Recurrent headaches may be caused by cerebral toxoplasmosis

Table 1 Demographic data and positive serum anti-Toxoplasma gondii IgG concentrations in 19 of 178 children hospitalized because of recurrent headaches

Pt	Age/sex	Living place	Contact with animals1	Serum anti-Toxo IgG concn (n ≤9 IU/mL)	Avidity index2
1	8/M	Town	Yes1	205.5	0.750
2	9/M	Town	Yes1	59.5	0.754
3	9/F	Town	Cat	59.0	0.202
4	12/F	Town	Cat	94.1	0.666
5	13/F	Town	No	168.0	0.782
6	13/F	Town	Yes1	83.0	0.800
7	13/F	Town	No	123.9	0.861
8	14/F	Village	Yes1	151.2	0.740
9	15/M	Town	Yes1	231.4	0.670
10	16/F	Town	Yes1	81.0	0.859
11	16/F	Town	Dog	74.7	0.767
12	16/M	Town	Ferret	165.7	0.778
13	17/M	Village	Yes1	175.03	0.788
14	17/F	Town	Yes1	145.0	0.772
15	17/F	Town	Yes1	40.5	0.687
16	17/M	Town	Yes1	> 240.0	0.843
17	17/F	Village	Yes1	71.7	0.925
18	17/M	Town	Dog, parrot	32.2	0.796
19	17/M	Village	Dog, cat, hens, ducks, cows	82.0	0.894

¹Dog, cat and/or turtle.

²Avidity index: < 0.4-low avidity, 0.4 to 0.5-moderate, and ≥ 0.5-high avidity. In Pt 13 control serum anti-Toxo IgG concentration examined 9 mo later was 552.7 IU/mL. It must be noted that Toxoplasma gondii IgG and IgA, but not IgM, antibody titers were also found to be increased in sera of immunocompetent mice in association with proliferation of tachyzoites in the brain during the chronic stage of infection[17].

Table 2 Characteristic features of headaches in the seropositive anti-Toxoplasma gondii IgG children

Pt	Frequency of headaches	Pain localization	Duration (h)	Pain intensity1	Pain character	Discomfort for patient
1	Once a month	Temples	< 2	6	Squeezing	No
2	Once a month	Forehead	2-6	4	Squeezing	N/A
3	Once a month	Back	< 2	5	Pulsating	No
4	Daily	Whole head	2-6	5	Squeezing	Yes
5	Once a month	Temples, forehead	2-6	5	Squeezing	Yes
6	Once a month	Forehead, occiput	< 2	3	Pulsating, paroxysmal	N/A
7	More than once a month	Forehead	< 2	6	Expanding	Manageable
8	Rarer than once a month	Stomach	< 2	2	Squeezing	No
9	More than once a month	Forehead, occiput	2-6	8	Expanding, piercing	Yes
10	More than once a month	Forehead, temples	2-6	5	Pulsating	Small
11	More than once a month	Forehead (left side)	2-6	10	Expanding	Yes
12	More than once a month	Temples, orbitae (left side)	2-6	7-8	Pulsating, squeezing	Yes
13	Rarer than once a month	Forehead	< 2	5	Pulsating	No
14	Once a month	Forehead, temples	2-6	4	Squeezing, pulsating	Yes
15	Once a month	Forehead, occiput	0.5-24	2	Dull	No
16	More than once a month	Forehead, temples	6-12	5	Pulsating	No
17	N/A	N/A	N/A	N/A	N/A	N/A
18	Once every 3 mo	Forehead, calvaria	< 2	4	Piercing	No
19	Once every 6 mo	Forehead, orbitae	< 2	8	Squeezing	No

¹Headache intensity was measured in a subjective 1-10 point scale. N/A: Data not available.

Table 3 Concomitant symptoms and comorbidities in the seropositive anti-Toxoplasma gondii IgG children with recurrent headaches

Pt	Concomitant symptoms	Comorbidities
1	Fatigue	Epilepsy, attention and concentration disturbances
2	Autoaggression	Epilepsy, behavior disturbances, psychomotor development delay
3	Vertigo, nausea and vomiting, discrete balance disturbances, photophobia	Infection of upper airways, right eustachitis, suspected allergic rhinitis
4	Nausea, vomiting, abdominal pain, photophobia	Allergic lesions of nasal mucosa and paranasal sinuses, heart systolic murmur (2/6), overweight, aggression and autoaggression behavioral disturbances, attention and concentration deficits, myoclonus during sleep
5	Nausea, vomiting, abdominal pain	Allergy to dust and mites, serous rhinitis
6	Vertigo, changes of mood and behavior, fatigue	Frequent upper airway infections
7	Psychomotor slowdown, episodes of awareness (switch-offs)	Bronchial asthma, paranasal sinusitis, allergic rhinitis, obliteration of right optical nerve disc
8	Impairment of cognitive abilities, psychomotor hyperactivity, clumsy gait	Metachromatic leukodystrophy, significant peripheral nerve lesions-sensorial-motor axonal-demyelinating polyneuropathy
9	Nausea, photophobia, abdominal pain	Bronchial asthma, chronic eustachitis and rhinitis, allergy to dust
10	Photophobia, fatigue, hyperacusis, faintings, syncope	Eye refractive error, serous cerebrospinal meningitis at the age of 6
11	Vertigo, hot flushes, weakness	Traffic accident injury of head and right thigh, diagnosed cerebral commotion, incisive wounds of forehead, nose and over upper lip, positive tetany tests-elevated plasma calcium levels
12	Aphasia, dysphasia, paresthesia of hands and forearms	Bronchial asthma
13		Chronic purulent tonsillitis, streptococcal infection, epilepsy (observation), sclerosis multiplex (observation)
14	Fatigue	Epilepsy
15	Hyperacusis, drowsiness	Epilepsy, attention and concentration disturbances, impaired perception skill, eye-motor concentration disturbances, allergic rhinitis
16	Photophobia
17	Individual incident of vertigo and limb numbness without loss of consciousness	Vision disorders and ventricular arrhythmia in anamnesis, left-eye divergent strabismus
18	Systemic vertigo, balance disturbances, nausea	Frequent upper airways infections, enlarged submandibular lymph nodes, right palpebral narrowing and discrete right-sided ptosis since early childhood
19	Nausea, vomiting, photophobia, numbness of tongue and right arm	Bronchial asthma, atopic dermatitis, mitral valve insufficiency

Table 4 Results of laboratory tests and head X-ray/neuroimaging studies in the seropositive anti-Toxoplasma gondii IgG children with recurrent headaches

Pt	ESR (mm/h)	WBC (103/mL)	CRP (mg/L)	EEG	Head X-ray/CT/MRI
1		6.4		Increased percent of slow waves	CT normal
2	10	14.9	0.10	Abnormal	CT normal
3		4.0; 6.5	20.25; 1.92	Normal	MRI-brain and fluid spaces normal, massive lesions of paranasal sinuses, total obliteration of the right maxillary sinus, thickened ethmoid mucosa
4		5.4	0.57	Paroxysmal parietal and temporal alterations without paroxysmal activity	MRI-arachnoidal cyst at the right frontal-parietal border
5	22	6.9		Normal	CT normal; X-ray-thickened right sphenoid mucosa
6		6.9		Discrete bilateral alterations in frontal regions	MRI-arachnoidal cyst, underdevelopment of Turkish saddle diaphragm; X-ray-thickened right maxillary sinus mucosa
7		6.5	0.27	Discrete bilateral alterations in temporal regions-increased slow waves	MRI-brain and fluid spaces normal, small and hypoplastic frontal sinuses with thickened mucosa, moderate thickening of ethmoid mucosa and moderate inflammatory or post-inflammatory lesions of maxillary sinuses
8	16	5.7	0.30	Generalized alterations	MRI-extensive lesions (differentiation between metabolic and demyelinating disorder)
9		7.1		Generalized alterations: many dispersed theta waves; biparietal paroxysmal alterations during HV	CT and sinus X-ray normal
10	12	8.4	0.60	Normal	CT normal
11		4.7	0.86	Readout unavailable-pending	Head CT and X-ray of cervical spine normal; MRI-modest lateral ventricle asymmetry, some minute fluid foci adjacent to pineal gland
12		7.5		Normal	MRI normal
13a	8	4.5	0.41	Increased percent of slow waves; increased number of theta waves during HV	MRI demyelinating foci (June 2009); partial regression of these abnormalities (February 2010)
14		6.9	0.39	Slowed down basal function, biparietal alterations	MRI normal
15	24	9.2	1.45	Paroxysmal bioccipital alterations	MRI-venous angioma suspected in right cerebellar hemisphere; X-ray-Kimmerle foramen in C1 of cervical spine
16	9	6.59			CT normal
17		10.6		Normal	MRI-discrete lesions in the vicinity of dorsal parts of lateral ventricle corpora, paraventricular foci of demyelination?
18			0.24	Normal	CT-isolated tiny hypodense foci in midbrain and pons
19	N/A	7.9	N/A	Normal	MRI-choroid plexus cysts

¹In Pt 13, the anti-streptolysin titer was 530 U (n≤ 200 U). WBC: White blood cells; CRP: C-reactive protein (n≤ 5 mg/mL); HV: Hyperventilation; N/A: Data not available; CT: Computed tomography; MRI: Magnetic resonance imaging; ESR: Erythrocyte sedimentation rate; EEG: Electroencephalography.

Table 5 Drugs tested for in vitro activity against Toxoplasma gondii (according to Jones-Brando et al[52]; with own modification)

Drug	Solvent	ID501 (μg/mL)	TD502 (μg/mL)	TI3
Valproic acid	Ethanol	4.5	62.4	13.9
Sodium valproate	Ethanol	4.1	52	12.7
Carbamazepine	Ethanol	72	100	1.3
Lithium carbonate	1 N HCl	> 100	> 100
Haloperidol	Ethanol	5.6	103	18.4
9-OH-Risperidone	Tartaric acid	20.1	134	6.7
Risperidone	Tartaric acid	74	129	1.7
Fluphenazine HCl	Toxo CGM	3.5	17.9	5.1
Clozapine	Ethanol	5.8	20	3.4
Olanzapine	DMSO	33.2	100	3
Chlorpromazine HCl	DMSO	2.6	6	2.3
Quetiapine fumarate	DMSO	18.6	33	1.8
Trimethoprim	DMSO	5.3	63.8	12.1

¹Median inhibitory dose, a measure of tachyzoite inhibition.

²Median toxicity dose, a measure of cytotoxicity.

³Therapeutic index, a measure of efficacy determined by TD₅₀/ID₅₀ ratio. Valproic acid at a concentration of 1 μg/mL inhibited 7% of the tachyzoites and trimethoprim at 3.2 μg/mL produced 2% inhibition, but the combination of these two compounds at those concentrations resulted in a potentiating effect inhibiting 55% of the tachyzoites. Recently, Fond et al[53] also reported that other antipsychotic drugs, such as amisulpride, cyamemazine, levopromazine, loxapine, tiapride and zuclopenthixol in vitro exerted anti-toxoplasmatic activity in the range of 0.19 to 1 μmol/L concentrations. The inhibitory concentration 50 (IC₅₀) for the last preparation was 8 ± 1.8 μmol/L while its serum levels varied from 0.01-0.12 μmol/L[54], but antipsychotic drugs usually achieve much higher and persistent concentrations in the brain tissue[55]. In human fibroblast cell cultures, IC₅₀ for fluphenazine, thioridazine and trifluoperazine against developing tachyzoites of the parasite RH strain was 1.7, 1.2 and 3.8 μmol/L, respectively[56]. DMSO: Dimethylsulfoxide; Toxo CGM: Toxoplasma cell growth medium; TI: Therapeutic index; TD: Median toxicity dose; ID: Median inhibitory dose.