The vast majority of patients developing an SAE complained of various symptoms developing within the 12–24 hours following treatment (Day 1, D1). The main complaints were fatigue, which could be severe and accompanied by anorexia, headache, and generalized arthralgia. Among the latter, the patients often complained of severe lumbar pain, which could be objectively appreciated by the characteristic bent-forward walk of the patients. The subjects often said that they were "broken". Stomach pain and diarrhoea have also been reported at D1.

Besides these signs, which are classically reported after ivermectin treatment of patients not infected with Loa loa, but at a lower degree of seriousness, more alarming signs sometimes developed as soon as D1. These were confusion, agitation, dysarthria, mutism, and incontinence. However, more often these signs were reported later, at Day 2 (D2) or Day 3 (D3). In their study, Ducorps et al., 7 measured the Karnofsky performance scale every day during the week after treatment. Among those patients with a pre-treatment Loa microfilaraemia exceeding 30,000 mf/ml, the proportions of patients presenting a functional impairment at D1, D2, D3 and Day 4 (D4), were 4%, 36%, 32%, and 37%, respectively. Thus, it appears that the neurological involvement generally appears first at D2. Although some cases of coma have been reported as soon as D2, this condition usually develops at D3 or D4.

It seems that the various signs related to oral expression (dysarthria, mutism, and confusion) are typical of the condition, as well as incontinence, which usually occurs in the course of development of the symptoms. This incontinence is often only urinary, but faecal incontinence may appear when the condition worsens.

All these signs are usually accompanied by fever, which tends to reach its highest level at D1, but is often reported only at D2–D3. The temperature may rise up to 40°C.

Detailed information on the objective neurological signs shown by the patients has been presented by Boussinesq et al., 5. Very few additional data are available from the medical records and forms from the other cases, even those hospitalized at CHY in 1999. When the cases are appropriately managed, it seems that the worst Glasgow scores are recorded on D4–D5. However, when the patients develop complications (see below), the neurological condition may continue to worsen progressively. A striking feature observed in some patients is the rapid variation with time of the degree of disorders of consciousness. Generally, the patients do not have seizures. The only cases reported so far are Bi. G., a little girl aged 6 years, who had seizures at D13 and D19, without fever; and Ob. JJ, a male 20-years old, whose condition at D2 included generalized itching, followed by disorders of consciousness and later by seizures and vomiting. On systematic examination, motor or sensory deficits were not found, but tendon reflexes were most often abolished or diminished, though they were brisk in some cases. Usually, there was no Babinski's sign, but meningeal signs were found in some patients. The signs most constantly found were extrapyramidal. Hypertonia was frequent, and the cogwheel phenomenon was one of the last signs to disappear.

To summarize, the condition is very variable between cases and, for a given case, may change very rapidly from one examination to another. This variability over time seems to be characteristic of the condition.

Loa microfilaraemia decreases very sharply after ivermectin treatment: in the patients who participated in the study by Ducorps et al., 7, and who had been treated with a single dose of 200 μg/kg, the loads recorded 24, 48 and 72 hours after treatment were about 40%, 25%, and 20%, respectively, of their initial values. The reduction rate is similar whatever the pre-treatment microfilaraemia. After D3, the loads continue to decrease, but in a very slow manner 19.

Ivermectin also provokes a massive Loa microfilaruria, whose incidence is correlated with microfilarial load. During the study reported by Ducorps et al., 7, a Loa microfilaruria was rarely found before treatment, being observed in only 4% of those patients with a microfilaraemia above 30,000 mf/ml. At D1, Loa mf were found in the urine of 24% and 57% of those patients with initial loads of 15,000 – 30,000 and > 30,000 mf/ml, respectively. The values recorded in these two groups were still higher at D3 (54 and 79%, respectively), and then decreased at D4. The microfilarial counts in the urine followed the same pattern over time, as did the prevalence, with a sharp decrease after D4. In all cases, these mf were mobile, and thus alive.

The most characteristic feature of the post-ivermectin Loa-related SAEs is the passage of Loa mf into the CSF. In the study reported by Ducorps et al., 7 Loa mf were found at D1 in the CSF of 17%, 25%, and 13% of the patients harbouring pre-treatment microfilaraemias < 15,000, 15,000 – 30,000, and > 30,000 mf/ml, respectively. The corresponding figures at D3 were 25%, 60%, and 77%. To verify whether these mf were or were not in the CSF before treatment, lumbar punctures were done before treatment in 10 patients with Loa loads above 10,000 mf/ml, none of them had mf in the CSF before treatment, but four showed a microfilarorachia at D3. As in the urine, these mf were alive. It is difficult to assess at what interval after treatment the Loa mf disappear from the CSF. They have been found two weeks after, but the examinations done in the patient of Ducorps et al., 7, who showed counts of 102 and 14 mf/ml of CSF at D6 and D13, respectively, suggest that the densities of Loa mf in the CSF decrease rapidly after one week.

These observations suggest that ivermectin treatment induces the Loa mf to flee from the blood circulation. Such a phenomenon had been reported in patients infected with O. volvulus, and treated with diethylcarbamazine (DEC) 2021.

Before treatment, less than 10% of the patients included in the study by Ducorps et al., 7 showed evidence of microscopic haematuria, whatever their microfilaraemia. This proportion increased progressively after treatment and, by D3–D4, 18% of patients with <15,000 mf/ml, 19% of those with 15,000–30,000 mf/ml, and 35% of the individuals harbouring >30,000 mf/ml developed haematuria. Ivermectin treatment also provoked the appearance of proteinuria, with an incidence of 70% in those patients with > 30,000 mf/ml 7.

Besides the mf (see above), and a moderate increase in the levels of proteins, which is observed in some cases only, no abnormalities have been recorded in the CSF.

The data collected as part of the study published by Ducorps et al., 7 show an increase in the leukocyte counts between D0 (pre-treatment) and D3. The counts varied from 7,120 to 7,280 per mm³ in the group with less than 15,000 mf/ml, from 7,510 to 8,080 per mm³ in the patients with 15,000–30,000 mf/ml, and from 6,960 to 8,100 per mm³ in the individuals harbouring more than 30,000 mf/ml. The same study shows that the eosinophil counts decrease dramatically within the first 24 hours after treatment, and that this decrease becomes more marked as the initial microfilaraemia increases. The counts recorded at D1 in the patients harbouring < 15,000, 15,000 – 30,000 and > 30,000 mf/ml were 84%, 62%, and 50%, respectively, of the pre-treatment counts recorded in these 3 groups. At an individual level, there was a positive correlation between the drop in the microfilaraemia from D0 to D1, and the decrease in the eosinophil counts during the same interval. After this dramatic decrease, the eosinophilia rose again rapidly, and at D3, the values recorded were 120–130% of the initial counts in all the three groups of patients. The changes after D3 were not studied by Ducorps et al., 7, but Martin-Prével et al., 22 reported a marked increase in the numbers of eosinophils 8–10 days after treatment with ivermectin, and then a slow decrease in the counts, with values similar to, and less than half of, the pre-treatment ones, at D23–D33, and D92–D109, respectively.

As indicated above, 52 of the 112 patients included in this study were also co-infected with O. volvulus, but with very low microfilarial loads. We have compared, within each group of patients, defined according to their Loa microfilaraemia (< 15,000; 15,000 – 30,000; and > 30,000 Loa mf/ml), the mean decrease in the eosinophil counts in the O. volvulus snip positive and the O. volvulus snip negative patients. In the two groups with the highest Loa loads, the values were similar, but with a slightly greater decrease in the patients with no skin O. volvulus mf (in the patients with 15,000 – 30,000 Loa mf/ml: decrease of 633 vs. 698 eosinophils per mm³; and in the patients with > 30,000 Loa mf/ml: decrease of 602 vs. 722 eosinophils per mm³). In both groups, the mean Loa microfilarial loads were similar for snip positive and snip negative patients. Thus, it seems that, in this study, infection with O. volvulus played a minor role in the decrease in eosinophilia between D0 and D1, and that the phenomenon can be attributed to the infection with Loa.

Besides these global trends, one should note that in some patients who develop Loa-related post-ivermectin SAEs, a dramatic drop in the eosinophilia can be observed a number of days after treatment. This was the case in two patients reported by Boussinesq et al., 5: the patient described as "case 1" had a nil eosinophilia at D13; and in "case 3" the eosinophil counts at D4 and D7 were 1,700 and 0 per mm³, respectively. This same phenomenon was also observed in two of the patients who were hospitalized at the CHY, in 1999, and who had a full blood count. One of them (Ol. Aw. L.) had 41 eosinophils per mm³ at D6, and the other (On. Ay. S.) had a nil count at D11.

The global changes in eosinophil counts recorded after ivermectin treatment in patients infected with L. loa are similar to those recorded by Ackerman et al., 23 and Cooper et al., 24 in onchocerciasis patients after treatment with DEC or ivermectin. These authors arrived at the conclusion that the "Mazzotti reaction", and its severity, were associated with eosinophil sequestration and activation-degranulation. This feature confirmed previous observations on the preponderant role of eosinophils in the development of the Mazzotti reaction 252627. Similar processes probably play a major role in the initiation of the post-ivermectin Loa-related reactions, however, this may not account for all the signs making up the picture of post-filaricide Loa-related SAEs.

No data are available concerning the changes in the erythrocyte sedimentation rate after ivermectin treatment of patients with Loa loa. In the study by Ducorps et al., 7, a marked increase in the C reactive protein (CRP) was observed within the 3 days following ivermectin treatment. The concentrations increased from 5.0 to 12.0 mg/l in the group with initial loads < 15,000 mf/ml, from 1.0 to 24.1 mg/l in the group with 15,000–30,000 mf/ml, and from 5.0 to 53.3 mg/l in the group harbouring > 30,000 mf/ml. It has also been shown in another study group that the CRP levels decrease between D3 and D7 19. In the study by Ducorps et al., 7, a slight but significant increase in the complement component 3 (C3) has been recorded between D0 and D3: the values changed from 0.71 to 0.74 mg/ml in the group with the lowest Loa counts, and from 0.65 to 0.69 mg/ml in the two other groups.

Ducorps et al., 7 reported a moderate but significant decrease (by about 15%) in the alkaline phosphatase between D0 and D3, whereas the mean values of aspartate and alanine aminotransferases (ASAT and ALAT) remained stable. A moderate increase (by 10%) in the creatine phosphokinase (CPK) was also reported by these authors.

Repeated electroencephalograms (EEG) were done in two patients who participated in the trial by Gardon et al., 4. As indicated by Boussinesq et al., 5, one patient showed, "at D15, periodic occurrence, during hyperventilation, of diffuse discharges of large amplitude; on D146, the tracing was asymmetric and characterized by slow activity with additional spikes, indicating focal activities in the right parieto-occipital area, which worsened during hyperventilation; on D233 the abnormalities had disappeared and the tracing did not show any pathologic activity". The EEG done on D19 on the other patient showed "a slow tracing with spontaneous occurrence of diffuse, paroxysmal, and monomorphic theta activity that lasted 2–3 sec.; the slowing of activity was increased by hyperventilation; by D105 an improvement was recorded but focal abnormalities persisted in the left occipital region, especially during hyperventilation; by D159 all previously recorded abnormalities had disappeared".

These results suggest the existence of a diffuse pathological process in the brain within the first weeks; that lesions are still present 3–6 months after the SAE; and that EEG abnormalities disappear only after this interval. It should be noticed that in the first of the two cases reported, the patient, in spite of his normal EEG after 7 months, may be considered as having mild sequelae. Although this may be regarded as a subjective observation, his relatives said that his mood had changed and that he was significantly calmer than before treatment.

Tomography was performed in two of the cases of Loa-related post-ivermectin SAEs hospitalized at the CHY in April 1999. In one case, the examination was done at D14, and showed a cortico-sub-cortical atrophy (probably related to pre-existing vascular phenomena), and hypodense areas of the brain stem (lateralised at the right side), and in the inner temporal areas (at both sides); there was no sign of cerebral oedema. In the other case, the examination was done 21 days after treatment, and no abnormalities were found.

When appropriately managed, most of the patients developing Loa-related post-ivermectin SAEs recovered completely, without sequelae. The neurological examination became normal after several weeks, usually before one month, the last signs to disappear being the extrapyramidal signs (cogwheel phenomenon). As indicated above, the EEG still showed abnormalities after several months, but became normal within 6–7 months.

If the patients remain confined to bed for a long time they may develop complications, the most frequent one being bedsores. As the latter are most often, in the African context, not appropriately managed, superinfections appear and the patient may die after several weeks from septic complications, dehydration, and malnutrition. Fairly detailed information is available for several patients who died from Loa-related post-ivermectin SAEs, and may be summarized as follows (all patients developed bedsores, which are not noted below): (i) case described in 28: death at D25, due to gastrointestinal bleeding possibly due to corticosteroid treatment; (ii) case 1 of 5: death at D21, partly due to a large abscess on one cheek; (iii) Ol. Aw. L. (dead at CHY in 1999): death at D18 due to a septic shock probably favoured by a pre-existing diabetes; (iv) On. Ay. S. (dead at CHY in 1999): death at D48, from progressive decline; (v) Nt. D. (dead at CHY in 1999): death at D6, high fever, cause unknown; (vi) Tc. J. (dead at Malantouen hospital in 1999): death at D6, high fever, cause unknown.

In other cases, the patients recover progressively, but with more or less severe sequelae. The latter can be summarized as follows: (i) case 2 of 5, change in mood, according to the relatives, calmer than before treatment; (ii) case 3 of 5, episodic amnesia, leading to interruption of school attendance; (iii) Bi. G. (hospitalized at CHY in 1999), dysphasia; (iv) On. A. (hospitalized at CHY in 1999), "scatterbrained and less gallant" than before treatment, according to the family, cogwheel phenomenon; (v) No. JM (hospitalized at Okola Hospital in 1999), walking disorders, cogwheel phenomenon.

These sequelae are a cause of concern, but in all cases they are much less severe than those recorded in patients who developed SAEs after DEC treatment.

Even though it is clear that high Loa microfilaraemia is the main factor associated with the risk of developing a post-ivermectin Loa-related SAE, one may wonder whether other factors may act as co-factors. Our studies show that not all the patients whose Loa loads exceed the threshold of risk develop an SAE. One may also wonder whether some, as yet unrevealed, specific factor exists in Cameroon, where most of the cases of SAEs have been reported.

As suggested by the title of the notice reporting the first case 28, one should first consider the possibility of a direct effect of ivermectin on the CNS. It is known that P-glycoproteins, which are drug-transporting proteins abundant in the endothelial cells of brain capillaries (part of the blood-brain barrier, BBB), limit the entry of ivermectin into the brain of normal animals, by transporting the drug from the inside of the cells to the outside. When treated with ivermectin, animals presenting a deficiency in P-glycoproteins develop a toxicosis related to high concentrations of the drug in the brain 5455. Although the phenomenon would certainly be rare 56, one may imagine that some individuals present a genetic deficiency in BBB P-glycoproteins. The spontaneous occurrence of genetic mutation of BBB P-glycoproteins has been demonstrated in mice 5758, and is frequent in the collie dogs 5960, which are the animals from whom cases of ivermectin toxicosis are the most frequently reported. In addition, a polymorphism of MDR1 gene, associated with a variability of the expression of P-glycoprotein in the intestine, has been reported in humans 61626364. However, there are a number of arguments against the direct implication of ivermectin in the SAEs reported above. First, the clinical picture is very different from the one reported in humans or animals developing an ivermectin toxicosis. In animals, besides the disorders of consciousness, they show ataxia, mydriasis, vomiting, drooling, muscle fasciculations, and apparent blindness, whereas in humans nausea/vomiting, salivation, tachycardia and hypotension are the most frequent signs of overdose 1. None of the SAEs reported after a standard dose of ivermectin developed such a picture. Second, it would be surprising that a mutation in the MDR1 gene would be limited to the geographic areas where the cases of SAEs have been reported.

It is clear that the main factor associated with the risk of post-ivermectin and post-DEC SAEs is the Loa microfilarial load. It is interesting to note that although the outcomes of these events occurring after ivermectin are usually less dramatic than those reported after DEC (i.e. in a simplified manner: 50% death, and 50% recovery with very serious sequelae), the threshold of microfilaraemia above which the encephalopathic process may occur is similar in both cases 30. The processes which take place in the two types of SAE might thus well be the same. If this is the case, and as no pathological information is currently available for post-ivermectin SAEs, most interesting lessons can be drawn from the observations done on autopsy material of post-DEC fatal encephalopathies 65666768. It is considered that these two drugs have different modes of action, but some similarities also exist between them. The fact that they provoke the passage of mf into urine and CSF (and, for O. volvulus mf, into the blood), and that there is a decrease in the eosinophil counts shortly after treatment, are such similar features.

Three main mechanisms could be proposed to explain the post-ivermectin SAEs, and as a matter of fact it is most likely that all of them occur simultaneously. The first one would be an obstructive process at the level of the cerebral microcirculation. The appearance of the retinal lesions described by Fobi et al., 8, which have also been described after DEC, would suggest that a similar phenomenon also occurs in the brain. Whether this obstruction is related to the embolism of great numbers of mf paralysed by the drug, or to other processes is difficult to ascertain. The second mechanism would be that the mf, fleeing from the blood after treatment, go through the brain capillary endothelium and penetrate into the brain tissue. Even if the way in which the mf might do so cannot be explained, it is clear, from pathological observations done on a patient who died from a post-DEC SAE, that Loa mf are indeed able to penetrate into the brain tissue 66. This would explain the diffuse EEG and scan abnormalities which have been observed in those cases which underwent such examinations. In this respect, one may also wonder whether the Loa mf do not cross the wall of the other capillaries to penetrate into all the connective tissues. This would explain the decrease in both the Loa microfilaraemia, and the eosinophil counts observed after ivermectin treatment. The third possible mechanism leading to the post-ivermectin SAEs would be the development of inflammatory processes at the cerebral level. It has been shown that in patients with onchocerciasis or lymphatic filariasis, the post-filaricide inflammatory reactions may be mediated by the release of products of Wolbachia endosymbionts 6970. Indeed, Wolbachia have also been found in Loa loa, but in such low quantity that they are unlikely to contribute to the reactions developed by loiasis patients 71. The inflammatory processes taking place in these patients would thus be probably mainly related to the filariae themselves. The release of Loa antigens, which has been demonstrated after ivermectin treatment 72, may play a role in the process.

If the Loa-related post-ivermectin SAEs are partly related to inflammatory processes similar to the Mazzotti reaction, one might wonder what treatment would be the best to limit the phenomenon. The drugs which are the most often proposed for treatment of post-filaricide reactions are antihistamines and corticosteroids. Studies performed in Ghana have shown that antihistamines and indomethacin are without effect on the Mazzotti reaction occurring after DEC treatment of onchocerciasis patients 7374. Similarly, diphenhydramine was found to be ineffective in preventing reactions developing in patients infected with Wuchereria bancrofti who had been treated with DEC 75. However, Carme et al., 76 have observed that when antihistamines are co-administered with DEC, the severity (but not the incidence) of reactions is reduced; and Samé-Ekobo et al., 77 reported that a daily antihistamine treatment by loratidine, during 10 days, brings about a decrease in the reactions which occurred in onchocerciasis patients treated with ivermectin.

As opposed to the antihistamines, corticosteroids seem most useful for dealing with the post-DEC reactions 27. Anecdotal reports have suggested that these drugs or their related hormones may have beneficial effects 78. It has been shown that starting a course of betamethasone or prednisone treatment 24–48 hours before the first dose of DEC in onchocerciasis patients reduces the severity of the Mazzotti reaction 79. Awadzi et al., 7980 have also demonstrated that treatment with prednisone should be continued for at least 4 days after the first dose of DEC if one wants to avoid the rebound in the reaction after stopping the corticosteroids. However, co-administration of corticosteroids might also delay the destruction of the mf, and reduce the microfilaricidal activity. This is the reason why Stingl et al., 74 evaluated whether starting dexamethasone treatment after the onset of the Mazzotti reaction would have an effect on the latter; these authors concluded that this was indeed so, but that the doses of corticosteroids had to be tapered rapidly.

If the post-ivermectin Loa-related SAEs are partly related to inflammatory processes similar to that associated with the Mazzotti reaction, our results on the changes in the eosinophil counts may suggest that the severity of the reactions could be reduced by administering corticosteroids within the two days following ivermectin treatment. At D3, the pathological processes are already in place, and the use of corticosteroids at that time might be too late to have any affect on the development of the reaction. Most of the cases of post-ivermectin SAEs have been managed using corticosteroids, and it seems that these drugs did not have any beneficial effect on the course of the condition. On the contrary, they may lead to the development of iatrogenic lethal complications. Additional studies should be performed to provide further information on the mechanisms of the post-ivermectin Loa-related SAEs. In this respect, one may consider the possibility of undertaking studies on animal models. The one which would probably reflect most closely what happens in humans would be drills (Mandrillus leucophaeus), mandrills (Mandrillus sphinx) or other monkeys experimentally infected with human Loa loa, and preferably splenectomised to obtain high microfilarial loads 8182838485.