Neurocysticercosis

All About NEUROCYSTICERCOSIS including pathophysiology, treatment guidelines and preventive measures

1. NEUROCYSTICERCOSIS CASE PRESENTATION PRESENTED BY DIYA WILSON VTH PHARM.D 15P02362

2. INTRODUCTION [1] Neurocysticercosis is a neurologic infection caused by the larval stage of the tapeworm  Taenia solium It is the most common preventable parasitic disease of the central nervous system and the most common cause of acquired epilepsy worldwide. The disease is the result of accidental ingestion of eggs of  Taenia solium   (i.e., pork tapeworm), usually due to : contamination of food by people with Taeniasis .  consuming undercooked pork , or contaminated water. The parasite can grow in the brain and spinal cord within the nervous system, causing severe headache and seizures beside other pathological manifestations. 2

3. TYPES [1] The two basic types of neurocysticercosis are: PARENCHYMAL: Associated with headaches, seizures, intellectual impairment, behavioral changes, and hydrocephalus. Impairment of the ability to coordinate voluntary movements (ataxia) and muscular weakness on one side of the body (hemiparesis) may also occur with this form of neurocysticercosis. EXTRAPARENCHYMAL Subarachnoid : associated with chronic inflammation of the membranes covering the brain (meninges) . Intraventricular : causes obstructive hydrocephalus . A variant of this form of cysticercosis known as racemose cysticercosis may occur . Racemose cysticercosis: characterized by accumulation of cysts at the base of the brain potentially resulting in mental deterioration, coma and life-threatening complications. 3

4. EPIDEMIOLOGY [2] The World Health Organization (WHO) lists neurocysticercosis as a “ Neglected Tropical Disease.” It estimates that about 50 million people worldwide have neurocysticercosis and that it causes about 50,000 deaths each year . It is also responsible for more than 50% of the cases of late-onset epilepsy in developing countries . The T. solium taeniasis/cysticercosis complex is endemic in many developing countries in sub-Saharan Africa, Latin America, and Asia. Although T. solium had virtually disappeared in developed countries due to industrialization, improved methods of husbandry, and health checks; Cysticercosis and neurocysticercosis are diagnosed anew in North America, Europe and Australia due to increased immigration from endemic areas.  4

5. 5 Although neurocysticercosis appears to affect men and women equally , there is some evidence to suggest that inflammation around the parasites may be more severe in women than in men.   In addition, despite the fact that neurocysticercosis appears to be the most frequent cause of seizures in children    and adults (peak incidence, 30-40 y), the exact incidence in children is not known . 

6. A complex idea can be conveyed with just a single still image, namely making it possible to absorb large amounts of data quickly. 6

7. INCIDENCE IN INDIA [3] In a community-based survey involving over 50,000 individuals in a district in Tamil Nadu in southern India, NCC was found to be the cause of active epilepsy (at least one seizure in the five years before the survey) in at least a third of the patients  . Based on the results of this large survey, the prevalence of NCC as a cause of active epilepsy in India was calculated to be one per 1000 population . Thus, at least 1.2 million persons in India are suffering from active epilepsy due to NCC. The most common form of the disease in India was the Solitary Cysticercus Granuloma (SCG) ( first identified in 1989) which was seen in up to 60 per cent of patients with NCC. 7

8. 8 The disease is prevalent in all states of India , although the prevalence varies between the states . The National Institute of Mental Health and Neuron Sciences (NIMHANS),Bangalore reported a diagnosis of NCC in 2% of unselected series of epilepsy patients. Low proportion of pork eaters amongst Indian patients is the other unusual feature of the disease and more than 95% of Indian patients with NCC are vegetarians.

9. ETIOPATHOGENESIS [4] NCC is caused by the dissemination of the larval form of the pork tapeworm,  Taenia solium in humans which then form cysts in various organs . When the eggs of  Taenia solium   are ingested by humans , the tapeworm eggs hatch and the embryos penetrate the intestinal wall and reach the bloodstream . The formation of cysts in different body tissues leads to the development of symptoms , which will vary depending on the location and number of cysts. 9

10. RISK FACTORS FOR ACQUIRING NEUROCYSTICERCOSIS [4] Living in areas where the parasite is endemic ( most commonly in rural developing countries where pigs roam freely and come into contact with human feces) Drinking water or eating food contaminated with tapeworm eggs Living in a household where another family member has intestinal tapeworm infection ( taeniasis ). Individuals who have taeniasis and  poor hygiene are also at increased risk of infecting themselves. 10

11. PATHOPHYSIOLOGY [5] 11

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13. 13 STAGE 1: 1-2 week after the oncospheres lodges in the brain, it expands to form a edematous lesion. If the cysts are small in number-does not produce any symptoms If they are many-increased intracranial pressure A diagnosis can rarely be made in this case. During this phase, a protoscolex develops. Patients remain asymptomatic usually in this phase. But those with massive infections uncontrolled seizures and progressive dementia may develop. STAGE 2: Approximately 2 months after ova ingestion, the cystecerci cellulosae matures and the cyst has a protoscolex surrounded by a bladder with clear fluid. The living cyst produces only a mild inflammatory reaction and this protects the cyst from the hosts immune system. The patient remains asymptomatic till the cysts remains viable (around 2-10 years +) until there are massive in number. Neuroimaging done during this stage shows that the cysts do not typically grow beyond their mature size

14. 14 STAGE 3 2-10 years later, the mature cystecercus dies ; the clear fluid becomes thicker and more opaque . Hyaline degeneration and mineralization begins. At this time, the C.cellulosae antigens begins to leak eliciting intense inflammatory response ( this immune response is both humoral and cell-mediated with fibroblasts forming a capsule-like structure around the cysts.) The cyst degeneration takes around 6-18 months Usually the oncospheres lodge in the brain parenchyma but in 10-15% of patients , they lodge in the ventricles or meninges and these do not become typical cysts .

15. 15 Sometimes, the cysticerci lodges in the subarachnoid space and can expand up to 5 cms These giant cysticerci produce focal neurological signs and increased intracranial pressure. Chronic inflammation in the subarachnoid space can cause vasculitis of the traversing arteries , resulting in thrombosis of brain stem & some may develop focal neurological signs from a stroke due to vasculitis. The arachoiditis can lead to lead to obstructive CSF pathways and cause hydrocephalus which leads to patients developing an altered mental status with dementia, confusion and stupor. Patients at this stage show signs and symptoms frequently with the common one being seizures which can be focal or generalized.

16. 16 STAGE 4 At this final stage , the cyst dies spontaneously or from the anthelmentic treatment. The wall collapses, and the cyst becomes a granoulous tissue with a thick collagenous capsule. As time passes, the granulomas calcify , therefore the CT scans show no lesions. As the cyst is already dead, the patient is asymptomatic ; but some patients do develop frequent seizures.

17. 17 SIGNS AND SYMPTOMS [6]

18. COMPLICATIONS [6] Headache, dizziness Stroke Neuropsychiatric dysfunction Cognitive decline Dysarthria Extra ocular movement palsy or paresis Hemiparesis or hemiplegia, which may be related to stroke Hemisensory loss Movement disorders Hyper/hyporeflexia Gait disturbances Death 18

19. DIAGNOSIS [5] HISTORY AND PHYSICAL EXAMINATION : Signs and symptoms caused by NCC are usually not specific. The most common symptoms are : seizures focal findings, headache intracranial hypertension. Focal neurological findings are less common, non-specific and due to a variety of types of lesions and mechanisms.  IMAGING: CNS imaging is essential to establish the diagnosis and to determine the type of disease , emergency measures required , choice of treatments . MRI is much superior to CT scanning to visualize brain structures and anatomy as well as cysts . However CT is superior to detect calcifications. 19

20. SEROLOGY: The best documented and most useful is a serum Western blot employing a specific fraction of  T. solium  cysts. The test is very specific for exposure and/or disease and to confirm the diagnosis. However, it lacks sensitivity in patients with minimal disease  Antigen detection tests using monoclonal antibodies (developed against the closely related  T. saginata ) in a capture ELISA format have been developed. They are specific for current viable infection ,  The concentration of antigen is higher in the CSF than the serum. Levels grossly correlate with the extent of involvement. STOOL EXAMINATION : Taeniasis may be established by detecting T.solium eggs and proglottids in a patient's stool .   20

21. MANAGEMENT [7] 21

22. TREATMENT OF VIABLE INTRAPARENCHYMAL NCC In patients with untreated hydrocephalus or diffuse cerebral edema , management of elevated intracranial pressure alone is required For diffuse cerebral edema treatment should be done using anti-inflammatory therapy such as corticosteroids and surgical approach is required for treatment of hydrocephalus In the absence of elevated intracranial pressure , we recommend the use of antiparasitic drugs in all patients with VPN . For patients with one to two viable parenchymal cysticerci: Albendazole monotherapy :15 mg/kg/day divided into two daily doses for 10–14 days with food (maximum dose of 1,200 mg/day) 22

23. Between the second and fifth days of antiparasitic therapy , there is usually an exacerbation of neurological symptoms , attributed to local inflammation due to the death of the larvae. For this reason, both albendazole and praziquantel are generally given simultaneously with steroids in order to control the edema and intracranial hypertension that may occur as a result of therapy. Albendazole (15 mg/kg/day) combined with Praziquantel (50 mg/kg/day) for 10–14 days. Retreatment with antiparasitic therapy for parenchymal cystic lesions persisting for 6 months after the end of the initial course of therapy is required. 23

24. TREATMENT OF DEGENERATING INTRAPARENCHYMAL NCC INCLUDING PATIENTS WITH SOLITARY CYSTICERCUS GRANULOMA (SEL) DUE TO NCC Patients with multiple enhancing lesions and seizures be initially treated with antiepileptic drugs, antiparasitic therapy, and corticosteroids. Albendazole (15 mg/kg/day in twice daily doses up for 1–2 weeks) with meal Patients with SEL treated with antiparasitic drugs should also be treated with corticosteroids initiated before antiparasitic therapy . 24

25. TREATMENT OF CALCIFIED PARENCHYMAL NEUROCYSTICERCOSIS (CPN) Symptomatic therapy alone is recommended instead of antiparasitic drugs in patients with calcified parenchymal lesions It is suggested that corticosteroids not be routinely used in patients with isolated CPN and perilesional edema. In patients with refractory epilepsy and CPN, evaluation for surgical removal of seizure foci is recommended 25

26. MANAGEMENT OF OCULAR CYSTICERCOSIS (OC) Intraocular cysticerci should be treated with surgical removal rather than with antiparasitic drugs. 26

27. CORTICOSTEROIDS [8] Corticosteroids are frequently used to decrease neurological symptoms due to the death of the parasite and are the primary management for chronic cysticercosis arachnoiditis (Upto 32 mg of dexamethasone per day is needed to reduce the brain edema accompanying this condition.) Administration of adjunctive corticosteroid therapy should begin before antiparasitic drugs . The most frequent regimen is dexamethasone at doses of between 4.5 and 12 mg/day. Prednisone at 1 mg/kg/day may replace dexamethasone when long-term steroid therapy is required. Mannitol, at doses of 2 g/kg/day, is also used for acute intracranial hypertension secondary to neurocysticercosis. 27

28. ANTI-SEIZURE MEDICATIONS Antiepileptic drugs are recommended in all NCC patients with seizures. Seizures secondary to neurocysticercosis usually respond well to first-line antiepileptic. Seizures are often well controlled with a single antiepileptic drug (AED). 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.   Recurrence of seizures after AED withdrawal is correlated with the presence of multiple lesions prior to starting cysticidal therapy, and persistence or calcification of lesions after therapy. In patients with few seizures before antiparasitic therapy , resolution of the cystic lesion on imaging studies, and no seizures for 24 consecutive months , tapering off and stopping antiepileptic drugs can be considered . 28

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30. SURGERY Surgical procedures are key in the treatment of complicated disease such as neuroendoscopy open surgery shunt placement. Neuroendoscopy is useful to remove cysts that are easily approached and causing symptoms; this may prevent prolonged use of corticosteroids and anthelminthics.  A treatment series of 4th ventricular lodged cysts, suggested medical therapy, sometimes requiring a shunt to control hydrocephalus, could successfully be employed. 30

31. HYPOTHETICAL CASE [9] 31

32. SUBJECTIVE NAME : Mr.X AGE : 38 years SEX : Male CHIEF COMPLAINTS : An episode of convulsion, presenting without fever or other neurological symptoms 32

33. PAST MEDICAL HISTORY: Six years previously, he had been admitted to the emergency department after collapsing. A cranial computed tomography (CT) scan revealed multiple punctiform calcifications in both cerebral hemispheres and in the cerebellum, surrounded by a small cyst and with an eccentric position, suggestive of parasitic infestation - cysticercosis. SOCIAL HISTORY: His last trip to Cape Verde had been two years previously. He has a history of alcohol and tobacco dependence. 33

34. PAST MEDICATION HISTORY: On the infectious diseases ward, treatment began with Albendazole and Dexamethasone. Beyond cysticidal treatment for NCC, Carbamazepine was started as the diagnosis of secondary epilepsy was established . 34

35. OBJECTIVE Physical examination: He had undergone a cranial CT scan ( Figs. 1 and 2 ,3) that showed similar findings to those found 6 years earlier. 35

36. 8 days later: He presented with sudden onset of left eyelid edema and left ocular pain that increased with horizontal eye movements. An orbital CT scan revealed thickening and densification of the left lateral rectus muscle ( fig. 4) with an apparent cystic lesion with hypodense centre, suggestive of infiltration by cysticercosis. 36

37. LABORATORY PARAMETERS 37 PARAMETERS PATIENT VALUES REFERENCE Haemoglobin 136 g/L 138 to 172 g / L WBC 6.57 × 10 9 /L (4.5 to 11.0 × 10 9 /L). Neutrophils 82% 40% to 60% Eosinophils 0.3% 1% to 4% Platelets 228 × 10 9 /L 150 to 400 ×  10 9 / L C-Reactive Protein 3 mg/L < 3.0 mg/L Bilirubin 17.1 μ mol/L, 1.71 to 20.5  µmol / L Alkaline Phosphatase 63 IU/L, 20 to 140 IU/L

38. ADDITIONAL DATA The patient’s carbamazepine levels were measured to assess his medication adherence Carbamazepine level <0.5 mg/L [Normal therapeutic range: 4-12 mg/L] 38

39. ASSESSMENT Intra –Ocular cysticercosis & Seizures related to Neurocysticercosis & Non-compliance to Carbamazepine. 39

40. PLAN [9] INITIAL PLAN: He was treated with dexamethasone 10 mg 8/8h, carbamazepine, albendazole and, 4 days later, praziquantel. 8 DAYS LATER: AFTER DIAGNOSIS OF INTRA-OCULAR CYSTICERCOSIS Analgesia was started, and the dexamethasone dose was increased from 10 mg 8/8h to 10 mg 6/6h, with significant clinical improvement. The patient was discharged and the outcome was favourable. At re-evaluation, he continued taking carbamazepine, and confirmed no recurrence of seizures or ocular symptoms. 40

41. INTERVENTIONS [7,9] In the initial treatment plan, it was already understood that the patient had calcified cysts and was still administered anthelminthic drugs. According to the 2017 Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) : Anthelminthic treatment is not indicated in calcified NCC because parasites are non-viable and only consist of calcified encapsulated cyst remnants along with varying degrees of host inflammatory reaction. Also , Medical treatment has no role in the management of intraocular cysticerci due to the potential sight-threatening side-effects of toxin release following the death of the parasite. Surgical treatment is the best choice in intraocular cysticercosis, 41

42. In this patient symptoms started 8 days after beginning treatment. Symptom exacerbation is common during the first week after antiparasitic treatment is initiated. The use of steroids is important at this point in order to decrease the effect of the strong inflammatory response, secondary to the release of toxins following the death of parasite. Steroids should have been administered for around 3 days before the cysticidal drugs are started, then continued for approximately 1 week following the end of the course. It is also likely that the dose of steroids was probably not sufficient. The combination of albendazole and praziquantel increases the parasiticidal effect in patients with multiple brain cysticercosis and are ineffective against calcified cysts. Hence antiparasitic therapy should be discontinued. 42

43. MY PLAN [7,11 13] Stop the antiparasitic treatment Dexamethasone :10 mg q 6 th hourly for a week Carbamazepine :200 mg orally twice a day. Continue for a period of 2 years. Surgical removal of calcified cysts and intraocular cyst 43

44. PATIENT COUNSELING REGARDING DISEASE [10] Neurocysticercosis is a preventable parasitic infection of the central nervous system and is caused by the pork tapeworm  Taenia solium . Humans become infected after consuming undercooked food, particularly pork, or water contaminated with tapeworm eggs, or through poor hygiene practices. 44

45. REGARDING DRUGS [11] Carbamazepine should not be stopped suddenly Carbamazepine may affect your judgment and slow your reaction time so be cautious when driving a vehicle or operating machinery. Do not drink alcohol while you are taking carbamazepine because this may increase the sedative effect of carbamazepine. Carbamazepine may cause hyponatremia (low sodium levels) Tell your doctor if you experience any symptoms such as a headache, confusion, new or increased seizure frequency, weakness Tell your doctor if your mood becomes depressed, or you start having thoughts of suicide or self-harm while taking carbamazepine. 45

46. REGARDING LIFE STYLE MODIFICATION [12] Wash your hands with soap and warm water after using the toilet, changing diapers, and before handling food Teach children the importance of washing hands to prevent infection Wash and peel all raw vegetables and fruits before eating Use good food and water safety practices while travelling in endemic countries such as: Drink only bottled or boiled (1 minute) water or carbonated (bubbly) drinks in cans or bottles Filter unsafe water through an “absolute 1 micron or less” filter & dissolve iodine tablets in the filtered water [“absolute 1 micron” filters can be found in camping and outdoor supply stores] 46

47. MONITORING PARAMETERS [11,13] 47 DRUG ADR MONITOING PARAMETERS BRAND NAME Dexamethasone Alteration in glucose tolerance, behavioral and mood changes, increased appetite, and weight gain;  Hemoglobin, blood pressure, serum potassium, glucose, bone mineral density DECDAN, DEXONA, WYMESONE  Carbamazepine Nausea, vomiting, Leucopenia, Dizziness, somnolence CBC with platelet count, liver and renal function tests, urinalysis, BUN, serum sodium TEGRITAL, VERSITOL , ZEPTOL

48. TAKE AWAY POINTS [10] NEUROCYSTICERCOSIS AND TAENIASIS ARE TWO DIFFERENT DISEASES CAUSED BY THE SAME PARASITE When the parasite  T. solium  is transmitted to human beings , it causes an intestinal infection of the adult tapeworm known as taeniasis . Cysticercosis develops when the larvae of  T. solium  invade body and develop in the muscles , skin and eyes . If larvae invade the central nervous system , the infection leads to Neurocysticercosis. T. SOLIUM  WAS RECENTLY NAMED THE FOOD-BORNE PARASITE OF “GREATEST GLOBAL CONCERN” WHO together with the Food and Agriculture Organization recently issued the warning to highlight the importance of cross-sector collaboration in tackling the spread of the disease. 48

49. FOOD HANDLERS CAN ALSO TRANSMIT  T. SOLIUM Neurocysticercosis is not just limited to rural areas or disadvantaged communities lacking basic sanitation. A growing concern is the lack of hygiene practices among food handlers where the practice of regular hand-washing is important. ELIMINATING NEUROCYSTICERCOSIS REQUIRES BREAKING THE LIFE CYCLE OF  T. SOLIUM WHO is working with countries to tailor intensified control strategies for  T. solium  and improve management of neurocysticercosis patients . Fortunately, pigs can now be treated with anti-parasitic medications and vaccinated against  T. solium . This prevents the parasite from being transmitted to humans . 49

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