Cysticidal Therapy for Diffuse Parenchymal and Calcific Neurocysticercosis

ROLE OF COMBINATION CYSTICIDAL THERAPY FOR DIFFUSE PARENCHYMAL AND CALCIFIC NEUROCYSTICERCOSIS (NCC)

Neurocysticercosis is caused by the infection of the human brain with the larval form of the pork tapeworm (Taenia solium). ¹ Headache, seizures, and raised intracranial pressure are the most common presentations, ² and NCC is the most common cause of acquired epilepsy worldwide. ^1,3 Human beings are the only definitive hosts for this parasite, whereas both human beings and pigs function as intermediate hosts. ⁴ The 2017 Infectious Disease Society of America (IDSA)/American Society of Tropical Medicine and Hygiene (ASTMH) guidelines for the diagnosis and management of NCC advocate antiparasitic therapy for viable parenchymal neurocysticerci (VPN), in addition to antiepileptics, analgesics, and anti-inflammatory agents. ² The treatment reduces the likelihood of seizure recurrence and disease progression. ^5–8 Monotherapy with a cysticidal drug (albendazole or praziquantel) is recommended for 1–2 VPN, whereas duotherapy with both is advocated for more than two lesions. ²

Current evidence does not recommend cysticidal therapy and steroids in patients with calcific parenchymal neurocysticerci (CPN) even in the presence of perilesional edema. ² In patients with refractory seizures due to CPN, evaluation for surgical removal is recommended, rather than cysticidal therapy. ² Although no upper limit regarding the number of VPN has been set for treatment with cysticidal therapy, many experts refrain from treating patients with VPN lesion load above 20 or a starry sky pattern on neuroimaging. ⁹ We highlight a potential role for combination cysticidal therapy in patients with diffuse parenchymal NCC (> 20 VPN) with a starry sky pattern, including those with calcific lesions.

Written, informed consent was taken from all patients or their caregivers after explaining the benefits and risks of treatment. All patients underwent magnetic resonance imaging (MRI) of the brain to rule out an intraventricular or subarachnoid NCC, hydrocephalus, diffuse cerebral edema, and raised intracranial pressure. An ophthalmological examination including ocular ultrasonography was performed to rule out intraocular cysts, in accordance with IDSA/ASTMH guidelines. ² Following this, combination cysticidal therapy and steroids were administered on an inpatient basis in the neurology unit. Patients were pretreated with intravenous dexamethasone (0.2 mg/kg/body weight divided into three doses). Oral antiparasitic drugs were initiated 3 days later. Albendazole was started first at a dose of 200 mg once daily, with food, and gradually increased to the target dose of 15 mg/kg/day (maximum: 1200 mg/day), with increments of 200 mg every 3 days (switching to twice daily dosage). Once the target dose of albendazole was reached, praziquantel was started at a dose of 300 mg once daily, and up-titrated by 300 mg every 3 days (switching to twice daily dosage) to the target dose of 50 mg/kg/day. Both were continued for 12 weeks after reaching the desired dose. Dexamethasone, in a dose of 0.2 mg/kg body weight, was given as parenteral therapy for 6 weeks, followed by oral therapy for 6 weeks (to cover all 12 weeks of antiparasitic treatment). Thereafter, it was tapered and stopped over 3 weeks. All patients received concomitant proton pump inhibitors and calcium supplements. Neuroimaging with non-contrast computed tomography (NCCT) head and MRI brain were performed in all patients before starting and 2 weeks after completing treatment. Hemogram, liver, and renal function tests were performed every week, to rule out drug toxicity. Cerebrospinal fluid examination and serum enzyme-linked immunotransfer blot were not performed in any patient, given the typical clinical and radiological findings. Chest X-ray, performed to rule out latent tuberculosis infection, was normal in all patients. Stool examination for ova of T. solium was not performed as many studies have shown it to be either ineffective in detecting carriers or unable to distinguish T. solium from other Taenia species.

CASE 1

A 21-year-old man presented with complaints of intermittent, right hemicranial, moderate intensity headache with nausea without vomiting, photophobia, and phonophobia, lasting for 3–4 hours, and seizures (focal motor seizures with impaired awareness) for 9 months. He was on oxcarbazepine 1,200 mg/day, levetiracetam 3 g/day, and clobazam 20 mg/day, but his seizures remained uncontrolled. He also complained of floaters in the right eye 6 months back when he was diagnosed to have a retinal cysticercal cyst. This was treated with pars plana vitrectomy with cyst excision. Magnetic resonance imaging showed more than 400 multiple cystic ring-enhancing lesions with eccentric scolices and perilesional edema in both cerebral hemispheres.

CASE 2

A 14-year-old boy presented with recurrent seizures (focal sensory seizures with impaired awareness and bilateral tonic–clonic evolution) for 6 months, refractory to polytherapy with phenobarbitone 60 mg/day, levetiracetam 1,500 mg/day, and valproate 1,000 mg/day. Computed tomography showed more than 400 calcific disc lesions in both cerebral hemispheres and left thalamus.

CASE 3

A 33-year-old woman presented with complaints of intermittent, holocranial, moderate-to-severe intensity headache, without nausea, vomiting, photophobia, or phonophobia, lasting for a few hours, and seizures (focal motor seizures with impaired awareness) for the past 1 year. Her symptoms were refractory to treatment with levetiracetam 1,500 mg/day, carbamazepine 1,200 mg/day, and clobazam 15 mg/day. Magnetic resonance imaging showed approximately 40 cystic ring-enhancing lesions with perilesional edema in both cerebral hemispheres.

None of the patients had a history of fever, night sweats, cough, hemoptysis, or weight loss. General physical examination and neurological examination were normal and did not reveal any focal deficits, pallor, cachexia, or lymphadenopathy.

Baseline neuroimaging (Figures 1A–E, 2A, 3A–D, and 4A–D) showed multiple viable and calcified parenchymal neurocysticerci in all patients without any intraventricular/subarachnoid/intraocular cysts. Posttreatment images (Figures 1F–J, 2B, 3E–H, and 4E–H) revealed near-complete clearance of both viable and CPN in all three patients. Case 1 had approximately 10-ring lesions and 21-disc lesions remaining (> 400 at baseline), case 2 had around 40 (> 400 at baseline), and case 3 had 13 (40 at baseline) remaining lesions.

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Magnetic resonance imaging brain. (A) Axial T1-WI, (B) T2-WI, and (C) fluid-attenuated inversion recovery show multiple cystic lesions with eccentric scolices and perilesional edema in both cerebral hemispheres. (D) Some of the lesions show ring enhancement on post-gadolinium T1-WI, (E) whereas some show blooming on susceptibility-weighted imaging. (F) Follow-up T1-WI, (G) T2-WI, and (H) FLAIR image show complete resolution of these lesions with prominent ventricles and sulci, suggesting brain atrophy. (I) No enhancing lesion is seen in post-gadolinium T1-WI (J) along with significant reduction in blooming on SWI.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-1124

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Non-contrast computed tomography (NCCT) head. (A) Multiple calcified disc lesions in both cerebral hemispheres and left thalamus. Follow-up NCCT. (B) Significant resolution of most of the lesions. The cortical sulci ventricles are somewhat prominent compared with first NCCT, suggesting brain atrophy.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-1124

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Magnetic resonance imaging brain. (A and B) FLAIR images and (C and D) contrast-enhanced T1-WI show multiple ring-enhancing lesions with perilesional edema in both cerebral hemispheres. The core of the cystic lesions in getting suppressed on FLAIR images. (E and F) Follow-up FLAIR images and (G and H) contrast-enhanced T1-WI show almost complete regression of most of the lesions.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-1124

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Non-contrast computed tomography (NCCT) head images. (A–D) Before and (E–H) after antiparasitic (for case no 3) treatment showing that the number of calcified disc lesions has regressed significantly.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-1124

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All patients tolerated the therapy without any major side effects apart from weight gain and steroid facies, and were seizure free during and after the cysticidal treatment at 6 months of follow-up. Antiepileptics were not tapered during this time, but in accordance with the IDSA/ASTMH guidelines, this is now being planned after 6 months of seizure freedom, ² following cyst clearance. No drug-related adverse effects such as alopecia, deranged liver function tests, or hemogram were documented.

Despite the evolution of treatment for viable cysts, the treatment of diffuse parenchymal NCC (starry sky or > 20 VPN) or calcific cysts continues to be limited to symptomatic treatment only. There is a fear of inducing cysticercal encephalitis or diffuse cerebral edema if diffuse parenchymal NCC is treated with cysticidal drugs and calcified cysts are presumed to be dead.

All our patients had diffuse parenchymal NCC with calcified cysts and were suffering from drug-refractory epilepsy which impaired their vocation or activities of daily living. These patients are most likely to be left untreated, based on existing practices. After carefully weighing the risks and benefits, they opted for treatment with a combination of cysticidals and had a remarkable outcome.

The rationale of using dual antiparasitic treatment was based on the findings that treatment with a single drug resulted in approximately 65% cyst clearance and complete resolution in less than 40% after a single course. ^10,11 Praziquantel acts by inducing muscle contractions, paralysis, and cytoskeletal damage, whereas albendazole causes microtubular degeneration, resulting in energy depletion and eventual death. ^12,13 Combining the two drugs has been based on this difference in their mechanisms of action, and the combination has been proven to be superior to single-drug therapy in trials. ^14,15 This is the basis of the new recommendation of dual therapy for individuals with greater than two viable cysts. ² However, in these clinical trials, patients with lesion load of > 20 were excluded because of fear of posttreatment inflammation triggering complications. ^14,15 Pandey et al. ¹⁶ studied the effect of albendazole monotherapy in patients with a combined CNS and non-CNS lesion load of more than 20 viable cysts (median 25) with a favorable clinical and radiological outcome. The brain load of cysticerci in their patients is not mentioned. We have not come across any other study, which used dual antiparasitic therapy with such a high lesion load (∼400 cysts).

The death of the cyst(s) after therapy results from the direct action of the drug(s) and also the effects of the host immune response to antigens released during treatment-associated damage. ¹⁷ Although the host immune response maybe crucial in cyst clearance, a pronounced immune response in the first few weeks after treatment initiation can lead to worsening of symptoms. Concomitant corticosteroids prevent this paradoxical response. ¹⁷ Of note, multiple calcific lesions in our patients disappeared with treatment. Calcific neurocysticerci have shown inflammatory reactions during antiparasitic therapy. ¹⁸ Gupta et al. ¹⁹ demonstrated a scolex and contrast enhancement using relevant MRI sequences in 14 patients diagnosed to have a solitary calcific NCC on NCCT head. This suggests that lesions appearing calcified may not be completely calcified. This also explains the intermittent perilesional edema that is seen with calcific forms of NCC, as cysticercal antigens leak through a pervious incomplete calcific cyst wall invoking an inflammatory response. Antiparasitic therapy might also act through the same breach leading to an inflammatory response and eventual cyst clearance. The histopathology of calcific NCC has never been systematically studied. Nash et al. ²⁰ have described a patient who underwent resection of a calcific lesion from the right frontal lobe. Histopathology revealed a degenerated cysticercus with intense intracystic and capsular inflammatory response but little or no calcium. However, dense concentrations of calcareous corpuscles were present, which are pathognomonic for cestodes. Also, any lesion having a Hounsfield value > 80 on CT is considered as calcific, irrespective of the mineral present in the lesion. ²¹ A significant disappearance of cysts, including calcified ones, in our patients raises a question of whether calcification is sine qua non with dead cysts or may also house live cysts. Two types of calcifications: amorphous calcification with little inflammation and calcareous calcification in degenerated but still recognizable cysts, has been reported. ²⁰ The presence of calcareous corpuscles indicates that they may be amenable to treatment with anti-helminthic therapy. We hypothesize that a significant number of calcific lesions in NCC may contain calcareous calcifications and they may respond to dual anti-helminthic therapy (albendazole and praziquantel), as shown in our cases.

Antiparasitic treatment has been found to improve both the prognosis of the NCC-induced seizure disorder and the disease per se. ^5,6,14,15 Patients with high lesion loads may benefit from this form of treatment. The fear of complications exists, but these can probably be avoided by a very slow up-titration of the cysticidal drugs under cover of steroids. We provide proof of concept for combination treatment with dual antiparasitic therapy and corticosteroids in patients with diffuse or calcific NCC. The safety and efficacy of treating patients with high lesion load or calcific NCC should be tested in a randomized controlled trial.