**6. Encephalopathy in loiasis: clinical features**

Loiasis encephalitis is usually a consequence of treatment with dimethyl carbamizine citrate (DEC) or ivermectin (Mectizan), although it may also occur spontaneously.

#### **6.1 Encephalopathy following treatment**

The symptoms occur gradually, staring 2 days after ivermectin treatment, or after 24-36 hours of DEC treatment. The patient's condition generally becomes serious after 3 to 5 days. The most common manifestations are vertigo, loss of balance, speaking difficulties, arthralgia, abdominal pain, diarrhea, fever, vomiting, diffuse hypertonia, loss of osteotendinous reflexes, no response to pain, conjunctival or retinal hemorrhage, pruritus, neurological disorders with altered consciousness (obnubilation), renal impairment, coma

Indirect diagnosis is based on hypereosinophilia (25%) in general among non indigenous population from endemic zone, and elevated total IgE. As most infected people are amicrofilaremic, indirect methods based on antibody or gene detection are valuable. One of the first such methods was the immunofluorescent antibody test (IFAT) using fixed microfilaria. Others include ELISA detection of specific IgG4 against a crude extract of *Loa loa* worm, a method that appears to be specific and sensitive for both microfilaremic and amicrofilaremic forms (Akue et al., 1994). Its sensitivity and specificity (relative to *Mansonnella perstans*) are reported to be better than 90% for parasitologically proven loiasis in a co-endemic area. However, crude extracts are in limited supply. A luciferase immunoprecipitation system (LIPS) based on detection of IgG to *Loa loa* recombinant antigen L1SXP-1 has been recently developed and shows high specificity but limited sensitivity. A rapid LIPS format improves the specificity by limiting cross-reactivity with *O. volvulus* (Burbelo et al., 2008). The same L1XP-1 antigen was used to develop an ELISA method for the detection of specific IgG4 antibodies, but sensitivity was poor (56%) (Klion et al., 2003). Molecular diagnosis may consist of detecting the ladder R3 gene (Ajuh et al., 1995) of *Loa loa* in DNA extracted from whole blood (Touré et al., 1997). However, although highly specific, the test is impractical in rural areas and non specialized laboratories. In general, these methods, although specific, are not sensitive enough to detect all cases of loiasis and

The treatment of loiasis is based on two major microfilaricides, namely ivermectin (Mectizan® or Stromectol®) and diethylcarbamazine (DEC or Notezine®). With ivermectin, a single dose of 200 µg/kg is sufficient. DEC treatment starts with one-quarter of a tablet (one tablet = 100 mg), then the dose is doubled every day until the maximum dose of 400 mg/day is reached. These treatments must be preceded by precise counting of microfilariae in the patient's blood. If the count is higher than 8000 mf/ml, DEC will be administered at a dose of 8 mg/kg for 21 days under hospital supervision. This treatment is usually combined with antihistamine and corticosteroid therapy during the first week. Proposed chemoprophylaxis includes the use of repellents, and weekly intake of one tablet of DEC (100 mg). Plasmapheresis may be envisaged in case of very high microfilaremia (Muylle et

Loiasis encephalitis is usually a consequence of treatment with dimethyl carbamizine citrate

The symptoms occur gradually, staring 2 days after ivermectin treatment, or after 24-36 hours of DEC treatment. The patient's condition generally becomes serious after 3 to 5 days. The most common manifestations are vertigo, loss of balance, speaking difficulties, arthralgia, abdominal pain, diarrhea, fever, vomiting, diffuse hypertonia, loss of osteotendinous reflexes, no response to pain, conjunctival or retinal hemorrhage, pruritus, neurological disorders with altered consciousness (obnubilation), renal impairment, coma

(DEC) or ivermectin (Mectizan), although it may also occur spontaneously.

*Indirect (presumptive) diagnosis* 

are not available at many points of care.

al., 1983; Abel et al., 1986).

**5. Treatment and prophylaxis of uncomplicated loaisis** 

**6. Encephalopathy in loiasis: clinical features** 

**6.1 Encephalopathy following treatment** 

and death after a few days. Laboratory tests show numerous *Loa loa* microfilaria in peripheral blood, cerebrospinal fluid (CSF) and urine. Loaisis encephalopathy is classified according to the neurological manifestations, their time of onset, and biological findings, in three categories: definite, probable and possible (Scientific working Group on SEA, 2003).

**6.1.1** Definite *Loa loa* encephalopathy: microscopic examination of brain tissue obtained by autopsy or needle biopsy is consistent with *Loa loa* encephalopathy (vasculopathy with evidence of *Loa loa* microfilariae), and onset of central nervous system (CNS) disorders within 7 days of treatment with mectizan, progressing to coma without remission.

**6.1.2** Probable *Loa loa* encephalopathy: encephalopathy (without seizures, usually febrile) in a previously healthy person with no other cause of encephalopathy, and onset of CNS symptoms and signs within 7 days of treatment with metizan, progressing to coma without remission; and >10 000 mf/ml of peripheral blood pre-treatment, or >1000 mf/ml within 6 months post-treatment, or >2700 mf/ml within 6 months of treatment, and /or L. loa microfilariae in CSF.

**6.1.3** Possible L. loa encephalopathy: encephalopathy (without seizures, usually febrile) in a previously healthy person with no other underlying cause of encephalopathy, and onset of CNS symptoms and signs within 7 days of treatment with mectizan, progressing to coma without remission, and semi-quantitatively or qualitatively positive (+, ++ or +++) for L. loa microfilariae in peripheral blood or CSF.

#### **6.2 Spontaneous encephalopathy**

Spontaneous cases are rare but may be under-estimated. A number of apparently cases of spontaneous encephalitis have been been reported ( Bonet ,1943; Gallais et al., 1954; Carayon et al., 1959; Same Ekobo et al., 1981; Tuna Lukiana et al., 2006). In some case described by Kivit (1952), patients might have taken antifilarial drugs. The symptomatology is variable and may start with calabar swelling accompanied by itching, asthenia, facial edema, abdominal pain, diarrhea, violent headache, renal failure, hemiplegia or double hemiplegia, with mental disorders, functional impairment, altered consciousness including coma, usually terminating in sudden death. The process can last between 1 and 3 months, with hyperthermia in some case. The electroencephalogram may be abnormal (Bogaert et al., 1955). Microfilaria will be present in CSF and usually in peripheral blood, with albuminuria, red blood cells and leukocytes in urine (Lukiana et al., 1996).

### **7. Treatment of loiasis encephalopathy**

Treatment of *L. loa* encephalitis is based on nursing, nutritional support and re-hydration. According to Serious Adverse events (SEA) Experts in *Loa loa* endemic areas (Scientific working Group on SAE, 2003) Corticosteroids and antihistamines should be avoided. The reasons for avoidance of corticosteroids are the lack of evidence of efficacy for this condition and potential harmful effect; while the antihistaminic treatment should be avoid because of the lack of efficacy and they sedate patient with a neurologic condition, interfering with diagnosis and neurologic assessment. The protocol suggested here is based on that described by Gardon et al., 1999. It is based on vital monitoring (pulse, arterial pressure, temperature, consciousness (Glasgow score), hydration, complete neurological and clinical examination every hour then every three hours. When the patient is dehydrated and systolic pressure is below 9 cmHg: perfuse 500 ml of Ringer lactate solution over 30 min; if no improvement, continue to perfuse until systolic pressure reaches 10 cmHg and

Encephalitis Due to *Loa loa* 351

neurotoxicity. This deficiency could be caused by genetic polymorphism, deficient glycoprotein P production, or glycoprotein P inhibition. Indeed, severe neurological adverse effects of ivermectin are observed in CF-I mice, that are deficient in MDRIA glycoprotein P (Kwei et al., 1999). Several drug carrier molecules such as MDR, MRP, OATP and glycoprotein P have been detected on the apical and basolateral membranes of epithelial cells in cerebral capillary membranes (Cordon Cardo et al., 1989; Huai-Yun et al., 1998; Kusuhara et al., 1998; Gao et al., 1999). Glycoprotein P is the most widely studied of these molecules. The risk of encephalitis could also be influenced by genetic factors. Indeed, dogs homozygous for a 4-bp deletion of the *MDR1* gene (resulting in premature termination of glycoprotein P synthesis) are highly sensitive to ivermectin (Mealy et al., 2001). In addition, CFI mice exhibiting low glycoprotein P production are more sensitive to ivermectin neurotoxicity than their wild-type counterparts (Umbenhauer et al., 1997). In addition to the neurotoxicity of ivermectin accumulating in the brain, through a deficiency in glycoprotein P or other carriers, neurotoxicity may result from interactions between drugs competing for the same carrier binding site. Other glycoprotein P substrates may compete with ivermectin, leading to a reduction in ivermectin efflux from the brain. This has been demonstrated in mice treated with both ivermectin and cyclosporine (Marques-Santos et al., 1999). It is important to note that ivermectin and DEC both lead to progressive neurological complications in patients with high microfilaremia and also ocular lesions (retinal or subconjunctival hemorrhage) linked to microemboli created by the parasite. It therefore appears that the etiology of *Loa loa*associated encephalitis associated with these two drugs is linked to clumping of dead

microfilaria in vessels, leading to emboli and local vascular inflammation.

Fig. 7. Two views of *Loa loa* microfilariae in blood of an hypermicrofilaremic individual

It seems that the adult worm and microfilaria are both risk factors for spontaneous encephalitis. Adult worms have been implicated in the neuropsychological complications of loaisis in two European patients (Kenny & Hewitt, 1950). In both cases, extraction of the adult worm led to a clinical improvement and to a decline in eosinophilia from 56-50% to 3%. Location of adult worms in the subarachidonic space at the base of the brain has also been implicated in neuropsychological complications (Bertrand-Fontaine et al., 1948). The abundance of microfilaria is an important risk factor, because of their mobility in small

diuresis 1 ml/kg/hour. Perfuse 2000 ml of 5% glucose (including 6 g of NaCl, 3-4 g of KCl, 2 g of calcium) or mixt sera (with 4 g of KCl and 2 g of calcium) for 24 hours for an adult weighing 60 kg, or 500 ml every 6 hours (28 drops/minute). If dehydration persists, perfuse 1000 ml of these solutions over 8 hours, depending on clinical status. In case of fever, add 1 ml of solution per kilogram for each degree above 37°C. In case of coma, the treatment aim is to avoid bedsores, bronchial accumulation and intercurrent disorders, by mobilizing the patient every three hours and massages to prevent complications of decubitus; urinary probing, mouth care with sodium bicarbonate solution, and eye care with 9% NaCl. Pose of orpharyngeal canicle. If the Glasgow score is less than 10/15, transfer to a specialized intensive care unit. If recovery is slow, use gastric gavage with milk, soja…. Complementary examinations are necessary to rule out any other causes of coma (meningitis, hypo- or hyperglycemia, cerebral malaria, etc.), including thick blood smear (to search for *Loa loa* and malaria); glycemia, glycosuria, proteinuria and lumbar puncture (the liquid should be clear, but *Loa loa* microfilaria should be present between days 3 and 7 in *Loa loa* encephalitis). Removal of eye worm has been reported to cure spontaneous encephalitis (Kenney and Hewitt, 1950).
