Neurocysticercosis

Mehila Z.March 19th 2007

Introduction Cysticercosis Cysticercosis is a systemic illness caused by

disseminated larval form of pork tapeworm, Taenia solium.

Encystment of larvae can occur in almost any tissue.

Involvement of the central nervous system, known as neurocysticercosis (NCC), is the most clinically important manifestation of the disease.

Introduction Neurocysticercosis

Most common helminthic disease of the nervous system.

Common in Latin America, Asia, sub-Saharan Africa, India, and east Asia as well as in industrialized nations with a high immigration rate.

50 million people worldwide.

In endemic regions, leading cause of hospital admissions and the major cause of acquired epilepsy.

Affect men and women equally. Inflammation around parasites may be more severe in women than in men.

Etiopathogenesis The adult tapeworm resides in the upper jejunum.

The scolex attaches by both sucking disks and two rows of hooklets.

Often 1 adult worm is present, which may live for years.

usually about 3 m long, as many as 1000 proglottids, each of which produces up to 50,000 eggs.

three to five proglottids are generally excreted into the feces,& the eggs in these proglottids are infective for both humans and animals.

The eggs may survive in the environment for several months.

Kingdom: AnimaliaPhylum: PlatyhelminthesClass: CestodaOrder: CyclophyllideaFamily: TaeniidaeGenus: TaeniaSpecies: T. solium

Etiopathogenesis Humans = definitive hosts.

Pigs are intermediate hosts

(Taeniasis), without symptoms.

Intermittent fecal shedding.

Embryos penetrate the GI mucosa of the pig (cysticerci).

When undercooked pork is consumed, intestinal tapeworm will again be formed, completing the life cycle

Within 60 to 90 days, the encysted larval stage develops.

Etiopathogenesis Human cysticercosis occurs when T solium eggs

are ingested via fecal-oral transmission from a tapeworm host.

The human then becomes an accidental intermediate host, with development of cysticerci within organs.

Cysticerci may be found in almost any tissue. The most frequently reported locations are skin, skeletal muscle, heart, eye, and most importantly, the CNS (NCC).

Etiopathogenesis Autoinfection.

Fecal-oral autoinoculation. Regurgitation of proglottids into the stomach.

Only 5 - 40 % of patients with cysticercosis have an adult worm in their intestine.

Most individuals with intestinal tapeworm infection do not develop symptomatic cysticercosis.

Cysticerci are liquid-filled vesicles consisting of a membranous wall and a nodule containing the invaginated scolex. The scolex has a head armed with suckers and hooks and a rudimentary body.

Stages Of Cysticercosis Three stages of development.

Vesicular phase, Parasite is a cyst with thin membrane liquid filled,

transparent. Can remain for decades in this stage. Or degenerate that ends up with the death of the parasite.

Colloidal-granular stage, Vesicular liquid becomes viscous and cloudy, Wall and scolex is transformed granular structure. No longer is viable.

Nodular calcified stage, Parasite becomes a calcified.

Vesicular

Vesicular-colloidal

Granular

Calcific

colloidal

Clinical Features Cysticercosis

Clinical syndromes of cysticercosis. Neurocysticercosis (NCC).

Parenchymal. Extra-parenchymal.

Intra-ventricular. Subarachnoid. Spinal involvement.

Extra-neural manifestations. Eye. Muscle. Subcutaneous tissue.

Oncospheres actively migrate Vs enter tissues passively during high blood flow.

Diagnostic Criteria (Cysticercosis)Adapted from Del Brutto et al. (Proposed diagnostic criteria for neurocysticercosis. Neurology 2001; 57:177–183)

Absolute criteria: Histological demonstration of the parasite, cystic lesions showing the scolex on CT or MRI, direct visualization of ocular parasites by fundoscopic examination

Major criteria: Lesions highly suggestive of neuro-cysticercosis on neuro-imaging, positive serum enzyme-linked immunoblot for anti-cysticercal antibodies, resolution of cysts after therapy after anti-parasitic therapy, spontaneous resolution of small single enhancing lesions

Minor criteria: Lesions compatible with neurocysticercosis on neuroimaging, clinical manifestations suggestive of neurocysticercosis, positive CSF ELISA for anti-cysticercal antibodies or cysticercal antigens, cysticercosis outside the CNS

Epidemiologic criteria: Evidence of a household contact with Taenia solium infection, individuals coming from or living in an area where cysticercosis is endemic, history of frequent travel to disease-endemic areas.

Definitive diagnosis: one absolute criterion or two major plus one minor and one epidemiologic criterion

Probable diagnosis: one major plus two minor criteria, one major plus one minor and one epidemiologic criterion, or three minor plus one epidemiologic criterion.

Multiple subcutaneous nodules on the chest wall and a few calcified lesions on chest X-ray

A 42-year-old man admitted at Nelson Mandela Academic Hospital (Umtata) South Africa presented with a history of recurrent generalized tonic-clonic epileptic seizures of six years duration, disseminated nodules all over the body of two-year duration and headache.

Clinical Features Neurocysticercosis

Many patients are asymptomatic.(80%).

Inflammatory response develops around a degenerating cysticercus.

It is not known what triggers this degeneration.

Peak presentation occur three to five years after infection, but it can be delayed for >30 years.

Sub acute to chronic onset, (except seizures).

Clinical Features Parenchymal cyst Calcific cyst Cysticercal encephalitis Sub-arachnoid cyst Racemose cyst Ventricular cysts Spinal cyst Other forms

Clinical Features Parenchymal cysts

29-62% percent

cerebral cortex or basal ganglia.

usually <1 cm in diameter but can be much larger.

frequently seizures, 50 to 80 percent of patients

The risk of epilepsy in sero-positive individuals is two to three times higher than in sero-negative controls

Clinical Features Parenchymal cysts

The seizures may be focal or generalized

Neurologic examinations are usually normal,

focal neurologic signs may be present.

Severe headaches, rarely fever or signs of meningeal irritation.

Symptoms of increased ICP.

Intellectual deterioration and psychiatric presentations also occur.

Clinical Features Calcific Cysts

Clinically active. Seizures and focal neurologic symptoms

Periodic or episodic peri-lesional edema

May be associated with severe symptoms including seizures and focal neurologic deficits

Clinical Features Cysticercal Encephalitis

Massive cysts in the brain parenchyma,

An intense immune reaction can occur,

Encephalitis and diffuse brain edema. Fever, headache, and hydrocephalus, with vomiting,

impaired consciousness, reduced visual acuity, and seizures.

Spontaneously, or provoked by therapy that causes a large number of cysts to degenerate.

This presentation is most common in children and young females for unknown reasons.

Clinical Features Subarachnoid Cysts

27-56%

Cysticerci that lodge in the sub-arachnoid space may grow to 10 cm or more since they are not limited by pressure from the brain parenchyma.

Meningeal inflammation and abnormal thickening of the leptomeninges at the base of the brain can result, which can lead to entrapment of the cranial nerves manifest as visual field defects and cranial nerve palsies.

Hydrocephalus can also develop from arachnoiditis and secondary occlusion of the foramen of Luschka or Magendie.

Inflammation can also involve the walls of blood vessels, leading to a proliferative angiitis and vascular obstruction with secondary cerebral infarcts. Focal neurologic motor signs, ataxia, and sensory dysfunction can result, and this presentation tends to be associated with a relatively poor prognosis.

Clinical Features Racemose Cysticercosis

Is characterized by proliferating lobulated cysts without scolices,

Usually found in the ventricular system and sub-arachnoid space.

These cysticerci undergo disproportionate growth of their membrane, with extensions of membranes that group in clusters resembling bunches of grapes.

Infrequent, but the most serious; associated with

arachnoiditis, basilar meningitis and hydrocephalus.

Clinical Features Ventricular Cysts

Floating freely or attached to the choroid plexus.

10 to 20 percent of patients.

Inflammatory responses > granular ependymitis > obstructive hydrocephalus and raised intracranial pressure of gradual or acute.

Associated symptoms; seizures, focal neurologic signs or dementia.

Mobile cysts in the forth ventricle > intermittent obstruction > leading to episodes of sudden loss of consciousness related to head movements (Bruns' syndrome).

Clinical Features Spinal cysticercosis

1 to 3 percent of cases of NCC.

Intra-medullary or in the sub-arachnoid space. Extra-medullary more common.

Lesions in the thoracic segments are most common.

Inflammatory & demyelinating changes in the peripheral nerve roots.

Patients typically present with radicular pain or paresthesias and may also have sphincter disturbances.

Cysticercosis at other sites Occular

1-3% often asymptomatic

Sub-retinal space or vitreous humor

exclude by a proper ophthalmologic examination in all patients with NCC prior to initiating therapy

Inflammation around degenerating cysticerci threatens vision

chorioretinitis, retinal detachment vasculitis.

Cysticercosis at other sites Subcutaneous and intramuscular cysticercosis

almost any body site, muscle(10%), subcutaneous tissues(75%). usually asymptomatic, subcutaneous pea-like nodule. more common in patients from Asia & Africa than from Latin

America.

heavy muscle involvement > acute myopathy

SC calcification can be detected incidentally with routine X-rays

Cysts in the heart may be asymptomatic or may result in arrhythmias and/or conduction abnormalities

In general History

Asymptomatic Epilepsy Headache Intracranial HTN Stroke Neuro-psychiatric Hydrocephalus Others

Intra-sellar Spinal Ocular systemic

Physical examination Cognitive decline Dysarthria Extra-ocular movement palsy

or paresis Hemiparesis or hemiplegia,

which may be related to stroke, or Todd paralysis

Hemi-sensory loss Movement disorders Hyper/hypo-reflexia Gait disturbances Meningeal signs

Diagnosis Extent of work-up depend on clinical

presentation. Incidental finding during unrelated reasons,

Seizures or neurologic symptoms, further investigation.

Routine lab tests Imaging Serology CSF examination Pathology Others Criteria

Diagnosis Routine lab tests.

Non specific CBC and liver function tests.

Moderate eosinophilia is occasionally present.

Stool examinations eggs are typically not found.

Plain x-ray. SC nodules.

IC calcification.

Diagnosis CT/MRI.

Nonspecific, other brain lesions, abscess or malignancies.

Pathognomonic lesion = scolex identified as a mural nodule within the cyst.

MRI preferred over CT. Sensitive in detecting small lesions, Brainstem or intra-ventricular lesions, Better for visualizing the scolex.

Diagnosis Serology.

Anti-cysticercal antibodies/ cysticercal antigens.

ELISA, crude or partially purified antigens, frequently cross-reacted with other helminthic antibodies.

75 percent sensitivity.

EITB, (enzyme-linked immunoelectrotransfer blot assay), uses affinity-purified glycoprotein antigens.

Sensitivity and specificity of 100 and 98 percent. Sensitivity of the EITB falls to <70 % with inactive

calcified lesions or a single cerebral lesion. Serum or CSF, higher sensitivity on serum. Antibodies can persist for years after the death of

parasites,

Diagnosis Serology.

Antigen testing. Detect live parasites. Monitoring patients following therapy. Parasite antigen levels typically fall by three

months after successful treatment.

Diagnosis CSF examinations.

Helpful. Raised intracranial pressure. Normal glucose, mildly elevated protein &

white cell. Sometimes the CSF white cells are

predominantly eosinophils. However, the degree of abnormality in the CSF

depends upon whether cysts are adjacent to or have contact with the sub-arachnoid space.

Serologic testing for anti-cysticercal antibodies or parasite antigens can also be performed.

Diagnosis Pathology.

A single brain lesion with no characteristic scolex. Negative serology. Epidemiology. Cyst location. Skin or muscle lesion.

The cysticercus will appear as. A white fluid-filled bladder about 5 to 10 mm in

diameter. Containing a solid 2 mm long larval tapeworm

scolex.

Macroscopic Pathology

Macroscopic aspect of parenchymatous cysticercus in diverse evolutionary stages: vesicular cysts (straight arrow), colloidal cysts (curved arrow), granulomas (arrow head) and calcifications (open arrow).

Microscopic Pathology

Diagnosis Adapted from Del Brutto et al. (Proposed

diagnostic criteria for neurocysticercosis. Neurology 2001; 57:177–183)

PCR not yet available. Diagnostic criteria. Absolute criteria:

Histological demonstration of the parasite, Cystic lesions showing the scolex on CT or MRI, Direct visualization of ocular parasites by fundoscopic examination.

Major criteria: Lesions highly suggestive of neuro-cysticercosis on neuro-imaging, Positive serum enzyme-linked immunoblot for anti-cysticercal antibodies, Resolution of cysts after therapy after anti-parasitic therapy, Spontaneous resolution of small single enhancing lesions.

Minor criteria: Lesions compatible with neuro-cysticercosis on neuroimaging, Clinical manifestations suggestive of neuro-cysticercosis, Positive CSF ELISA for anti-cysticercal antibodies or cysticercal antigens, cysticercosis outside the CNS.

Epidemiologic criteria: Evidence of a household contact with Taenia solium infection, Individuals coming from or living in an area where cysticercosis is endemic, History of frequent travel to disease-endemic areas.

Definitive diagnosis: One absolute criterion or two major plus one minor and one epidemiologic criterion.

Probable diagnosis: One major plus two minor criteria, One major plus one minor and one epidemiologic criterion, Or three minor plus one epidemiologic criterion.

Absolute CriteriaHooks(open arrow) and the spiral canal (small arrows)

Funduscopic visualization of a sub-retinal cystCystic lesions showing the scolex on neuro-imaging

Massive non-encephalitic neurocysticercosis. Cysticercosis

Working Group in Peru.

Diagnosis PCR not yet available. Diagnostic criteria. Absolute criteria:

Histological demonstration of the parasite, Cystic lesions showing the scolex on CT or MRI, Direct visualization of ocular parasites by fundoscopic examination.

Major criteria: Lesions highly suggestive of neuro-cysticercosis on neuro-imaging, Positive serum enzyme-linked immunoblot for anti-cysticercal antibodies, Resolution of cysts after therapy after anti-parasitic therapy, Spontaneous resolution of small single enhancing lesions.

Minor criteria: Lesions compatible with neuro-cysticercosis on neuroimaging, Clinical manifestations suggestive of neuro-cysticercosis, Positive CSF ELISA for anti-cysticercal antibodies or cysticercal antigens, cysticercosis outside the CNS.

Epidemiologic criteria: Evidence of a household contact with Taenia solium infection, Individuals coming from or living in an area where cysticercosis is endemic, History of frequent travel to disease-endemic areas.

Definitive diagnosis: One absolute criterion or two major plus one minor and one epidemiologic criterion.

Probable diagnosis: One major plus two minor criteria, One major plus one minor and one epidemiologic criterion, Or three minor plus one epidemiologic criterion.

Major Criteria

Lesions highly suggestive of NCC on neuro-imaging studies, including: sub-arachnoid racemose cysts (A), enhancing lesions (B), and parenchymal brain calcifications

CT before (left, top and bottom), 1 month (center, top, and bottom), and 3 months after (right, top and bottom) a 1-week course of albendazole. Note the resolution of parenchymal brain cysticerci as the result of therapy.

Contrast-enhanced MRI (A) showing a small single enhancing lesion corresponding to a colloidal cysticercus. Control MRI (B) was taken 16 weeks after showed spontaneous resolution of the lesion.

Diagnosis PCR not yet available. Diagnostic criteria. Absolute criteria:

Histological demonstration of the parasite, Cystic lesions showing the scolex on CT or MRI, Direct visualization of ocular parasites by fundoscopic examination.

Major criteria: Lesions highly suggestive of neuro-cysticercosis on neuro-imaging, Positive serum enzyme-linked immunoblot for anti-cysticercal antibodies, Resolution of cysts after therapy after anti-parasitic therapy, Spontaneous resolution of small single enhancing lesions.

Minor criteria: Lesions compatible with neuro-cysticercosis on neuroimaging, Clinical manifestations suggestive of neuro-cysticercosis, Positive CSF ELISA for anti-cysticercal antibodies or cysticercal antigens, cysticercosis outside the CNS.

Epidemiologic criteria: Evidence of a household contact with Taenia solium infection, Individuals coming from or living in an area where cysticercosis is endemic, History of frequent travel to disease-endemic areas.

Definitive diagnosis: One absolute criterion or two major plus one minor and one epidemiologic criterion.

Probable diagnosis: One major plus two minor criteria, One major plus one minor and one epidemiologic criterion, Or three minor plus one epidemiologic criterion.

Minor Criteria Lesions compatible with NCC on neuro-imaging studies,

hydrocephalus (A), and multiple filling defect in the column of contrast material in a myelogram (B)

Treatment Intestinal T. solium

Praziquantel is first line treatment for all tapeworm infections

5 to 10 mg/kg in a single dose is administered for taeniasis (T. saginata and T. solium) and diphyllobothriasis;

Efficacy is >95 percent.

Niclosamide an alternative for Taeniasis & other tapeworms.

The recommended dose Is 4 tablets in a single dose (2 g) for adults, 2 tablets (1 g) for children 11 to 34 kg, And 3 tablets (1.5 g) for children >34 kg.

Niclosamide is no longer available in the united states.

Current consensus guidelines for treatment of neurocysticercosis.Clin Microbiol Rev 2002 Oct;15(4):747-56.

A panel of experts recommendations : (i) individualize therapeutic decisions, including whether

to use anti-parasitic drugs, based on the number, location, and viability of the parasites within the nervous system;

(ii) actively manage growing cysticerci either with anti-parasitic drugs or surgical excision;

(iii) prioritize the management of intracranial hypertension secondary to neurocysticercosis before considering any other form of therapy;

(iv) manage seizures as done for seizures due to other causes of secondary seizures (remote symptomatic seizures) because they are due to an organic focus that has been present for a long time.

Treatment Therapy should be individualized

according to the form of NCC Cysticidal drugs, (Praziquantel,

albendazole) Symptomatic drugs, (anticonvulsants,

steroids) Surgical resection of lesions, Placement of ventricular shunts

Treatment  Anthelminthic/ Cysticidal therapy.

Therapy? Which agent? And in whom?

Praziquantel and albendazole.

Treatment If the parasite is dead,

Treatment is directed primarily against the symptoms (e.g., Anticonvulsants for management of seizures).

If the parasite is viable or active Patient has vasculitis, arachnoiditis, or encephalitis,

A course of steroids or immuno-suppressants is recommended before the use of anti-cysticercal drugs.

If only parenchymal, subarachnoid, or spinal cysts are present without the complications mentioned,

Anti-cysticercal treatment can be considered, with the concomitant use of steroids, even in patients with massive brain infection.

Treatment Praziquantel.

Synthetic heterocyclic isoquinolone-pyrazine derivative. 50 mg/kg/d for 15 days, but recommended dosages have

ranged from 10 to 100 mg/kg for 3 to 21 days. It has also been suggested that exposing cysticerci to high concentrations of praziquantel by giving three doses of 25 to 30 mg/kg at 2-hour intervals might be sufficient to destroy the parasites.

50 mg/kg per day for 15 days causes the disappearance of 60 to 70 percent of these cysts three months after administration.

It does not cross the blood-brain barrier well, so CSF levels are only approximately 20 percent of plasma levels.

The cytochrome P-450 hepatic metabolism of praziquantel is induced by corticosteroids, phenytoin and phenobarbital. Thus, serum levels of praziquantel are lowered.

Treatment Albendazole

It does not interact with anticonvulsant medications, and reports suggest coadministration of prednisolone has no adverse effect on albendazole levels

Albendazole was initially administered at doses of 15 mg/kg/d during 1 month. Further studies showed that at similar doses, the length of therapy could be shortened to 1 week without lessening the efficacy of the drug.

15 mg/kg per day [usually 800 mg/day in divided doses] for 15 days results in the destruction of 75 to 90 percent of parenchymal brain cysts

More recent studies have shown that eight days of albendazole therapy is equally as effective as 15 days. It is possible that even a three-day course of albendazole may be sufficient, but these studies are ongoing

Consequently, praziquantel is generally considered to be second-line therapy behind albendazole

Treatment Anticonvulsant therapy.

Indication: seizures or high risk. Carbamazepine or phenytoin can be used. Duration of treatment not settled. Highest risk: degenerating lesions and

inflammation. The disappearance of cysts = better epilepsy

control. Not been proven. Calcified and inactive lesions = focus for seizures. The current practice in most situations is to

continue anticonvulsant therapy for one year (sometimes two) and then stop if a patient has remained seizure-free.

Treatment Corticosteroids.

Are the primary form of therapy for. Cysticercotic encephalitis, angiitis, & arachnoiditis causing

progressive entrapment of cranial nerves. Up to 32mg per day of dexamethasone. May be used in association with mannitol at 2 mg/kg per day. Followed by chronic oral therapy with prednisolone (50 mg/d).

Corticosteroids must be administered before, during, and even some days after the course of cysticidal drugs in patients with.

Giant subarachnoid cysticerci(cerebral infarction), Ventricular cysts (acute hydrocephalus), Spinal cysts, (spinal cord swelling). Multiple parenchymal brain cysts, (massive brain edema).

Simultaneous administration of corticosteroids and cysticidal drugs ameliorate the secondary effects of headache and vomiting that may occur during cysticidal drug therapy.

Treatment Surgical care:

Hydrocephalus due to intraventricular cyst, Ventricular shunt is recommended, followed by surgical

extirpation of the cyst and subsequent medical treatment. Multiple cysts (the racemose) in subarachnoid space,

Surgical extirpation, on an urgent basis, is recommended. Obstruction is due to arachnoiditis,

Placement of a ventricular shunt should be followed by administration of steroids and subsequent medical therapy.

Surgical treatment in the particular case of medically refractory epilepsy due to a single lesion has been reported.

Prevention Screen contacts

Particularly relevant in nonendemic countries

Preventing human tapeworm infections Inspection of pork for cysticerci, which are visible

in raw meat ("measly meat")

Freezing or adequately cooking meat to destroy cysticerci;

Pickling and salting are not adequate

Administering antiparasitic agents to pigs

Prevention Preventing egg transmission to humans.

Education regarding routes of transmission.

Good personal hygiene and hand washing prior to food preparation.

Identifying human carriers of tapeworms, possibly through a history of proglottid passage, and instituting targeted treatment.

Mass community anthelminthic programs to treat tapeworm carriers.

Prevention Preventing infections in pigs.

Confining the animals and not allowing them to roam freely to avoid contact with infectious eggs excreted in human feces.

Improved sanitary conditions and proper disposal of human stool.

Vaccine development. There is no current human vaccine against T. solium.

Pigs actively infected or previously infected with the cyst stage are immune to re-infection with oncospheres, suggesting that vaccination should be feasible.

HIV and T.solium Concurrent infection is expected to occur more frequently

because of the increasing frequency of HIV in endemic areas of cysticercosis.

However, little is known about the influence of HIV infection on the frequency and the clinical course of cysticercosis.

Giant cysts & racemose neurocysticercosis seem to be more frequent in HIV-infected patients

may be secondary to an uncontrolled parasitic growth because of an impaired cell-mediated immune response.

In patients with advanced HIV disease and compromised cell-mediated immunity, NCC may is exist without significant host response and is likely to be asymptomatic. For this reason, in symptomatic patients with CD4 counts under 200 cells/mm3 alternative diagnoses should be considered more likely.