“Neurocysticercosis: Perilesional brain oedema and seizures”

Taeniosis and cysticercosis, diseases caused by the parasitic tapeworm Taenia solium, are distributed worldwide where pigs are eaten and sanitation is poor, and also in the more developed countries as a result of increasing migration. Neurocysticercosis is the commonest parasitic disease of the human nervous system. Immunological assays detect positivity for human cysticercosis in 8—12% of people in some endemic regions, which indicates the presence of antibodies against the parasite but not necessarily active or central-nervous-system infection. The only reliable tool for diagnosis of neurocysticercosis is imaging by CT or MRI. The presence of viable cysts with a mural nodule, associated with degenerative cysts and calcifications, is typical. Classification of neurocysticercosis into active, transitional, and inactive forms gives a good clinical-imaging correlation and facilitates medical and surgical treatment. The main clinical manifestations of neurocysticercosis are seizures, headache, and focal neurological deficits, and it can have such sequelae as epilepsy, hydrocephalus, and dementia. Treatment should be individually fitted for each patient, with antiepileptic drugs, analgesics, corticosteroids, or a combination of these. Anthelmintic drugs (praziquantel and albendazole) are used routinely, but so far no controlled clinical trial has established specific indications or definitive doses of treatment. Parenchymal forms of neurocysticercosis have a good prognosis in terms of clinical remission. The most effective approach to taeniosis and cysticercosis is prevention, which should be a primary public-health focus for less developed countries.

Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case—control study

Neurocysticercosis, which occurs when cysts of the tapeworm Taenia solium form in the nervous system, is a common cause of seizures in developing countries. When the viable cyst degenerates, the remaining lesion can become calcified, and in some cases oedema is seen around calcified lesions. This paper advances understanding of the potential association between perilesional oedema and seizure activity by assessing the occurrence of oedema and seizures in patients with calcified neurocysticercosis in Peru. The greater incidence of oedema in the patients who had seizure relapse compared with patients who were seizure free implicates such oedema in at least a proportion of neurocysticercosis-associated seizures.

Background
Cysticercosis due to Taenia solium is a cause of adult-acquired seizures and epilepsy even in patients with only calcified larval cysts. Transient perilesional brain oedema is seen around the calcified foci but its importance, association with seizures, incidence, and pathophysiology are unknown.
Methods
110 patients with only calcified lesions and a history of seizures or severe headaches were followed prospectively in a cohort design to assess the incidence of seizure relapse. In a nested case-control substudy, perilesional oedema was assessed by MRI at the time of seizure in symptomatic patients and in matched asymptomatic controls taken from the study population.
Findings
Between November, 1999, and December, 2006, 29 patients had an incident seizure during a median follow up of 32·33 (SD 19·99) months, with an estimated 5-year seizure incidence of 36% (95% CI 25% to 49%). 24 of 29 (83%) patients with seizure relapse had an MRI evaluation within 5 days of the event; perilesional oedema was seen in 12 patients (50%) compared with two (9%) of 23 asymptomatic matched controls.
Interpretation
Perilesional oedema is common and associated with episodic seizure activity in patients with calcified neurocysticercosis. Our findings are probably representative of symptomatic patients in regions where T solium neurocysticercosis is endemic and suggest a unique and possibly preventable cause of seizures in this population.(Theodore E Nash, , E Javier Pretell, et al. In The Lancet Neurology, Volume 7, Issue 12, Pages 1099 - 1105, December 2008)

Perilesional brain oedema and seizure activity: cause or effect?
We read the article by Nash and coauthors1 with great interest. In their study, new oedema around calcified lesions occurred in 50% of the participants who had seizures. The authors attributed the oedema to an inflammatory response to calcified granulomas and proposed that this is an important part of the epileptogenesis seen in patients with calcified lesions. However, further characterisation of the nature of the oedema (ie, whether it was cytotoxic or vasogenic) with other MRI modalities was not done.
There is, indeed, substantial evidence to implicate calcified lesions as seizure-causing foci, but whether the presence of perilesional oedema proves this point is doubtful, because seizures per se can also cause oedema.
Reversible peri-ictal MRI abnormalities (RPMA) are well established findings that develop immediately after one or a cluster of seizures and resolve within a few days or weeks of the ictus. RPMA are thought to be a consequence of the epileptic activity, rather than the cause.2—4 When they are confined to the region of the epileptiform discharges seen on EEG, RPMA can be local; when the changes are located in areas that are distant from the region of the epileptiform activity, RMPA can be remote.3, 4 RMPA can be seen as T2-weighted hyperintensity, T1-weighted hypo-intensity, fluctuations in the apparent diffusion coefficient on diffusion-weighted imaging, vasogenic and cytotoxic oedema, contrast enhancement, and evidence of mass effect (sulcal effacement or ventricular compression). Occasionally, the changes might be irreversible.3, 4
The precise pathogenesis of RPMA is unknown. Several mechanisms related to excessive activity of focal seizures, such as hyperperfusion, impaired autoregulation, disruption of the blood—brain barrier, cytotoxic and vasogenic oedema, and excitotoxic cell damage, have been implicated.2, 3 These changes can be seen even after just one seizure and in the ictal-onset zone in non-lesional epilepsy.4, 5 Moreover, in the study by Nash and coauthors, all the patients who had perilesional oedema after a seizure had MRI within 5 days of the ictus, which is the period during which peri-ictal changes are most likely to develop. RPMA must, therefore, be deemed to be a potential cause of the perilesional oedema, and to regard perilesional oedema as an important cause of neurocysticercosis-associated morbidity might be erroneous.
The occurrence of perilesional oedema in the control group, who did not have seizures, is intriguing, and might indicate an underlying subclinical epileptic focus, with the patient being seizure free when on antiepileptic medication. The EEG data could help to resolve this conflict.
The puzzling question of why perilesional oedema occurred in some patients but not in others was also discussed by the authors. Similarly, the question of why only some patients develop RPMA is still unanswered. These changes can first appear days or weeks after seizure onset, which suggests that there is a threshold of seizure duration or severity, below which the changes will not occur. This threshold is likely to vary from person to person and might be affected by many factors, such as: seizure type and location; seizure duration and the severity of ictal discharge; and the characteristics of the host (eg, age, pre-existing disorders, cardiovascular and metabolic reserve, and pharmacological intervention).3 (Abhijit Das, Chandrasekharan Kesavadas In The Lancet Neurology, Volume 8, Issue 3, Page 225, March 2009.)

References
1 Nash TE, Pretell EJ, Lescano AG, et alfor the Cysticercosis Working Group in Peru. Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case—control study. Lancet Neurol 2008; 7: 1099-1105.
2 Briellmann RS, Wellard RM, Jackson GD. Seizure associated abnormalities in epilepsy: evidence from MR imaging. Epilepsia 2005; 46: 760-766.
3 Cole AJ. Status epilepticus and periictal imaging. Epilepsia 2004; 45: 72-77.
4 Raghavendra S, Ashalatha R, Krishnamoorthy T, Kesavadas C, Thomas SV, Radhakrishnan K. Reversible periictal MRI abnormalities: clinical correlates and long-term outcome in 12 patients. Epilepsy Res 2007; 73: 129-136.
5 Oh JB, Lee SK, Kim KK, Song IC, Chang KH. Role of immediate postictal diffusion-weighted MRI in localizing epileptogenic foci of mesial temporal lobe epilepsy and non-lesional neocortical epilepsy. Seizure 2004; 13: 509-516.

Authors' reply
In our article,1 we prospectively evaluated the incidence of perilesional oedema only in patients with neurocysticercosis who had calcified granulomas. Because we found perilesional oedemas in 50% of the patients who had seizures, we made the association between the two. The design and purpose of our study was not to assign cause—the pathophysiology and cause of perilesional oedema are not known—and we reiterated this point in our introduction. In earlier studies,2, 3 there were opportunities to discuss the potential causes of perilesional oedema, including seizure activity itself; however, space limitations prevented an expanded discourse on this in our discussion. We do mention that the “most plausible hypothesis is that oedema is an inflammatory response to the calcified granulomas”; most of the pathophysiology of cysticercosis is caused by the host's inflammatory response to the parasite, and this might be a continuation of that process.
Patients with other types of epilepsy or seizures can have reversible oedema.4, 5 However, even though oedema has been seen at seizure foci, and some oedema are similar to the perilesional oedema seen in patients with neurocysticercosis, for the most part this oedema is associated with status epilepticus or heavy seizure activity,6, 7 and is a rare6 or uncommon occurence.7 The characteristics and patterns of perilesional oedema commonly differ from those of other types of oedema.7 We have shown, universally, the presence of enhancement on MRI8 around the calcification and oedema, which is most intense around the enhanced calcified focus and commonly spreads into the white matter. This pattern suggests angiocentric oedema. A main point of our study is that perilesional oedema is common in patients with neurocysticercosis, but is rare in non-cysticercosis epilepsy. Obviously, neither perilesional oedema associated with calcified granulomas nor oedema associated with non-cysticercosis epilepsy is well characterised, but at this juncture we have pointed out that there are differences. (Theodore E Nash, Hector H Garcia in The Lancet Neurology, Volume 8, Issue 3, Pages 225 - 226, March 2009 )

References
1 Nash TE, Pretell EJ, Lescano AG, et al. Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested case—control study. Lancet Neurol 2008; 7: 1099-1105.
2 Nash TE, Patronas NJ. Edema associated with calcified lesions in neurocysticercosis. Neurology 1999; 53: 777-781.
3 Nash TE, Del BH, Butman JA, et al. Calcific neurocysticercosis and epileptogenesis. Neurology 2004; 62: 1934-1938.
4 Henry TR, Drury I, Brunberg JA, Pennell PB, McKeever PE, Beydoun A. Focal cerebral magnetic resonance changes associated with partial status epilepticus. Epilepsia 1994; 35: 35-41.
5 Meierkord H, Wieshmann U, Niehaus L, Lehmann R. Structural consequences of status epilepticus demonstrated with serial magnetic resonance imaging. Acta Neurol Scand 1997; 96: 127-132.
6 Raghavendra S, Ashalatha R, Krishnamoorthy T, Kesavadas C, Thomas SV, Radhakrishnan K. Reversible periictal MRI abnormalities: clinical correlates and long-term outcome in 12 patients. Epilepsy Res 2007; 73: 129-136.
7 Milligan TA, Zamani AA, Bromfield EB. In: Etiologies of status epilepticus associated with MRI changes. Blackwell Publishing, 2004: 114.
8 Nash TE, Pretell J, Garcia HH. Calcified cysticerci provoke perilesional edema and seizures. Clin Infect Dis 2001; 33: 1649-1653.

(With permission and thanks from The Lancet Neurology)