Ivermectin: Organs and Systems
Cardiovascular
Supine and postural tachycardia with postural hypotension can occur; in one large study, such effects were found in three of 40 patients. In another there was hypotension in 13 of 69 cases, but in some series these effects have not been observed at all. A massive community study in Ghana noted hypotension in only 37 of nearly 15 000 patients treated. Transient electrocardiographic changes are sometimes seen.
Respiratory
In the treatment of Wuchereria bancrofti filariasis in 23 patients with single doses up to 200 micrograms/kg respiratory capacity was evaluated; there was a transient but significant fall in vital capacity some 24-30 hours after administration, apparently due to bronchodilatation. Frank dyspnea occurred in 2% of cases in the study cited above. In other studies, a few patients have developed a transient cough and in others pneumonitic patches have been seen in the chest X-ray.
Nervous system
Headache and vertigo are very common and even usual as part of the flu-like reaction to ivermectin.
A puzzling reaction was recorded in a small hospitalized Canadian population of elderly subjects treated for scabies with a single dose of ivermectin (150-200 micrograms/kg). Within 6 months, 15 of the 47 patients had died. All those who died had developed a sudden change in behavior, with lethargy, anorexia, and listlessness before death. The effect may have been an artefact with some extraneous cause, and it is notable that other groups using this treatment for scabies have not recorded similar reactions.
Loa loa encephalopathy
When treating Loa loa infections on a large scale with ivermectin, the encephalopathy that was a much-feared complication with diethylcarbamazine again seems to occur, especially with heavily infected or older individuals.
For this reason, mass use of ivermectin in areas of endemic Loa loa infection is no longer recommended. Ivermectin appears to promote the passage of Loa loa microfilaria into the cerebrospinal fluid, with a maximum after 3-5 days, followed by an intense allergic reaction to the dying microfilaria. The Mectizan Expert Committee defined a definite case of Loa loa encephalopathy related to ivermectin as having to satisfy two criteria:
- encephalopathy in which there is microscopic evidence of vasculopathy in the brain associated with Loa loa microfilaria;
- the onset of symptoms of disturbed nervous system function within 5 days after treatment with ivermectin, progressing to coma without remission.
A probable case of Loa loa encephalopathy was defined as having to satisfy four criteria:
- coma in a previously healthy individual;
- the onset of nervous system signs within 5 days of treatment with ivermectin progressing to coma;
- an initial microfilaremia of over 10 000/ml, or 1000/ml in a blood sample taken within 2 months of treatment;
- the presence of Loa loa microfilaria in the CSF.
Clinically common features of this condition are impaired consciousness appearing 3-4 days after treatment and lasting for 2-3 days.
There is no consensus on the proper management of ivermectin-associated Loa loa encephalopathy, and it is uncertain if co-administration of glucocorticoids is of any use. In several patients with more severe reactions, conjunctival hemorrhages were seen.
A systematic examination of the conjunctivae in 1682 patients complaining of any adverse reactions showed that these hemorrhages were closely correlated with the pretreatment microfilaria counts. This sign can be found 2 days after treatment and may thus single out patients susceptible to encephalopathy and needing closer follow-up. Although the incidence of such cases is very low (in the order of 1 in 10 000 treated patients), this serious adverse effect makes mass treatment of Loa loa infection problematic, and also mass treatment of onchocerciasis in areas in which Loa loa is endemic. To illustrate this point three probable cases of Loa loa encephalopathy after ivermectin treatment for onchocerciasis have been described. All three were young men treated with ivermectin 150 micrograms/kg in a mass-treatment campaign in onchocerciasis.
- A 26-year-old previously healthy man developed nervous system symptoms in the form of an inability to stand or eat and stiffness of the neck by the third day. On the fourth day he had difficulty swallowing and speaking. On the fifth day he could not speak and was incontinent of urine. He was given dexamethasone, diazepam, furosemide, and atropine. On the sixth day he became comatose. On the ninth day he developed a high fever, and was given penicillin and tube-feeding. His condition gradually worsened and he died on the 21st day. Serum microfilaria counts on day 13 after treatment were still high (3600/ml), and live Loa loa (10/ml) were found in the CSF.
- A 32-year-old man with alcoholism had a very high pretreatment serum microfilaria count (50 000/ml). After starting ivermectin he took to his bed and would not speak. On the third day he developed a fever, possibly attributed to malaria and treated with chloro-quine. On the fourth day he was unable to stand, and alternately restless or somnolent; his CSF contained live Loa loa microfilaria. He became more incoherent and fidgety and had a marked grasp reflex. Later in the day he developed spastic hypertonia. On the fifth day he became incontinent and still would not speak. Over the following days he gradually improved and 4 months later had no neurological abnormalities, although his relatives found that his behavior had changed and that he was much calmer then in the past. An electroencephalogram on day 15 showed periodic diffuse discharges of large amplitude during hyperventilation and on day 146 an asymmetric tracing with focal activity in the right parieto-occipital area, which worsened during hyperventilation. On day 233 the electroencephalogram was normal.
- An 18-year-old previously healthy man was given ivermectin. On the second day he was unable to work and stayed at home. On the third day he was found unconscious in bed, incontinent of urine and feces. On the fourth day he did not move and had absent pain sensation. There was hypertonia in the arms with marked cogwheeling. On the fifth and sixth days there was a swinging horizontal movement of the eyeballs, but otherwise he appeared to improve. On the seventh day he could stay seated in bed with help and spoke several sentences. He could perform slow voluntary movements and his muscle strength and sensation returned to normal, although the cogwheel phenomenon still persisted. He gradually returned to normal over the following weeks. After 5 months the neurological examination was normal but he still complained of headaches and episodic amnesia. His pretreatment serum microfilaria counts were high (152 940/ml) and the CSF collected on the fourth day contained live Loa loa microfilaria. An electroencephalogram on the 19th day was slow with spontaneous, diffuse, paroxysmal, monomorphic theta activity, lasting 2-3 seconds. An electroencephalogram on the 105th day showed improvement, but focal abnormalities persisted in the left occipital region. On the 159th day all previously recorded abnormalities had disappeared.
Sensory systems
Careful ophthalmological examination shows a striking increase in the number of microfilariae in the anterior chamber of the eye in a significant minority of patients, and a new inflammatory infiltrate can appear during treatment in already damaged areas of the retina. However, no permanent ocular sequelae have been documented. Most of the other ophthalmic symptoms, including edema and local inflammation, are those of the primary infection.
Conjunctival hemorrhages have been recorded in patients living in areas in which loiasis is endemic. Although ivermectin is usually well tolerated, these patients had serious adverse reactions after taking ivermectin, including an encephalopathy similar to that seen after treatment with diethylcarbamazine. In retrospect, these cases all had high Loa loa microfilaremia and Loa loa microfilariae in the cerebrospinal fluid. The authors suggested that ivermectin might have provoked the passage of Loa loa microfilariae into the cerebrospinal fluid. In a subsequent study of 1682 patients with loiasis treated with ivermectin 150 micrograms/kg, conjunctival hemorrhages were found in 41, nine of whom had previously received a microfilaricidal drug. The initial mean Loa loa microfilaremia was 14 900 microfilariae/ml (range 0-182 400; median, compared with 14.5 microfilariae/ml (range 0-97 600; median in those without conjunctival hemorrhage. In addition, male sex and Dipalonema perstans microfilaremia were associated with conjunctival hemorrhages. There was a close relation between conjunctival hemorrhages and retinal lesions. Based on observations in three patients who all developed coma after ivermectin the authors suggested that retinal lesions may reflect what occurs in the cerebral circulation in patients with high Loa loa microfilaremia and neurological problems after ivermectin.
Hematologic
When 28 Sudanese patients were treated with a single dose of ivermectin for onchocerciasis they developed a prolonged prothrombin time, which continued to lengthen significantly during the next 4 weeks; there were no changes in other clotting parameters. After a month, two of them developed hematomas, which continued to enlarge for the next 3^1 days. Both of these patients had received ivermectin 150 micrograms/kg. One was given a transfusion; the swellings in both cases resolved within a week. For a time it was considered that the prothrombin changes observed in some such cases were a potential problem; more recent work suggests that the prolongation of prothrombin ratio is in fact hardly more than with placebo, and that in fact ivermectin merely has a mild effect on vitamin K metabolism and little effect on coagulation. However, lymphadenitis has been noted in a few patients. In one Guatemalan study of biannual treatment of the population to eradicate Onchocerca volvulus infection, upper limb edema was noted in nearly 20% of cases receiving the treatment for the first time.
Gastrointestinal
In the late stages of Strongyloides hyperinfection, ileus can develop and hamper the absorption of oral medication.
A 39-year-old Afro-Caribbean man with stage IVB T cell lymphoma due to HTLV-1 infection had invasive Strongyloides hyperinfection that did not respond to oral ivermectin plus albendazole because of concurrent ileus. He was treated with two 6 mg doses of a veterinary formulation of ivermectin subcutaneously. There were no adverse effects, apart from pain at the injection site.
Urinary tract
Proteinuria is unusual but has been described; it was detected 14 days after a single dose and disappeared during follow-up.
Observations that proteinuria and hematuria may occur in patients with filariasis bancrofti and loiasis, which may exacerbate after treatment with diethylcarbamazine or ivermectin, led to the study of kidney function in patients with onchocerciasis before and after treatment with ivermectin.
The occurrence of renal abnormalities was studied in a population-based study in a meso-endemic village (40% microfilaria carriers), in a group of patients with a generalized or hyper-reactive form of onchocerciasis, and in 46 patients treated with ivermectin in a single oral dose of 150 micrograms/kg. All individuals in all three study groups were examined clinically and had skin snips, serological testing for onchocerciasis, and nodulectomy (when relevant). Tests for malaria, schistosomiasis, intestinal nematodes, and hepatitis B, and serum glucose, creatinine, IgE, and electrophoresis were also performed.
The urine was tested for erythrocytes, leukocytes, protein, nitrites, pH, glucose, ketone bodies, urobilinogen, and creatinine. All the patients underwent renal ultrasound examination. There was no difference in renal function and renal ultrasound between patients with and without onchocerciasis. A raised urinary protein concentration (over 70 mg/g of creatinine) was common and occurred in 47% of the patients with onchocerciasis and 63% of the patients without onchocerciasis. In the 46 patients treated for onchocerciasis with a single dose of 150 micrograms/kg there was a slight but statistically significant increase in total urine protein after 2 and 5 days, especially in 16 patients with high pretreatment skin microfilaria counts. The abnormalities were minor and insignificant. Neither onchocerciasis itself nor treatment with ivermectin was associated with abnormalities of renal function.
Skin
A degree of pruritus, soreness, or burning sensation is common with ivermectin, and rashes or skin edema can occur, while pre-existing conditions of this type can be aggravated. The skin over hematomas can be discolored. Swelling of the limbs and face, like the dermatological symptoms, is probably a reaction to breakdown products of the helminth.
Patients with severe skin involvement (“sowda”) as a facet of their onchocerciasis can experience transient aggravation of the condition, but the course is favorable, and they are less likely to have the same problem if it is later necessary to repeat treatment.
Rashes and swelling of the lymph nodes seem to be more common in patients with AIDS who take ivermectin.
Musculoskeletal
Joint or bone pains are common but usually mild; in one study myalgia occurred in 33% of cases and arthralgia in 33%.
Reproductive system
Orchitis or epididymitis with scrotal tenderness occurs in a few patients as a manifestation of the acute reaction as the parasite succumbs.