Neurocysticercosis

BRAIN INFECTION

1. NEUROCYSTICERCOSIS DR. SUBODH KUMAR MAHTO PGIMER,DR.RML HOSPITAL. NEW Delhi

2. Introduction Pathogenesis Classification Clinical presentations Investigations Diagnostic criteria Differential diagnosis Treatment

3. Introduction- History Neurocysticercosis is an ancient disease Hippocrates recognised human tapeworms Aristotle compared their appearance to hail stones Kuchenmeister in 1855 confirmed larval stages Van Beneden demonstrated cysticerci in the pig muscles.

4. Introduction NCC is the infection of the CNS by the larvae of Taenia solium . Neurocysticercosis (NCC) is the most common parasitic disease of the nervous system. It is the leading cause of adult onset epilepsy (29 % of epilepsy in endemic regions world wide). It is endemic in Central and South America, sub-Saharan Africa, and in some regions of the Far East, including the Indian subcontinent, Indonesia, and China, reaching an incidence of 3.6% in some regions . Of note is the near absence of infection in Muslim countries, where the consumption of pork is forbidden by Islam

5. Figure 2: Worldwide prevalence of neurocysticercosis. Burneo J G et al. CMAJ 2009;180:639-642 ©2009 by Canadian Medical Association

6. Introduction Pathogenesis Classification Clinical presentations Investigations Diagnostic criteria Differential diagnosis Treatment

7. Cestodes / T apeworms Either Taenia solium Human- intermediate host Echinococcosis Sparganosis Coenurosis Human- definitive host Taenia saginata Diphyllobothrium Hymenolepis Dipylidium caninum

8. Taeniasis Solium The pork tapeworm T. solium can cause two distinct forms of infection in humans: Adult tapeworms in the intestine or Larval forms in the tissues ( cysticercosis ). Humans are the only definitive hosts for T. solium ; Pigs are the usual intermediate hosts, although other animals may harbor the larval forms.

9. Mode of infection Hetero-inoculation Eggs from the environment Internal auto-inoculation Regurgitation of the proglottids into the stomach External auto-inoculation From self??

10. Neuropathology Asyptomatic viable cysts Dying cysts Calcified cysts Racemose cysts Meningitis Vasculitis Hydrocephalus Intraventricular cysts Spinal disease Disseminated disease

11. Types of cyst Cysticercus cellulosae : Less virulent Small (<2cm, round, thin walled) In the parenchyma or Subarachnoid space Often remain silent

12. Cysticercus racemose : The racemose ( ie , appearing like a cluster of grapes) form refers to the presence of multiple cysts without a scolex .  May form giant vesicles up to 10 cm in diameter with predilection for basal cisterns Cysticercotic arachnoiditis Presents as hydrocephalus / meningitis Can occlude vessels  stroke Intense inflammation and seizures

13. Neurocysticercosis

14. While in the nervous system, the  T solium  parasite goes through different stages of involution , which include the following : Stage Parasite Host response Cystic or Vesicular stage Viable parasite ( scolex ) Downregulation of host immunity  mild inflammatory reaction Colloidal stage Degenerating scolex Severe inflammatory reaction  granuloma Granular stage Degenerated scolex Astrocytic gliosis Calcified stage Calcified nodule Intense gliosis around the cyst

15. Introduction Pathogenesis Classification Clinical presentations Investigations Diagnostic criteria Differential diagnosis Treatment

16. Classification Anatomical classification Sotelo et al Carpio et al Chorobski

17. Anatomical classification: ( Sorvillo et al., 1992) Parenchymal NC Ventricular NC Basal meningites Mixed forms

18. Sotelo et al classification Active forms Arachnoiditis Hydrocephalus secondary to meningeal inflammation Parenchymal cysts Brain infarction secondary to vasculitis Mass effect due to large cyst or cyst clumps Intraventricular cysts Spinal cysts Inactive forms of NC Parenchymal calcifications Hydrocephalus secondary to meningeal fibrosis

19. Carpio et al Active form Live, viable parenchymal or extraparenchymal cysts, rarely produces symptoms apart from the rare instance of mass effect Transitional form Symptomatic seizures occur with this form. Degenerating subarachnoid cysts produce meningitis, arachnoiditis and hydrocephalus, ventricular cysts lead to acute hydroephalus Inactive form Single or multiple parenchymal calcifications or hydrocephalus secondary to meningeal fibrosis.

20. Chorobski classification Group Clinical features Surgical implications Group I Space occupying intracranial tumor like behaviour producing focal neurological manifestations and ultimately raised ICT Exeresis often indicated Group II Diffuse cerebral syndrome due to numerous cysticerci leading to cerebral edema, intracranial hypertension, organic brain syndrome Exeresis rarely useful but may be undertaken in life threatening conditions Group III Basasl meningeal or ventricular cysticerci giving rise to hydrocephalus and intracranial hypertension, rarely focal signs and mental disturbances. CSF diversion procedure

21. Introduction Pathogenesis Classification Clinical presentations Investigations Diagnostic criteria Differential diagnosis Treatment

22. Clinical features Neurocysticercosis is a pleomorphic disease Most symptomatic patients are 15–40 years old, and the disease has no gender or race predilection Many are asymptomatic (80 %) Peak is estimated to occur 3-5 years after infection The onset of symptoms is usually subacute to chronic , with the exception of seizures, which present in an acute fashion

23. Cysticerci can be found anywhere in the body but are most commonly detected in the brain, cerebrospinal fluid (CSF), skeletal muscle, subcutaneous tissue, or eye. Physical findings depend on where the cyst is located in the nervous system. Symptoms are mainly due to mass effect, inflammatory response, or obstruction of foramina and ventricular system of brain.

24. Parenchymal NC Epilepsy It is the most common presentation (70%) of neurocysticercosis It is the leading cause of adult-onset epilepsy . SPS, GTC >> CPS Risk of seizures in seropositive individuals 2-3 times higher than seronegative controls. Headache , nausea, vomiting Strokes Lacunar infarcts and large cerebral infarcts due to occlusion or vascular damage. Hemorrhage can also occur as a result of rupture of mycotic aneurysms of the basilar artery.

25. Frontal lobe involvement Psychosis, dementia, parkinsonism, intellectual impairement Cerebellar ataxia Encephalitis and diffuse brain edema Common in children and young females Risk of developing severe neurological sequelae

26. Intraventricular Constitutes 5-10% 4 th ventricle most common site of obstruction Lateral ventricular cysts less likely to cause obstruction Hydrocephalus without localizing signs Bruns ’ syndrome : Unattached cysts may cause sudden positional mechanical obstruction causing nausea, vomiting and vertigo.

27. Meningeal cyst Meningeal Irritation signs Raised ICT from inflammation, edema

28. Intracranial hypertension: Obstruction of CSF flow by basal or ventricular cysticercosis . May also be due to large cysts displacing midline structures , granular ependymitis , arachnoiditis , or the so-called cysticercotic encephalitis caused by the inflammatory response to a massive infestation of cerebral parenchyma with cysticerci . Patients may have seizures and deterioration of their mental status, mainly due to the host's inflammatory reaction.

29. Neuropsychiatric disturbances They appear to be related more to the presence of intracranial hypertension than to the number or location of parasites in the brain . Hydrocephalus(10-30%) Communicating hydrocephalus due to inflammation and fibrosis of the arachnoid villi or inflammatory reaction to the meninges and subsequent occlusion of the foramina of Luschka and Magendie . Noncommunicating hydrocephalus may be a due to intraventricular cysts.

30. Presentations of other forms of neurocysticercosis Intrasellar neurocysticercosis : ophthalmologic and endocrinologic manifestations mimicking those of pituitary tumors . Spinal neurocysticercosis : It is a rare manifestation (1-3%) Thoracic lesions the most common . E xtramedullary form : most frequent and is responsible of symptoms of spinal dysfunction such as radicular pain, weakness, and paresthesias . Intramedullary presentation may cause paraparesis , sensory deficits with a level, and sphincter disturbances .

31. Ocular cysticercosis (1-3%) Most commonly in the subretinal space. Patients may present with decreased visual acuity, visual field defects, or monocular blindness.

32. Systemic cysticercosis It is most common in the Asian continent. The parasites may be located in the subcutaneous tissue or muscle. Peripheral nerve involvement as well as involvement of the liver or spleen have been reported.

33. Introduction Pathogenesis Classification Clinical presentations Investigations Diagnostic criteria Differential diagnosis Treatment

34. Peripheral eosinophilia only if cyst is leaking Raised IgE levels

35. Immunologic Testing ELISA : Antibody detection in CSF is more reliable than on serum It is the most widely used test of CSF; It is 87%sensitive 95% specific Also used for serum antibodies detection.

36. Enzyme-linked immunoelectrotransfer blot (EITB) assay Test of choice for detecting anticysticercal antibodies Uses affinity-purified glycoprotein antigens The test is 95% sensitive and 100% specific Superior to both ELISA & PCR Serum testing is more sensitive than on CSF . Disadvantage False-negative in up to 50% of patients with a single cerebral cyst or in those with calcifications alone. May be positive in patients who are exposed to the adult parasite without developing cysticercosis .

37. CSF Analysis Indicated in every patient with a solitary brain lesion . It is insensitive and nonspecific in the diagnosis of cysticercosis Contraindication: Large cysts causing severe edema and displacement of brain structures Obstructive hydrocephalus .

38. Results: Normal: Brain parenchyma lesions, Abnormal : 50-80% case of basal cisterns or ventricular lesions. CSF findings Mononuclear pleocytosis ,  usually not exceeding 200-300 cells/mm3 Normal glucose levels, Elevated protein levels,(50-200 mg/ dL ) Eosinophilia High immunoglobulin G ( IgG ) index, Oligoclonal bands( in some).

39. Stool Examination Taeniasis may be established by detecting  T solium   eggs and proglottids in a patient's stool. Taeniasis and neurocysticercosis coexist in 10-15% of patients with neurocysticercosis . Intestinal taeniasis is very common in patients with massive infestation with cysticerci but without cysticercotic encephalitis . Tapeworm carriers may be identified by examining the stool of the relatives of a patient with cysticercosis encephalitis .

40. CT Scan It is the preferred imaging study for detection of parenchymal calcifications .

41. Stage Cyst wall Scolex Comment Vesicular Non-enhancing Well defined membrane Only one viable scolex Eccentric hyperdense hole-with-dot” appearance Suggestive of viable larva Colloidal Ring Enhancing with perilesional edema Degenerating scolex Fluid becomes more turbid Earliest stage in the cyst involution - larval degeneration Granular Focal nodular enhancing necrotic lesions with perilesional edema Degenerating scolex Eosinophilic structure Bladder and scolex are in various stages of disintegration Calcified Small hyperdense nodules without perilesional edema

42. CT- Vesicular stage

43. CT- Collodal stage: Post contrast ring enhancement

44. CT- G ranular stage

45. CT- calcified stage

46. Cysticercotic encephalitis: Diffuse edema Collapsed ventricles Multiple enhancing parenchymal lesions. Subarachnoid neurocysticercosis Hydrocephalus Basal fibrous arachnoiditis : abnormal leptomeningeal enhancement Cysts within CSF cisterns Multilobulated appearance Behave as mass occupying lesions

47. Cysticercotic encephalitis

48. MRI Imaging modality of choice for : Intraventricular and cisternal / subarachnoidal cysts Very small cysts Cystic degeneration and pericystic inflammatory reaction Newer MRI techniques MRC Magnetic resonance cisternography FLAIR Fluid-attenuated inversion recovery

49. Stage Cyst fluid Perilesional region Other comments Vesicular T1WI: Isointense T2WI: Isointense No edema No enhancement Single : Pea-in-the-pod Hole-with- dot Multiple: Swiss cheese Colloidal T1WI: Hyperintense T2WI: Hyperintense Surrounding edema is T1WI : hypointense T2WI : hyperintense On T2WIs, the hypointense cyst wall stands out between the hyperintense cyst fluid and edema Granular Same as above More edema Thicker ring enhancement Calcified Edema with high signal surrounding low signal cyst

50. CT VS MRI MRI preferred since it is more sensitive in detecting: Small lesions Brainstem, Cisternal cysts  & intraventricular lesions Perilesional edema around calcific lesions Scolex Degenerative changes in the parasite CT scan preferred for Cheaper Small areas of calcifications . Cysticercal infestation of extraocular muscles. * Perform CT scan first followed by MRI in patients with inconclusive findings or in those with negative CT scans where strong clinical suspicion persists .

51. MRI showing a cysticercus in the lateral ventricle , with resultant hydrocephalus

52. Computed tomography shows multiple intracranial calcifications ( starry sky appearance )

53. CT cysternography CT cisternography is reserved for rare refractory cases in which MRI is not diagnostic or is contraindicated.

54. MR angiography Occlusion of intracranial artery in subarachnoid neurocysticercosis

55. Biopsy Biopsy of a subcutaneous nodule or muscle lesion: Demonstration of the organism is diagnostic of cysticercosis .

56. Ultrasonography It is useful in the diagnosis of ocular NCC The cysts are well delineated when they occur in a subretinal location. The cyst wall is well depicted against the vitreous humor, and the cyst elevates the retina. Drawbacks User dependant A cyst without a scolex cannot be differentiated from other cystic lesions of the eye.

57. Brain Biopsy Only in extreme cases. A trial of anticysticercal drugs with follow-up imaging shortly thereafter ( ie , 2 months) is recommended before considering biopsy .

58. Biopsy - Histologic Features A cysticercus is a liquid-filled vesicle with a 3-layer wall and scolex , although the scolex may not be found. The parasite can adopt 3 different presentations The cystic form They are approximately 7 mm in diameter and May be single or multiple. F requent locations : leptomeninges & cerebral cortex . The racemose form (multiple cysts in the basal cisterns) They do not have a scolex . Because of their location, the racemose form can produce hydrocephalus Sometimes they give the impression of an "infiltrative" aspect ( Trelles " canceriform " presentation) M ixed form: presence of both of the cystic and racemose forms .

59. Introduction Pathogenesis Classification Clinical presentations Investigations Diagnostic criteria Differential diagnosis Treatment

60. “ Del Brutto diagnostic criteria”

61. “Del Brutto diagnostic criteria” in endemic areas

62. International Debate over Criteria Category Debate Biopsy Not possible in all suspected patients Ocular Direct visualization rarely reported Scolex Uncommon on CT/MRI Major criteria Majority of Indians have single enhancing, yet this is only a “major” criteria Different DDX CNS tuberculosis, fungal granuloma, malignancies and multiple pyogenic abscesses Serology EITB not available, not sensitive Treatment Albendazole / praziquantel role is unclear Minor” and “ Epi ” Criteria Not specific enough?

63. Indian studies - Conclusion Current criteria more suitable for the patients in regions where both NCC and other CNS infections are uncommon , as opposed to India or other developing countries, which have high prevalence of these.

64. Introduction Pathogenesis Classification Clinical presentations Investigations Diagnostic criteria Differential diagnosis Treatment

65. Classification of intra cranial space occupying lesions Congenital Dermoid , Epidermoid , Teratoma Traumatic Subdural & Extradural haematoma Inflammatory Abscess, Tuberculoma , Syphilitic gumma , Fungal Granulomas Parasitic Cysticercosis , Hydratid cyst, Amebic abscess Schistosoma japonicum Neoplasm

66. Etiological categories Radiological categories

67. Algorithm for diagnosis

68. Cysticercus vs Tuberculoma Cysticercus granuloma Tuberculoma Round in shape Irregular shaped Cystic Solid 20mm or less with ring enhancement or visible scolex Greater than 20 mm Cerebral edema not enough to produce midline shift or focal neurological deficit Associated with severe perifocal edema and focal neurological deficits MRS: choline/ creatine ratio less than 1 MRS: choline/ creatine ratio greater than 1

69. Introduction Pathogenesis Classification Clinical presentations Investigations Diagnostic criteria Differential diagnosis Treatment

70. Treatment options Cysticidal therapy + steroids Corticosteroids alone Supportive Anticonvulsants Anti edema Analgesics Surgery

71. Antiparasites Albendazole superior to Praziquantel Giant cysts Subarachnoid Intraventricular , Spinal Parameter Albendazole Praziquantel Cost Cheaper Costlier CSF penetration Good Poor Efficacy More ( 75-90%) Less ( 60-70%) With anticonvulsants Does not interact Interact With steroids Does not interact Interact

72. Although there are no blinded randomized controlled trials comparing albendazole to praziquantel till now, because of the above reasons, Praziquantel is generally considered second-line therapy

73. Dosage Praziquantel Initial regimen 50 mg/kg/day 15 days Suggested Single parenchymal cyst 3 individual doses of  25-30 mg/kg at 2-hour intervals 6 hours Multiple cyst 50 mg/kg/day 15 days Albendazole Initial regimen 15 mg/kg/day 1 month Suggested Single parenchymal cyst 15 mg/kg/day 3 days Multiple cyst 15 mg/kg/day 1 week Large subarachnoid cysts up to 30 mg/kg/day Prolonged

74. Steroids Antiparasites are generally given simultaneously with steroids to control the edema and intracranial hypertension. Drug Dose Dexamethasone 4.5 - 24 mg/day Prednisone 1 mg/kg/day

75. BEFORE INITIATING Apply PPD . Consider treating with a single dose of ivermectin before beginning corticosteroids, as many patients have risk factors for strongyloidiasis . Look for conditions precluding anticysticidal theraphy .

76. Cysticidal drugs not a first line ?? Cysticercotic encephalitis with hydrocephalus Giant subarachnoid cysticerci Ventricular cysts Calcifications alone Spinal Ocular

77. Treatment concensus

78. Parenchymal- viable cysts Viable cysts Mild (1 to 5 cysts) Antiparasitic treatment + steroids Antiparasitic treatment; steroids used only if side effects related to therapy appear No antiparasitic treatment; neuroimaging follow-up Moderate (more than 5 cysts) Antiparasitic treatment + steroids Heavy (more than 100 cysts) Antiparasitic treatment + high-dose steroids Chronic steroid management; no antiparasitic treatment; follow-up

79. Parenchymal Enhancing lesions (degenerating cysts) Mild or moderate No antiparasitic treatment; neuroimaging follow-up Antiparasitic treatment + steroids Antiparasitic treatment; steroids only if side effects develop Heavy ( cysticercotic encephalitis) No antiparasitic treatment ; high-dose steroids and osmotic diuretics Calcified cysticerci Any number No antiparasitic treatment

80. Extraparenchymal neurocysticercosis Ventricular cysticercosi Neuroendoscopic removal if available. Subarachnoid cysts, including Giant cysts Racemose cysticercosis Chronic meningitis Antiparasitic + steroids, Hydrocephalus  ventricular shunt Hydrocephalus with no visible cysts on neuroimaging Ventricular shunt (no antiparasitics ) Extracranial Spinal cysticercosis Primarily surgical; (anecdotal reports of successful use of albendazole with steroids) Ophthalmic cysticercosis Surgical resection of cysts

81. Anticonvulsants Recommended for patients who present with seizures First seizures due to inflamed cysticercal lesions should be considered acute symptomatic seizures. & should be treated only for the duration of the acute condition. However, treatment may be continued during the period when the inflammatory response is active , which might last several months Should be stopped a fter resolution of the acute lesion Seizures occurring after resolution of edema or calcification of the degenerating cyst should be considered unprovoked , and, long-term AED administration is warranted Should be considered in patients w/ multiple cysts who have no history of seizure activity

82. Anti-epileptics duration ??? Duration remains undefined and depends neither on the type of seizure at presentation nor on other risk factors for recurrence, such as age at onset and number of seizures before diagnosis. Although the usual practice has been to use AED for 2 years seizure-free interval , shorter durations of AED have been proposed. It seems prudent to withdraw anticonvulsants after a 1-year seizure-free interval in cases where the lesion has disappeared and the EEG has normalized; longer durations are needed for those with persistent or calcified lesions.

83. Surgical Intervention Hydrocephalus due to an intraventricular cyst: placement of a ventricular shunt is recommended, followed by surgical extirpation of the cyst and subsequent medical treatment. [16 ] In cases of multiple cysts in the subarachnoid space ( ie , the racemose form), surgical extirpation , on an urgent basis, is recommended. If the obstruction is due to arachnoiditis , placement of a ventricular shunt should be followed by administration of steroids and subsequent medical therapy . Because of frequent shunt dysfunctions due to entry of inflammatory tissue as well as parasitic debris inside the ventricular cavities, Sotelo designed a device that functions at a constant flow without the valvular mechanism of Pudenz -type shunts .

84. Surgical treatment in the particular case of medically refractory epilepsy due to a single lesion has been reported. Neuroendoscopy is a tool with great potential for use in the management of ventricular cysticercosis . Most patients with ocular or spinal lesions require surgical management Surgical intervention also recommended for cysts: Attached to middle cerebral artery Compressing the optic chiasm

85. Follow-up Follow-up imaging study is recommended after 2-3 months following treatment, especially in cases in which anticysticercal medications are used as a diagnostic tool . The use of imaging will guide the requirement of future trials of anticysticercal medication in cases of subarachnoid cysticercosis .

86. TREATMENT OF EXTRANEURAL CYSTICERCOSIS None if patient asymptomatic Surgical excision for intraocular disease Medical therapy for involvement of extraocular muscles or optic nerve . NSAIDs for patients w/ symptomatic subcutaneous or intramuscular lesions . Excision of solitary lesions if NSAIDs fail or not tolerated.

87. Prognosis In most cases , the prognosis is good . Seizures seem to improve after treatment with anticysticercal drugs. The racemose   form is associated with poor prognosis and elevated mortality rate (> 20%). 22% have recurrent seizures. Others include headaches, neurologic deficits related to strokes, and hydrocephalus. Patients with complications such as hydrocephalus, large cysts, multiple lesions with edema, chronic meningitis, and vasculitis do not respond very well to treatment.

88. Treatment vs no treatment There is insufficient evidence to determine whether cysticidal therapy is of any clinical benefit to patients with neurocysticercosis . - R. Salinas, C. Counsell et al. Tropical Medicine and International Health, vol. 4, no. 11, pp. 713–718, 1999 .

89. A meta-analysis of randomized trials searched 764 papers : Evidence indicates that cysticidal drug therapy results in better resolution of both colloidal and vesicular cysticerci , in a lower risk of seizure recurrence in patients with colloidal cysticerci , and in a reduction in the rate of generalized seizures in patients with vesicular cysticerci . -Del Brutto OH, Roos KL, et al.   Ann Intern Med . Jul 4,2006;145(1 ):43-51.

90. Antiparasitic therapy in patients with viable parenchymal cysts is safe and effective ; however, 6 months after treatment, only 38% of patients had cysts that disappeared on neuroimaging in comparison with 15% of patients who used placebo - Garcia et al.   N Engl J Med . Jan 15 2004;350(3 ): 249-58 D isappearance of cysts were seen in 35% of patients with viable cysts in comparison with 12% of the placebo group. In both studies, these differences were statistically significant (p < 0.05 ). - Carpio et al. J Neurol Neurosurg Psychiatry. 2008 Sep;79(9 ): 1050-5

91. Based on these 2 studies, cysticidal treatment using albendazole is effective in terms of disappearance of viable parenchymal cysts in one third of patients But there are no definitive data exist pertaining to combination antihelminthic therapy or whether the use of steroids increases or decreases antihelminthic dosage requirements.

92. PREVENTION Human Tapeworm Infections Inspection of pork for cysticerci Freezing or adequately cooking meat to destroy cysticerci Administering antiparasitic agents to pigs Infection in Pigs Confining animals and not allowing them to roam freely Improved sanitary conditions Egg Transmission to Humans Good personal hygiene and hand washing prior to food preparation Identifying human carriers of tapeworms Mass community programs to treat tapeworm carriers . Possible Vaccine – porcine vaccine currently in the works

93. Conclusion Neurocysticercosis , is the major cause of epileptic seizures in developing countries. Varied clinical presentation preclude clinical diagnosis in most cases and demand Imaging . Amidst controversies, treatment of neurocysticercosis is still dubious . Neurocysticercosis is potentially eradicable . Early diagnosis, individual case based treatment & community measures for prevention remain the corner stones of disease management.

94. Thank you