency, severe anemia and hypoglycaemia.1 At thesame time of widespread resistance to chloroquine, new antimalarial drugs, e.g.,artemisinine derivatives, have been introduced

Pathophysiology of Cerebral Malaria

Two main pathophysiological mechanisms of cerebral malaria, namely sludging

of red blood cells (RBC) and change in capillary permeability, are thought to beresponsible for cerebral malaria

The Sludging Theory

Sequestration of the late stages of intra-erythrocytic cycle is believed to causecerebral malaria Pathological observations in patients with fatal cerebral malariashowed a high concentration of parasitized erythrocytes Sequestration of parasit-ized erythrocytes in the relatively hypoxic venous beds allows optimal parasite growthand prevents parasitized RBCs from being destroyed by the spleen Several decadesago, Gaskell and Millar postulated that parasitized RBCs reduce blood flow andinduce sequestration This hypothesis was criticized for three reasons: 1) sequestra-tion was observed elsewhere in arterial and capillary venules; 2) anoxic changes wereinconstantly observed in histological samples; and 3) sequestration was never ob-

served with P vivax which has large trophozoites and schizonts.

Several authors have noted the discrepancy between autopsy findings and cal features of cerebral malaria although a study has shown correlation between thedegree of parasitized red blood cell sequestration and depth of coma

The Permeability Hypothesis

The permeability hypothesis of cerebral malaria was based on an experiment byMaigraith and Fletcher The essential observation was an increase in blood-brain

barrier permeability to I-labelled albumin in rhesus monkeys infected with P knowlesi.

This increase in capillary permeability was rapidly reversed by hydrocortisone creased capillary permeability results in leakage of plasma and cerebral edema Based

In-on this theory corticosteroids were widely used in cerebral malaria The ity hypothesis of cerebral malaria has been criticized for following reasons: 1) Dex-amethasone has been found to be deleterious in severe falciparum malaria.2 In adouble blind placebo controlled trial, coma was significantly prolonged in the corti-costeroid group; 2) many studies carried out in Africa have shown that cerebrospi-nal fluid pressure was not significantly increased in cerebral malaria; and 3)computerized tomography studies have never demonstrated features of brain edema

permeabil-in cerebral malaria

Cerebral malaria is presently considered a result of a cascade of events includingparasite cytoadherence, enhanced cytokine secretion in the background of a highparasite load and specific host factors.3

Cytoadherence

Parasitized RBCs appear to stick to vascular endothelium through a specific teraction between plasmodium-derived protein on the surface of parasitized RBCsand ligands on the endothelial cells Cytoadherence is the result of rosetting, “knob”formation and attachment of infected erythrocytes to specific endothelial receptors.Rosetting is a phenomenon where parasitized red cells agglutinate around normalred cells (Fig 16.1) This complex of red cells induces sequestration in deep capilla-ries The second component in cytoadherence is the presence of protrusions, or

in-“knobs” on red cells These knobs contain specific falciparum antigens such as dine rich protein and RESA (ring erythrocyte surface antigen) protein and plasmo-dium falciparum erythrocyte membrane protein-1(PfEMP-1) These proteins showclonal variation allowing them to evade host immune responses Knobs are essentialfor cytoadherence and facilitate the attachment of the red cells to the vascular en-dothelial cell The third component implicated in cytoadherence is a number ofspecific endothelial receptors: ICAM-1, CD-36 protein, VCAM-1, E-selectin,thrombospondin and chondroitin-sulfate-A (CSA) Infected red cells are attached

histi-to these recephisti-tors Some of these, such as thrombospondin and CD36, are expressed

in a wide range of vascular beds and are not related to the severity of the disease Onthe other hand, other receptors such as ICAM-1 and E-selectin are expressed in thecerebral capillaries of patients with cerebral malaria highlighting the role ofcytoadherence This phenomenon appears to play an important role in parasite sur-vival It is generally believed that sequestration initiates many pathogenic processesassociated with cerebral malaria and malaria during pregnancy The role of CSA hasbeen recently demonstrated in pregnant women, especially during first pregnancy

In the primigravida, large number of parasitized red blood cells (PRBCs) sequester

in the maternal compartment of the placenta, binding to CSA Preliminary studieshave shown that antibodies developed after multiple pregnancies are associated withreduced number of parasitized RBCs in the placenta and block CSA-binding ofparasitized RBCs, suggesting that protection is conferred by a conserved Pf-antigen.4

Cytokines

Plasma concentration of cytokines are elevated in adults and children with severemalaria Cytokines have an important role in the pathogenesis of cerebral malaria.Injection of TNFα into mice resulted in a disorder similar to cerebral malaria Therole of TNFα was suggested in the pathogenesis of fever, hypoglycemia and pulmo-nary edema associated with cerebral malaria Kwiatowski has shown that the severity

of falciparum malaria strongly correlated with TNFα levels.5 However, its nism of action remains unclear Currently the best hypothesis about the pathogen-esis of cerebral malaria would be the recruitment and modulation of endothelialreceptors which could also enhance nitric oxide and lactic acid production whichmay interfere with synaptic transmission, causing coma

mecha-TNF release has been correlated with severity of malaria but there are still anumber of inconsistencies Increased TNF secretion was noted in different patient

groups with malaria, especially in patients infected by P vivax Secondly, although

cytokine release in rodent models has been demonstrated, their implications in man malaria remain doubtful Thirdly, TNF was not the only cytokine involved inthe pathophysiology of cerebral malaria Gamma interferon, IL-1, GMCSF, IL-2and IL-10 are also implicated in macrophage activation and TNF secretion

hu-Host Factors

Genetic factors, immunity and nutritional status may play a part in the genesis of cerebral malaria and may account for why some patients develop cerebralmalaria and others do not Among the genetic factors, sickle cell anemia and thalas-semia may protect against cerebral malaria Studies in Africa have demonstratedthat heterozygous children with sickle cell traits (AS) in malaria endemic areas havefewer parasites and a better outcome than children with normal hemoglobin (AA).Moreover, polymorphic genes could explain the resistance of some individuals against

patho-Fig 16.1 Rosetting phenomenon Agglutination of infected red blood cells around a normal erythrocytes.

malaria infection Some genes are linked to the HLA system (BW3 alleles) and

control liver stages of Plasmodium falciparum Others (DRW-3) play a role in

pro-tection against severe anemia These genes could be implicated in semi-immunepatients but are inefficient against severe falciparum malaria with high parasitemia

Neverthe-child The individual response against P falciparum malaria is linked to host

immu-nity Two types of responses have been observed: 1) either an increase in T4 phocyte production with a high TNF secretion; or 2) a low response of T4lymphocytes, decreased TNF secretion and blockage of specific inhibitors In thislatter situation the host is also protected by genetic factors and immunity againstcerebral malaria.6

lym-Parasite Factors

Differences in virulence between plasmodium strains were noted in infected aotus

monkeys but were never demonstrated in P falciparum-infected humans Moreover,

there is no strong evidence to correlate the severe falciparum malaria to the lum or the level of chemoresistance of the strain The main parasite factor impli-cated in severe falciparum malaria remains within the susceptibility level toantimalarial drugs Despite these new advances, the cause of coma in cerebral ma-laria remains unclear Many hypotheses have been proposed, such as changes inneurotransmitter synthesis, release of nitric oxide and raised intracranial pressure,but none of these are proven.3

inocu-Pulmonary Edema

The pathophysiology of pulmonary edema in cerebral malaria remains unclear

In severe falciparum malaria, increased capillary permeability, hypoalbuminemiaand overhydration are the main causes of acute pulmonary edema Pregnant womenand children are at increased risk of developing pulmonary edema which can de-velop even after several days of appropriate chemotherapy In those patients oneshould be cautious in maintaining fluid balance, and hypertonic solutions such asbicarbonates, hypertonic saline and mannitol should be avoided In some patients,the course of pulmonary edema is similar to adult respiratory distress syndrome.Ultrastructural studies of the lung show neutrophil deposits, formation of hyalinemembranes and septal thickening of lung alveolus which are attributed tocytoadherence and cytokines

renal cortical blood flow has been noted in earlier studies using133 Xe clearance methodand contrast urography In most clinical studies, renal dysfunction is strongly asso-ciated with high parasitemia, jaundice, hemoglobinuria and pulmonary edema Thesechanges could be due to cytoadherence, increased TNF secretion and immune com-plex deposition in glomeruli In view of this, hemoglobinuria in cerebral malariashould be distinguished from black water fever and hemolysis induced byglucose-6-phosphate dehydrogenase (G-6-PD) deficiency In the former, sensitiza-tion of red cells has been observed after intermittent use of aminoalcohol drugs such

as quinine, quinidine, halofantrine and mefloquine In the latter group nuria occurs in patients with G-6-PD deficiency who take oxidant drugs such asprimaquine or certain foodstuffs

hemoglobi-Hematological Disorders

Anemia is an unavoidable complication of P falciparum malaria In cerebral

malaria, erythrocyte destruction is often underestimated because of red cells tration in deep capillaries The mechanisms of anemia in cerebral malaria are multi-factorial, involving dyserythropoiesis, iron deficiency, RBC sequestration in the spleenand hemolysis In some patients, immune-mediated hemolysis may be the mecha-nism of anemia in endemic areas Coombs’ test may be positive in those patients

seques-Thrombocytopenia

Thrombocytopenia is commonly observed in malaria In cerebral malaria therole of disseminated intravascular coagulation has been probably over-emphasizedfor thrombocytopenia; this, however, may be observed in severe disease with acuterenal failure and pulmonary edema Thrombocytopenia is attributed to enhancedspleen sequestration or peripheral destruction by an immune mechanism involvingCD4+ lymphocytes and antiplatelet IgG antibodies Other hemostatic abnormali-ties include failure to synthesize clotting factors such as prothrombin complex, ac-celerated fibrinogen metabolism and changes in platelet function

ma-Clinical Features

In the past, many patients with impaired consciousness, neck stiffness, febrileconvulsions or focal neurological signs were considered to have cerebral malaria.Mostly, those manifestations resulted from other diseases such as meningitis, men-ingoencephalitis and vascular diseases Moreover, impairment of consciousness may

be observed in patients with high fever or in children after febrile seizures For thesereasons, Warrell et al proposed a strict definition of cerebral malaria This definition

requires an unarousable coma in P falciparum malaria defined in adults by a Glasgow

scale lower than 10 and in children by a Blantyre scale lower than 3 (Table 16.1), inthe absence of another cause of altered sensorium.7

In adults, cerebral malaria commonly occurs after several days of fever or specific symptoms Convulsions are usually explained by hypoglycemia, particularly

non-in pregnant women with or without qunon-innon-ine treatment Neck rigidity is

mon, but opisthotonous and neck retraction may be observed in severely ill tients Corneal, pupillary and gag reflexes are usually normal Bruxism and forciblejaw closure are commonly observed in children and adults with severe impairment

pa-of consciousness Muscle tone and tendon reflexes are pa-often increased Abdominalreflexes are often absent and are a good sign to distinguish hysterical adults withfever due to causes where these reflexes are present In advanced stages of cerebralmalaria, decerebrate and decorticate rigidity, nystagmus and sixth nerve palsies may

be observed In children, the depth of coma may be assessed by the response topainful or vocal stimuli Convulsions may be generalized or focal and may occur inchildren of any age irrespective of the level of body temperature

Brain imaging using computed tomography and magnetic resonance imagingshows various abnormalities such as brain swelling and cerebral edema in some pa-tients In a prospective study conducted in Thailand in 24 patients with cerebralmalaria, no cerebral edema was observed Focal lesions, hemorrhage and corticalinfarcts (Fig 16.2) were noted in a small number of patients.8

Associated Manifestations

Neurological features in cerebral malaria are often associated with one or more

of the following complications (Table 16.2): 1) severe normocytic anemia as withhematocrit below 15% or hemoglobin level below 5 g/dl; 2) renal failure defined as

a urine output below 400 ml/24 h and or serum creatinine concentration above 265mmol/l; 3) hypoglycemia defined as a blood glucose concentration below 2.2mmol/l; 4) circulatory collapse or low blood pressure below 50 mm Hg in childrenaged one to five years, or below 70 mm Hg in adults; 5) spontaneous bleeding orlaboratory evidence for disseminated intravascular coagulation; 6) pulmonary edema

or adult respiratory distress syndrome; 7) hyperparasitemia This criteria may beinterpreted according to the immune status Thus, a high asymptomatic parasitemia(>5%) is frequently observed in children living in endemic areas who are partiallyimmume, whereas in nonimmune patients a high parasitemia is dangerous; 8) jaun-dice detected clinically or defined by a serum bilirubin more than 50 mmol/l; and9) high temperature of >400C

One or more of these criteria associated with the presence of different stages ofmalarial parasite suggest severe falciparum malaria

Diagnosis

The diagnosis of cerebral malaria is based on clinical suspicion Malaria mustalways be considered in any febrile patient who has stayed in or traveled in an en-demic area Atypical presentations which can mimic other diseases and delay diag-nosis, especially in travelers, must be considered In returning travelers cerebral malariamay masquerade as encephalitis, meningitis or psychosis Moreover, severe malariamay be missed in patients with jaundice, renal failure, pulmonary edema or severehemolysis In these patients, fever is frequently considered due to other causes

In endemic areas, cerebral malaria must be distinguished from other infectiousdiseases such as meningitis, trypanosomiasis or viral encephalitis (arbovirus diseases,hemorrhagic fever, measles) and a lumbar puncture must always be performed Inchildren, seizures and hypoglycemia can complicate any fever and must be differen-tiated from cerebral malaria.9 In pregnancy, hypoglycemia must be considered if thepatient presents with abnormal behavior, convulsions or sudden loss of consciousness.Cerebral malaria is rapidly fatal, therefore, this diagnosis must be considered inany patient with an unexplained fever and neurological symptoms Antimalarial

Table 16.1 Coma score in cerebral malaria