Parasitic infections of the central nervous system (CNS) present diagnostic challenges due to their infrequency in the United States and the variability of their presentations. However, modern foreign travel practices have made general familiarity with the spectrum of parasitic diseases important for the practitioner. Children, as immunologically naive visitors to areas where parasites are endemic, are especially vulnerable to infection. Children traveling abroad also tend to exhibit behaviors (pica, outdoor activities, exposure to water) which make them at high risk for exposure to a number of parasites. In addition, the increasing prevalence of the immunocompromised child further emphasizes the need to consider parasitic etiologies for the child with clinical manifestations of CNS infection. The protozoal and helminthic infections most commonly encountered in clinical practice will be reviewed.
PROTOZOAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM
Two forms of amebic infections of the CNS are typically encountered in children: fulminant primary amebic meningoencephalitis (PAM), caused by Naegferia fowlen, and more insidious granulomatous amebic encephalitis (GAE), caused by Acanthamoeba. Entamoeba hisiolytíca is also known to cause encephalitis in endemic areas, but it does not generally cause this disease in children.
Noegieria fowlen is a ubiquitous ameboflagellate, found in natural and domestic water sources and even in the nasopharyngeal flora of the normal human. Incidence is worldwide. Most persons acquire humoral antibodies to Noegleria fowleñ by late childhood. Despite such widespread exposure, infection is uncommon. The Centers for Disease Control and Prevention (CDC) reported only four fatal cases in the United States in 1991. Primary amebic meningoencephatitis has been reported in Virginia, Florida, Texas, Nevada, North Carolina, New York, and Puerto Rico.
Most patients acquire the disease while swimming in warm, fresh water. Infections are typically described in immunocompetent persons. The amebae enter the swimmer's nose and pass through the oliactory neuroepithelium, the olfactory nerves, and into the subarachnoid space, resulting in a fulminant leptomeningitis. After an incubation period of 1 to 2 weeks, patients present with headache, fever, anorexia, photophobia, nuchal rigidity, and occasionally, seizures. A prodrome of anosmia, corresponding to inflammation of the olfactory epithelia, is described but not universal. Within 72 hours, patients typically progress to coma, herniation, and death. Myocarditis is an incidental finding.
Antemortem diagnosis of PAM is difficult. Brain computed tomography (CT) reveals a basilar arachnoiditis with effacement of the basal cisterns. Cerebrospinai fluid generally mimics that of bacterial meningitis, with a poìymorphonuclear pleocytosis, elevated protein, and very low glucose. Occasionally, motile amebae are incidentally found on cerebrospinal fluid (CSF) cell count or Gram's stain. If significant numbers of "atypical mononuclear cells" are reported on cell count, fresh CSF should be centrifuged at high speed, trichrome stained, and examined for amebae. Culture of amebae on EscherichiaEnreroÍKicter-derived agar, serological diagnosis, and polymerase chain reaction are possible but generally impractical due to the rapid progression of the disease.
Three survivors are reported in the literature; all received therapy based on early diagnosis. One survivor received intravenous amphotericin B, intrathecal amphotericin B and dexamethasone, and oral rifampin. Another reported survivor was treated with intravenous/intrathecal miconazole and oral rifämpin.
Prevention measures are confounded by the ubiquitous nature of Naegleria. Resistance to serum complement appears to be a virulence factor for Naegleria strains, and complement -deficient persons, postulated to be at particular risk for PAM, should avoid freshwater swimming.
In contrast to PAM, it is most often immunocompromised hosts (ie, human immunodeficiency vims patients) who contract GAE, caused by Acanthamoeba. These amebae also cause keratitis and other systemic infections. Acanthamoeba are widespread in fresh and salt water. Although respiratory routes have been implicated in a few GAE cases, invasion to the brain is primarily hematogenous, originating from a skin lesion. After an incubation period of weeks to months, patients present with signs of increased intracranial pressure and mass effect: hemiparesis, lethargy, convulsions, and behavioral changes. Ataxia, double vision, and cranial nerve defects also are described.
On brain computed tomography scan, cerebral edema and one or more focal lesions generally are seen. At autopsy, these multiple, necrotic granulomas often can be found in perivascular spaces throughout the brain and brainstem. Immunocompromised states may mute these findings. Typical CSF features include a mild mononuclear pleocytosis, a slight elevation in protein, and a normal to low glucose. Definitive diagnosis requires brain biopsy to stain for Acanthamoeba.
Although fluconazole, ketoconazole, 5-fluorocytosine, neomycin, and riiampin have been postulated as chemotherapy for GAE, surgery remains the standard. The few reported survivors underwent early excision of lesions. In general, prognosis is poor, with progression to coma and death. The disease course is relatively indolent in acquired immunodeficiency syndrome patients.
Amebic diseases of the central nervous system are well reviewed by Visvesvara and Stehr-Green1 and Campbell.2
Toxoplasma ganda is a coccidian parasite that can infect immunocompetent and immunocompromised hosts. In the immunocompetent person, a heterophilenegative infectious mononucleosis-like illness is seen. Congenitally acquired Toxoplasma infection is well described. In the immunocompromised host, Toxoplasma has a strong affinity for the central nervous system.
Outside the perinatal period, humans generally become infected by ingesting oocysts from cat litter; raw meat, or goat's milk. Infection is also possible from contaminated blood. products and organ transplantation.3 After enterai ingestion of oocysts (which develop into tachyzoites and migrate into the bloodstream) orparenteral entry of tachyzoites, the tachyzoites hematogenously spread to tissue and organs, including the brain. In the brain, the parasite changes into a microscopic cyst form with little or no surrounding inflammation.3
Symptoms are variable, with asymptomatic states and incidental diagnosis at autopsy common in immunocompromised hosts. When symptoms do occui; headache, confusion, lethargy, and signs of increased intracranial pressure with mass effect are characteristic.
Lesions are typically seen on CT/magnetic resonance imaging. Lumbar puncture reveals elevated opening pressure, with elevated CSF protein, normal glucose, and white blood cell (WBC) count normal or with a mild mononuclear pleocytosis.4 Toxoplasma gpnaii can be isolated by inoculation of fresh CSF into mice or onto tissue culture. Serum immunoglobulin (Ig) M and IgG titers can determine acute versus chronic infection in immunocompetent patients but are not reliable for the immunocompromised child. Histological analysis of brain biopsy may detect the organism but fails to indicate whether infection is acute or chronic. An enzyme-linked immunosorbent assay (ELISA) has been developed with a sensitivity of about 60% in acute infection. Polymerase chain reaction testing is promising but not universally available.3
Combination therapy with pyrimethamine and sulfadiazine is the treatment of choice. Two to 6 weeks of the combined regimen is indicated in the immunocompetent host; 4 to 6 weeks is advised for the immunocompromised host. Clindamycin, spiramycin, and trimethoprim-sulfamethoxazole present less optimal alternatives, although cîindamycin is indicated in ocular toxoplasmosis.3
The World Health Organization (WHO) reports more than 400 million cases of malaria yearly, and the Centers for Disease Control and Prevention report more than 1000 US cases per year.5 Cerebral malaria is associated with Píosmoíüum falciparum infection, which comprises an ever- increasing portion of all malaria cases.6 Studies show that between 0.8% and 7.5% of all falciparum malaria cases involve a diffuse encephalopathy called "cerebral malaria." Women of child-bearing age and children are at increased statistical risk for falciparum malaria with CNS involvement.5
Three theories of the pathogenesis of cerebral malaria exist. It is likely that malaria- infected erythrocytes stick to the endothelium of cerebral vasculature, occluding blood flow to the brain. Other hypotheses include a cytokine (TNL and IL·! alpha) -mediated mechanism of inflammation, as well as a postulate of increased blood-brain barrier permeability.6
Systemic and metabolic effects of malarial disease (ie, fever, anemia, and hypoglycemia) can impact the CNS without direct intracerebral infection. This has traditionally made the diagnosis of cerebral malaria difficult. Some studies have based the diagnosis of cerebral malaria on the presence of malaria, neurological changes, and clinical improvement after antimalarial therapy.5 The WHO has adopted strict guidelines for the diagnosis; criteria include the presence of falciparum parasitemia, unrousable coma lasting more than 30 minutes or more than 2 hours after seizure, and exclusion of other physiologic causes of coma.5
The diagnosis of cerebral malaria should be considered in the child who presents with fever, impaired consciousness, and a history of foreign travel/exposure to malaria. A travel history of every locale visited (even when a patient never left an airplane on stopover) is essential. An exact record of antimalarial prophylaxis, medical visits or procedures done during travel, and blood products received is also helpful.
In Warrell's study of cerebral malaria in children and adults, children were likely to present with rostrocaudal progression of the disease, abnormal or absent brainstem reflexes, signs of increased intracranial pressure and hemiation (irregular respirations and high opening pressure on lumbar puncture), and persistent neurological defects.6 Molyneux et al7 found that cerebral malaria progressed much more rapidly in children than in adults. Most children admitted for cerebral malaria had a history of symptoms for less than 48 hours. Early findings included cyclical fever, anorexia, vomiting, cough, and seizures. Late presentations included coma, seizures, disconjugate gaze, upper motor neuron signs, and extensor posturing. Concomitant problems may cause or exacerbate coma in the falciparum malaria patient: hypoglycemia, profound anemia, shock, and renal failure may all coexist in malarial disease.7
In the child suspected of having malaria, thin and thick smears from capillary blood taken at the bedside every 8 to 12 hours (not mixed in anticoagulant) should be examined for falciparum ring forms by an experienced pathologist. Brain CT is typically unremarkable, and cerebrospinal fluid findings are generally normal, although opening pressure is frequently high.5 Early treatment is vital in an attempt to reduce severe disease. Therapy with quinine and its derivatives is the standard, although artemesin-derived drugs may be found to be superior.6
Supportive management for comatose children with cerebral malaria is similar to that of any encephalopathic child. Correction of anemia, fever control, airway protection, aspiration prevention, and intracranial pressure (ICP) monitoring all deserve consideration. Empiric intravenous glucose generally is recommended to combat hypoglycemia caused by both the disease and antimalarial therapies. Seizure prophylaxis is controversial.
Mortality statistics in cerebral malaria vary widely from 5% to 50%, even with adequate medical care. Bad prognostic signs include prolonged coma, absent brainstem reflexes, and decerebrate posturing.5 Survivors generally regain consciousness 30 to 80 hours after antimalarial therapy begins. Neurological sequelae, reviewed by Brewster et al,8 are seen in approximately 20% of pediatrie survivors. Hemiplegia, cortical blindness, ataxia, and recurrent seizures are seen most commonly.
TAPEWORM INFECTIONS IN THE CENTRAL NERVOUS SYSTEM
Neurocysticercosis, caused by the tapeworm Taenia soUitm, is the most common parasitic disease of the central nervous system. In endemic areas, it is the chief cause of new-onset epilepsy in adults.9 In the United States, multiple outbreaks have been described.
Humans acquire intestinal infection by ingesting the larval forms in uncooked/undercooked pork. In the human bowel, the larva matures into an adult form, implanting the scolex into the bowel wall and growing by the posterior extension of multiple eggcontaining proglottids. Eggs are then shed in human stool. Cysticercosis is acquired when the human host ingests the eggs shed in human stool. Three mechanisms of infection are described; all involve eggs reaching the stomach. A patient may pass eggs from his or her own anus to mouth (autoinfection) or ingest eggs from another persons stool (heteroiniection). Régurgitation of egg-filled proglottids from a patient's small bowel to his or her stomach is also a mechanism of autoinfection. Eggs hatch in the stomach and larval forms traverse the bowel wall and migrate hematogenously to viscera (CNS and muscle). After approximately 2 months, the larva matures into visceral cyst (cysticercus).
Cysticerci can be located within the brain parenchyma, within the ventricles, in the subarachnoid space, or as racemose (basilar) cysts. Sizes range from 2 mm to 2 cm.JO The cysticerci have three stages: the living larval form, the dying larva with caseous necrosis, and the calcified cyst.9 Living Larval forms typically evoke little to no immune response and often cause no symptoms unless situated at a critical site. As the larva dies, granulomatous change is followed by calcification, with accompanying clinical changes.
Clinical presentation characteristically occurs 5 to 7 years after ingestion of eggs. Symptoms are quite variable and depend on the number, location, and stage(s) of the cysts.10 One in four patients with neurocysticercosis has a normal neurological exam.11 In numerous studies, seizure onset is the most common clinical presentation, with headache, papilledema, emesis, pyramidal tract defects, cognitive changes, ataxia, movement disorders, stroke, cavernous sinus syndrome, and visual changes occurring less often.11 Hydrocephalus occurs when a cysticercus obstructs a CSF outlet.10 Racemose cysticerci can produce a posterior fossa syndrome. Spinal cord cysts can lead to cord compression.11
Clinical, Therapeutic, and Prognostic Features of Parasites Affecting the CNS
Clinical, Therapeutic, and Prognostic Features of Parasites Affecting the CNS
Like the clinical presentation, radiographie appearances in neurocysticercosis vary. Cysts may be single or multiple, remain cystic or become calcified, enhance with contrast or not. Lacunar infarctions, where cysticerci have occluded arterial flow, may be visible on contrasted CT. Mitchell and Crawford found that in children, most lesions are solitary, enhancing, and contain a visible scolex.12 Magnetic resonance imaging is superior to CT in the detection of lesions within ventricles, cisterns, or at the base of the brain.10 Differential diagnostic considerations include malignancies, vascular events, and other parasitic (echnococcosis, paragonimiasts, schistosomiasis, and trichinosis) and nonparasitic infections.9
Cerebrospinal fluid analysis is usually remarkable in neurocysticercosis. There is a lymphocytic pleocytosis in more than half the cases, with elevated protein and low glucose. Elevated opening pressure is common. Controversy exists regarding whether CSF or peripheral eosinophilia is typical of CNS disease. Stool analysis for ova and parasites is generally negative, although family members of neurocysticercosis victims should have stool ova and parasite analyses in order to detect infected persons to be able to prevent reinfection or autoinfection.9 While ELISA assays are helpful in symptomatic disease when a host immune response has occurred, enzyme-linked immunoelectrotransfer blot (EITB) assays have superior sensitivity and specificity.10
Chemotherapy with cysticidal drugs is controversial in CNS disease and contraindicated in ocular disease. It shows little efficacy in intraventricular or calcified cyst disease.10 However, the majority of studies advocate cysticidal therapy for parenchymal or subarachnoid lesions. Surgery is indicated for intraventricular cysts and racemose cysts leading to hydrocephalus.
Outcomes are generally good in neurocysticercosis when cysticidal therapy is implemented, with mortality rates less than 10%. Death is usually a result of increased intracranial pressure.10
Echinococcws gramdosus, the dog tapeworm, is seen worldwide and causes the majority of hydatid cyst disease in humans. Dogs acquire the disease by ingesting E gramdosus larvae in the viscera of sheep or cattle. The tapeworm matures in the dog bowel and releases eggs in the dog's stool, which are ingested by humans. The egg encysts in the human small bowel and releases an embryonic form that penetrates the bowel wall and migrates hematogenously to form a hydatid cyst in the liver, lung, or less often, brain.12 Hematogenous infection of a viscera may be primary (directly from bowel) or secondary (after a hydatid cyst elsewhere ruptures). While only 2% of all E granidosus hydatid cyst disease involves the brain,14 70% of intracerebral hydatid cyst cases are reported in children less than 15 years of age.15
Children typically present with signs of increased intracranial pressure and mass effect. Morning headache and vomiting are very common. The majority of patients present with papilledema and hemiparesis. Seizures, confusion, and visual changes are sometimes seen. Spinal cord disease is rare in the pediatrie patient because this typically represents a progression over many years from vertebral disease.13
Radiographically, intracerebral hydatid cysts appear as nonring-enhancing, discrete, round, cystic lesions within the brain parenchyma. Typically, intracystic fluid has an appearance similar to CSF Rarely, meningeal, intraventricular, or brainstem lesions are seen. Multiple cysts are extremely rare.13 As hydatid cyst disease rarely exists only in the brain, simultaneous scans of the liver and lung may be helpful. In comparison to neurocysticerci, hydatid cysts are generally larger (>5 mm in diameter), more discrete, noncalcified, and rounder. In children, both cysticerci and hydatid cysts tend to be solitary.13 The CT appearance of hydatid cysts can be variable. Magnetic resonance imaging can enhance visualization of hydatid cysts preparatory to surgery.
Due to the mass effect created by hydatid cysts, lumbar puncture is generally not advised, and cerebrospinal fluid is typically normal. Concomitant lesions in the liver or lung are helpful in making the diagnosis. When extracerebral disease coexists, serological assays (indirect hemagglutination and latex fixation) and immunoelectrophoresis are useful but may cross-react with T soiium.13
Surgical resection is the treatment of choice for intracerebral hydatid cysts. As mebendazole and albendazole have shown little efficacy, they are reserved for use only if the cyst is irresectable.
ROUNDWORM INFECTIONS OF THE CENTRAL NERVOUS SYSTEM
Visceral Larva Migrans
Visceral larva migrans (VLM) is usually caused by Toxocara canis, the dog roundworm. Humans, as accidental hosts, ingest eggs from canine stool. Puppies are more likely to excrete the parasite than are adult dogs; almost all puppies in the United States harbor T cam's. Humans also can ingest the eggs of the roundworm Baylisascaris procyonis, from the stool of raccoons. Children under 5 years of age are especially at risk for exposure to VLM from play in sandboxes and eating dirt. Hermann et al showed a 30% seroprevalence for toxocariasis among low-income African-American children studied.16 Ocular larva migrans is beyond the scope of this article.
Toxocaral organisms do not mature in the human host, so disease extent depends on the quantity of eggs ingested. After eggs hatch in the human gastrointestinal tract, larvae cross the bowel wall and migrate hematogenously to the viscera. Organ damage results from both direct mechanical damage from the larva and from host immune response. The liver, lung, and heart are commonly involved; brain involvement is relatively rare. In extracerebral locations, disintegrating larval forms are sequestered in eosinophilic granulomas. However, brain lesions present as necrosis with a mild surrounding immune response.17
The majority of VLM infections are clinically asymptomatic, with mild peripheral eosinophilia and seroconversion. Extracerebral disease, when symptomatic, manifests as fever; liver enlargement, lung infiltrates, and leukocytosis.17 In patients with advanced intra-abdominal disease, the onset of seizures (tonic-clonic or absence), lethargy, meningismus, coma, dementia, and behavior changes indicate CNS involvement. Baylisascaris procyonis is associated with meningoencephalitis more often than T canis. Neurological symptoms may be insidious or transient. Fortenberry et al18 reported a 10-month-old child with static encephalopathy and spastic quadriparesis with proven toxocariasis.
A peripheral and CSF eosinophilia is characteristic of VLM meningoencephalitis. Enzyme-linked immunosorbent assays are available from the CDC and are good in toxocaral infection but limited for Baylisascaris procyanis infection. Enzyme-linked immunosorbent assays are unable to distinguish acute from chronic infection.17,19 Serum IgM is elevated in acute disease.
Surgery has been reported as successful. Antihelminthics potentially can exacerbate intracerebral disease by killing larvae and potentiating host immune response.20 When therapy is desired, thiabendazole or diethylcarbazine is recommended with steroids or antihistamines.
Eosinophilic meningitis technically describes any of a number of CNS infections with eosinophilic CSF pleocytosis but has traditionally become synonymous with Angiostrongylus cantonensis infection of the nervous system. TKe definitive host for this "rat lungworm" is the rat, with mollusks as the intermediate host. Disease from A cantonensis is found throughout the Pacific basin, including Hawaii, although sporadic cases are reported elsewhere. The roundworm has been brought to the United States by rats on Pacific ships.20 Victims typically have eaten freshwater mollusks containing the larval forms. Larvae pass through the bowel wall and migrate to viscera (typically the lung, rarely the brain).
After an incubation period of 2 to 35 days, intracerebrat infection presents with headache (almost universally relieved with lumbar puncture), nuchal rigidity, nausea, vomiting, and focal weakness. Fever is atypical.
Diagnosis is facilitated by eliciting a history of consumption of freshwater mollusks, including certain escargots. In contrast to neurocysticercosis or echinococcosis, there is generally no mass lesion on CT, but signs of increased intracranial pressure are seen occasionally. Cerebrospinal fluid classically shows a leukocyte count of 150 to 2000 (eosinophils >50%) (53), elevated protein, and normal to low glucose. Larvae cannot usually be detected in the CSF. Peripheral leukocytosis (WBC > 10 000) is usual. Serological assays are under investigation for clinical use, with an ELISA assay appearing reliable.21-22
Eosinophilic meningitis is a self-limiting disease, with gradual recovery in 3 to 6 weeks the rule. Deaths are very rare. No antihelminthic therapy is advised, increased intracranial pressure is managed with repetitive lumbar puncture and glucocorticoid therapy.21'22
The Table summarizes the clinical, therapeutic, and prognostic features of the parasites discussed in this article. Additional parasitic diseases that involve the central nervous system include: trichinosis, strongyloidiasis, schistosomiasis, paragonomiasis, and trypanosomiasis. Central nervous system manifestations of these conditions are less often seen in US children than the ones previously described.
1. Visvesvara GS, Stehr-Green JK. Epidemiology of ftee-living ameba infections. / Protozool. 1990:37:138455.
2. Campbell S. Amebie brain abscess and meningoencephalitis.Semm Neural. 1993;13;153160.
3. Wilson CB, Remington JS. Toxoplasmosis, In: Feigin RU Cherry JD, eds. Teabook of Pediatrie Infectious Diseases. 3rd ed. Philadelphia. Pa: WB Saunders Co; 1992:20572069.
4. Bell WE Parasitic infections of the brain. In: Rudolph AM, ed. Monies, 18th ed. Norwalk, Conn: Appleton & Lange; 1987:1706-1709.
5. Hamer DH. Wyler DJ. Cerebral malaria. SCTIOT Neural. 1993; 13: 180-1 88.
6. Warrell DA. Cerebral mataría. Sdnuuz Med Wodunsar. 1992(122:879-866.
7. Molyneux ME, Taylor TE, N irima JJ. Borgsrein A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 corootose Malawian children. Quarterly Journal of Metterne. 1989;7 1=441 -459.
8. Brewster DR. Kwiakowski Il White NJ- Neurological sequelae ni cerebral malaria in chiUren. lancet. 199ft3 36: 1039- 1043.
9. Barry M. Kaldjian LC. Neirnicysticercosis. Semin Neural. 1993;13:?31?43. 10. Turner )A. Cestodes, In: Feigin RD, Cherry )u eds. Textbook of Peaatiic hijecuous Diseases. 3rd ed. Philadelphia. Pa: WB Saunders Co; 1992: 2098-1112.
11. Sorelo J, Guerrero V, Rubio V. Neutocysticercois: a new classification based on active and inactive forms. A study of 753 cases. Arch intern Med. 1985;145:442-445.
12. Mitehell WG, Crawford TQ lntraparenchymal cerebral cysikercosis in children; diagnosis and treatment. Pediatrics. 1938:82:76-82,
13. Kammerer WS. Echinococccisis affecting the central nerwms system. Semin Neural. 1993; 13: 144- 147.
14. Schanc PM. Localilacion de Ia hidntidosis en el sistema nervioso central. Bol Oficina Soni! Panarn. 1 972:63; 1 90-202.
15. Slim MS, Khayat G, Nasi AT, Jidejian YD. Hydatid disease in children. J ftdorr Stag. 1971:6:440-448.
16. Herrmann N, Glickman LT, Schanti PM, Westen MG. Domanski LM. Seroprevalence of ioonotk toxocariasis in the United Stares: 1971-1973. Am J Epidemial, 1985; 22:890-896.
17. Hotez PJ. Visceral and ocular larva migrans. Semin Neural. 1 993; 13: 175- 179.
18. Fortenberry JD, Kenney RQ Younget J. Visceral larva migrans producing static encephalopathy inaninfent. ftdiorr Infect Dis i. 1991;10;403-406.
19. Schantz PM.Toxocara larva migrans now. AmJTrup Med Hjg. 1989;41:2I-34
20. Kazacos KR. Visceral and ocular larva migrans. Semin Neural. 199 1;6:22 7-235.
21. Weller PF, Liu LX. Eosinophilic meningitis. Semin Neural. 1993;13:16?-168.
22. Stechenherg BW. Eosinophilic meningitis. In: Feigin RD, Cherry JD; eds. Tiiiboofe of Fafcaric In/ecootts Diseases. 3rd ed. Philadelphia. Pa: WB Saunders Qi; 1992: 437-439.
Clinical, Therapeutic, and Prognostic Features of Parasites Affecting the CNS
Clinical, Therapeutic, and Prognostic Features of Parasites Affecting the CNS