Presynaptic Hemiparkinsonism Following Cerebral Toxoplasmosis: Case Report and Literature Review

ABSTRACT

Background

Cerebral toxoplasmosis (CTx) is a central nervous system opportunistic infection with variable neurological manifestations. Although tropism of Toxoplasma gondii for the basal ganglia is well known, movement disorders (MDs) represent only a small percentage of CTx‐related neurological complications. CTx‐associated MDs are usually hyperkinetic, whereas parkinsonism associated with evidence of presynaptic dopaminergic deficit has never been described.

Case

We report a human immunodeficiency virus–positive patient who developed a complex MD featuring unilateral tremor combined with parkinsonism and dystonia following an acute episode of disseminated CTx. Her dopamine transporter scan (DaTscan) documented contralateral presynaptic dopaminergic deficit. Levodopa initiation improved both tremor and parkinsonism after ineffective trials of several other medications over the years.

Literature Review

A total of 64 patients presenting with CTx‐related MDs have been described. The most common MD was chorea (44%), followed by ataxia (20%), parkinsonism (16%), tremor (14%), dystonia (14%), myoclonus (3%), and akathisia (2%). DaTscan was performed only in 1 case, of Holmes tremor, that demonstrated reduced presynaptic dopaminergic uptake. Positive response to dopaminergic treatment was reported in 3 cases of Holmes tremor and 2 cases of parkinsonism.

Conclusions

Presynaptic dopaminergic deficit may occur in CTx‐related tremor combined with parkinsonism. Its identification should prompt initiation of levodopa, thus avoiding unnecessary trials of other drugs.

Toxoplasmosis is the most common central nervous system opportunistic infection, particularly in the setting of human immunodeficiency virus (HIV) coinfection, and more rarely in hematologic malignancies and organ transplantations. ¹ Its neurological manifestations are variable, depending not only on the size, number, and localization of the encephalitic lesions but also on the presence of meningitis, edema, vasculitis, and hemorrhage. ² Although it is well known that Toxoplasma gondii–associated lesions have predilection for the basal ganglia (BG), movement disorders (MDs) usually constitute a small percentage (6%–7%) of the neurological manifestations. ³ , ⁴ Notwithstanding, MDs can be the presenting feature of cerebral toxoplasmosis (CTx), and early clinical suspicion can prompt initiation of specific treatment(s). ⁵ Hyperkinetic MDs, especially hemi‐chorea/ballismus, are the most common MDs in CTx, ³ whereas hemiparkinsonism associated with evidence of presynaptic dopaminergic deficit has never been described. MDs secondary to focal brain lesions, as in the case of CTx, are usually difficult to treat, and levodopa (l‐dopa) initiation in those conditions where nigrostriatal system involvement is documented might be the best therapeutic choice. ⁶

We herein report the case of an HIV‐positive patient who developed a complex MD featuring unilateral tremor combined with parkinsonism and dystonia following resolution of an acute episode of CTx. Contralateral presynaptic dopaminergic deficit was documented on dopamine transporter scan (DaTscan). We additionally reviewed all cases of MDs in CTx reported so far and summarized their phenomenology and natural history.

Case Report

A 41‐year‐old Black African woman presented with an acute episode of disseminated toxoplasmosis in the context of previously undiagnosed HIV infection at the age of 27 years. She was profoundly immunosuppressed, with a baseline CD4 cell count of 20/mm³ and an RNA‐HIV viral load of 2.2 million copies/mL. T. gondii was isolated from blood, cerebrospinal fluid, lymph nodes, and bronchial washing, and her brain magnetic resonance imaging (MRI) at onset showed multiple infra‐ and supratentorial ring‐enhancing lesions consistent with cerebral abscesses, 2 of which involved the left anterior midbrain and left thalamus. After a long intensive therapy unit admission during which she was treated for toxoplasmosis and started on antiretroviral therapy, she eventually recovered with a right spastic hemiparesis. Approximately 5 months later, she developed right‐sided combined rest and action tremor, which has remained stable for 9 years. Trials of levetiracetam, gabapentin, clonazepam, and botulinum toxin resulted in modest or no effect. There was no history of exposure to dopamine receptor antagonists, and HIV infection was well controlled at the time of MD onset. Her first neurological examination in the MD clinic at age 36 (Video 1, segment 1) revealed supranuclear horizontal gaze palsy to the right, right central facial palsy, and right hemiparesis with brisk reflexes. She had a rest tremor in the right hand associated with mild postural and kinetic tremor and intermittent rest tremor in the leg. Muscle tone was increased in her right limbs due to a combination of moderate spasticity and mild cogwheel rigidity. There was decreased right‐side shoulder shrug and slowness of ipsilateral limbs, but true bradykinesia was difficult to access due to the pyramidal syndrome overlap. She had an additional dystonic posture in the right hand. Her gait was mainly spastic with circumduction of the right lower limb. Although right limb spasticity and dystonia dominated the clinical picture, tremor, which was associated with mild parkinsonian features and minimal response to previous treatments, was the patient's main complaint. In view of that, she underwent a DaTscan, which showed unilateral dopaminergic deficit with absent uptake on the left side and normal uptake on the right BG (Fig. 1). Follow‐up brain MRI showed partial involution of the toxoplasmosis lesions without evidence of any active, acute process; small, round T2‐hyperintensity lesions persisted in the cerebellum hemispheres and supra‐tentorial compartment, namely, 1 involving the left anterior midbrain and adjacent thalamus (Fig. 2). She was therefore started on l‐dopa (Video 1, segment 2), with mild improvement in her tremor and slowness of movements, and developed right foot dyskinesia when the daily dose was increased to 800 mg.

Video 1.

. Segment 1: patient at first neurological observation (2016, 36 years old). She has right‐sided rest, postural, and kinetic tremor. Evaluation of the intentional component is limited by the ipsilateral hemiparesis. There is slowness of movements on the right limbs and ipsilateral hand dystonia. Gait is spastic with circumduction of the right lower limb. Segment 2: patient observed 6 weeks later on 300 mg of levodopa. She reported a slight improvement of the rest tremor and gait.

FIG. 1.

Dopamine transporter scan performed in 2016, 9 years after the episode of CTx, showing complete absent tracer uptake in the left basal ganglia and normal tracer activity in the right basal ganglia.

FIG. 2.

Brain magnetic resonance imaging (MRI) performed in 2018, showing T2 hyperintensity in the cerebellum hemispheres (upper left panel) and in the anterior left midbrain (upper middle panel, arrow), extending superiorly toward the medial left thalamus (upper right panel, arrow). Caudate or putaminal lesions were not observed in T1, T2, and gadolinium‐enhanced sequences at the striatum level (lower panels).

Literature Review

To further investigate the relationship between CTx and MDs, we conducted a systematic review. We searched PubMed without time limit for English‐language articles using the following search strategy: “cerebral toxoplasmosis” AND “chorea” (8 results), “cerebral toxoplasmosis” AND “ballismus” (1 result), “cerebral toxoplasmosis” AND “dystonia” (6 results), “cerebral toxoplasmosis” AND “myoclonus” (2 results), “cerebral toxoplasmosis” AND “tremor” (12 results), “cerebral toxoplasmosis” AND “parkinsonism” (11 results), “cerebral toxoplasmosis” AND “movement disorders” (14 results), “cerebral toxoplasmosis” AND “ataxia” (8 results), and “cerebral toxoplasmosis” AND “tics” (1 result). After result deduplication, a total of 38 articles were obtained.

All articles were screened by reviewing the title and/or abstract, and we performed full‐text review of all case reports or studies describing MDs in patients with CTx. A total of 7 articles were excluded due to lack of relevance (not related with CTx, not describing patients with MDs and CTx, or MD best attributed to neuroleptic treatment). In addition, 7 articles were included via screening of the references of articles. Clinical cases were reported in 38 articles for a total of 64 patients presenting with CTx‐related MDs.

Results are presented in Table 1. Chorea was the most common MD in CTx, affecting 28 (44%) patients; in most cases, chorea involved 1 hemibody and was associated with ballistic movements in the presence of contralateral subthalamic nucleus lesions. Other MDs observed were ataxia (n = 13, 20%), parkinsonism (n = 10, 16%), tremor (n = 9, 14%), dystonia (n = 9, 14%), myoclonus (n = 2, 3%), and akathisia (n = 1, 2%). Ataxia was more frequently axial, and appendicular dysmetria was identified in 4 patients. Unilateral Holmes tremor (HT) was the predominant form of tremor (n = 5/9) and was related to midbrain lesions, ipsi‐ (n = 2/5) or contralaterally (n = 3/5) to the tremor side. Parkinsonism was poorly detailed, being generally correlated with bilateral BG lesions. Dystonia affected 1 hemibody in 6 patients, the cervical region in 1 case, and was focal to a limb in 3 patients (concurrent with chorea in 2). MDs were rarely observed as isolated neurological manifestations because the majority of cases had a complex neurologic syndrome comprising other MDs, lethargy, cognitive deterioration, cranial nerve palsy, and/or pyramidal syndrome, which is in accordance with the diffuse supra‐ and infratentorial involvement verified in CTx. MD presentation can be acute or subacute, emerging simultaneously with other clinical manifestations of CTx (mainly in the cases of chorea‐ballismus and ataxia) or afterward, with a time interval varying between a few days and 6 months. As for treatment response, HT was reported to improve with different types of symptomatic medication (clonazepam, trihexyphenidyl, primidone, l‐dopa, pramipexol, isoniazid) and to various degrees (complete resolution in only 2 cases). The response to l‐dopa was only mentioned in 3/10 patients with parkinsonism (mild in 2 and absent in 1), and in 2 cases, improvement was linked to the initiation of specific therapy for CTx. Chorea was the MD with the best prognosis, as almost all cases had significant improvement, which was attributed to the initiation of CTx therapy and successful infection control. Notably, radiological improvement was frequent, but did not correlate with the evolution of the MD because the latter could persist despite a size reduction of the brain lesions. In 1 case of CTx with acute ataxia, follow‐up MRI showed bilateral T2 hyperintensity at the level of the ventral medulla, compatible with hypertrophic olivary degeneration. ²² DaTscan was performed only in 1 case of HT that demonstrated reduced presynaptic dopaminergic uptake in the putamen contralateral to the side of the tremor. ¹² CTx was associated with HIV infection in the majority of cases (n = 58, 91%); other immunosuppressive conditions (n = 4) were observed in HIV‐negative patients, including liver transplantation (due to Wilson's disease in a patient without neurological manifestations prior to the transplantation), ⁸ diffuse large B cell lymphoma, ²⁰ stem cell transplantation, ²⁷ and X‐linked hyper immunoglobulin M syndrome. ²¹

TABLE 1.

Literature review

Author, year	No. of patients, sex	Type of MD	Other neurological manifestations	Age in the article, years	Latency between CTx onset and MD a	Related CTx cause (other CNS infections)	Brain MRI/CT	Evolution of the MD b	Radiological improvement
Tremor
Koppel, 1990 7	1, male	Holmes tremor (L hemibody)	Lethargy, dysarthria, L Weber syndrome	35	0	Drug user	CT: ring‐enhancing mass lesions in L frontal lobe and L midbrain	Tremor progressed to involve the jaw in 1 month; no response to clonazepam, levodopa, or primidone; mild improvement with trihexyphenidyl and isoniazid (died)	Partial resolution (3 weeks)
Coelho, 1996 8	1, male	Intentional and rest tremor, 4 limbs rigidity	Dysarthria, dysphagia, spasticity	16	0	Liver transplantation in Wilson's disease c (CMV)	CT: hypodensity of the thalamus, BG, and external capsule	Moderate improvement with levodopa and trihexyphenidyl (died)	NA
Micheli, 1997 9	1, male	Action and postural tremor (4 Hz, R hemibody)	R hemi‐sensory motor syndrome	39	1 month	HIV	MRI: enhancing lesions in L posterior thalamus and posterior arm of internal capsule	Unchanged at 2 months, residual at 11‐month follow‐up; medication not specified	Marked improvement (2 weeks)
Pezzini, 2002 10	1, male	Holmes tremor (L UL)	L hemiparesis	46	4 months	HIV	CT: multiple supratentorial nodular lesions, including R thalamus and R midbrain with edema and homogenous enhancement	Rest tremor improved with levodopa; postural/kinetic component improved with isoniazid; no response to clonazepam and trihexyphenidyl	Reduction in size (2 weeks)
Mattos, 2002 11	1, male	Holmes tremor (L UL)	HIC	36	NA	HIV (cerebral TB)	CT: lesions in L midbrain and L cerebellar hemisphere	Disappeared with anti‐TxT	Disappeared
Strecker, 2007 12	1, male	Holmes tremor (R UL)	L Weber syndrome	51	5 months	HIV	MRI: ring‐enhancing lesion in midbrain (L red nucleus and CP); DaTSCAN: reduced uptake in L putamen	Tremor slowly evolved for 5 months; significant improvement after introduction of pramipexole	NA
Lekoubou, 2010 13	1, male	Holmes tremor (L hemibody)	Confusion, cerebellar dysarthria, L hemi‐sensory motor syndrome	35	18 days	HIV	CT: ring‐enhancing lesion in R internal capsule, R thalamus, with edema extending to upper midbrain	Improvement with anti‐TxT, clonazepam, and trihexyphenidyl; resolution in 8 days	NA
Dystonia
Tolge, 1991 14	1, male	L UL dystonia, intentional tremor	–	29	0	HIV	MRI: enhancing lesions in R thalamus, R LN, and L temporal lobe, with edema	Persisted at 6‐month follow‐up; medication not specified	Marked improvement
Linazasoro, 1994 15	3, 1 male/1 male/1 female	R hemi‐dystonia	NA	25/25/27	NA	HIV	CT: lesions in GPi, thalamus, and STN	NA	NA
Micheli, 1994 16	1, female	R hemi‐dystonia, R hemi‐chorea‐balllismus	–	11	0	–	CT and MRI normal	No response to trihexyphenidyl; improvement with anti‐TxT; complete resolution at 2‐month follow‐up	–
Mattos, 2002 11	1, male	R hemi‐dystonia	NA	28	NA	HIV	CT: hypodense lesion in L BG	No improvement; medication not specified	Improvement
Factor, 2003 2	1, male	R torcicollis, R hemi‐dystonia, head and UL rest tremor, myoclonus	Stupor, R CNIII palsy, papilledema, increased muscle tonus, bilateral Babinski sign, R hemiparesis	44	14 days	HIV	CT: nonenhancing mass lesions in R caudate, L thalamus, and L frontal lobe, with midline shift	No improvement with anti‐TxT	NA
Ataxia
Navia, 1986 4	6, NA	6 ataxia (2 with limb dysmetria)	Headache, lethargy, CNVI palsy, aphasia, HH	NA	3 days–3 weeks	HIV	CT: single to multiple enhanced cortical lesions (1 cerebellum involvement)	Improvement mentioned in 3, death in 1	NA
Ormerod, 1996 17	1, male	Ataxia	Seizures, dysarthria, L hemiparesis, HH, cognitive decline, nystagmus	42	NA	HIV	MRI: lesions in R frontal and bilateral parietal lobes	NA	NA
Tsai, 2021 18	1, male	Ataxia	Headache, nausea	26	0	HIV	MRI: multiple ring‐enhancing lesions in the cerebellum, BG, and L occipital lobe	Clinically well at 1‐year follow‐up	Marked improvement (2 weeks); resolution (1 year)
Pott, 2013 19	1, male	Ataxia, limb dysmetria	Headache, confusion	50	0	HIV	MRI: ring‐enhancing lesion in R cerebellar hemisphere	Resolution after 2 weeks of anti‐TxT	Reduction (2 weeks)
Savsek, 2014 20	1, female	Ataxia, limb dysmetria	Cognitive decline, HH, R UL paresis	62	0	Diffuse large B cell lymphoma	MRI: ring‐enhancing lesions in cortical and cerebellar hemispheres	Improvement with anti‐TxT	Reduction, with hemorrhagic inclusions in some lesions (6 weeks)
Liu, 2017 21	1, male	Ataxia	Lethargy	2	0	Primary immunodeficiency disease (XHIGM)	MRI: ring‐enhancing lesions in bilateral cerebral hemispheres, BG, and thalamus	Died	NA
Behzadi, 2021 22	1, female	Ataxia	Headache	54	0	HIV	MRI: ring‐enhancing lesions in R caudate, R thalamus, bilateral SCP	NA	Improvement, bilateral HOD (6 weeks)
Myoclonus
Mattos, 2002 11	1, male	Myoclonus	NA	NA	NA	HIV	NA	NA	NA
Akathisisa
Carrazana, 1984 23	1, male	R akathisia	R hyperreflexia	54	0	HIV	CT: enhancing nodular lesions in L STN, L LN, and L parietal lobe, with edema	Worsened with haloperidol (died)	NA
Parkinsonism
Carrazana, 1984 23	1, female	Bilateral parkinsonism with severe dysarthria	Lethargia, R hyperreflexia, spastic tetraparesis	66	0	HIV	CT: enhancing lesions in bilateral internal capsules with edema	No response to levodopa (died)	NA
Noël, 1992 24	1, male	R parkinsonism	R pyramidal syndrome	28	NA	HIV	CT: enhancing lesion in L LN	NA	NA
Linazasoro, 1994 15	1, male	Parkinsonism (postural and rest tremor)	NA	30	NA	HIV	CT: bilateral BG lesions	NA	NA
Maggi, 2000 25	1, male	Bilateral parkinsonism with moderate dysarthria	Abulia, R CNVII palsy	31	30 days	HIV (cerebral TB)	MRI: abscesses involving L LN and R BG	Died	Slight regression (2 months)
Murakami, 2000 26	1, male	Asymmetrical L > R parkinsonism will pill‐rolling tremor	Confusion, downward and horizontal gaze palsy, LL hyperreflexia	49	MD 3 months before CTx diagnosis	HIV	MRI: multiple lesions with edema in subcortical WH of bilateral parietal lobes and R LN, some with ring enhancement	Partial improvement with anti‐TxT and levodopa (300 mg/day); resolution of downward gaze limitation	Reduction (2 months)
Mattos, 2002 11	2, NA	Parkinsonism	–/Benedikt syndrome	NA	NA	HIV	CT: hypodense mass in R BG/MRI: enhanced lesion in midbrain	NA/improvement with anti‐TxT	NA
Arbune, 2016 1	1, female	Parkinsonism, choreoathetosis	Coma, R convergent strabismus, tetraparesis	58	6 months	HIV	MRI: multiple nodular enhancing lesions in frontoparietal region, cerebellum, and BG	Mild improvement with levodopa and clonazepam	Improvement (1 year)
Tateno, 2017 27	1, male	Parkinsonism	Seizure	53	0	Stem cell transplantation	MRI: diffuse T2 hyperintensities in bilateral BG, without ring enhancement	Died	NA
de Almondes, 2020 28	1, male	Parkinsonism	Seizure, aphasia, R hemiparesis	63	NA	HIV	MRI: bilateral BG and cortico‐subcortical frontal lesions with edema	NA	NA
Chorea
Navia, 1986 4	2, NA	Chorea, rigidity/choreoathetosis	Lethargy/headache, hemiparesis	NA	4–5 weeks	HIV	CT: hypodense lesions in bilateral BG/ring‐enhancing lesion in L internal capsule, R occipital lobe	No response (died)	NA
Nath, 1987 29	3, 1 female/1 male/1 male	3 R hemi‐chorea‐ballismus	1 Headache/−/−	26/56/47	NA	HIV (1 cryptococcal meningitis)	CT: contrast‐enhancing lesions in L frontal lobe and L BG/L STN abscess/multiple abscesses, 1 L BG	Improvement with anti‐TxT/NA/NA	NA
Sanchez‐Ramos, 1989 30	1, female	L hemi‐chorea‐ballismus	Headache, nausea	33	0	HIV	CT: ring‐enhancing lesions in L caudate, R thalamus, R STN, and R cerebellum, with edema	Dramatic improvement after 4 days of anti‐TxT, with resolution in day 20	Marked improvement (2 weeks)
Piccolo, 1999 31	2, male	R hemi‐ballismus/generalized chorea, ataxia	−/L hemiparesis	27/35	0	HIV	MRI: ring‐enhancing lesions in L STN/MRI: T2‐hyperintensities in midbrain, R CP, R BG, L thalamus‐capsule, L frontal operculum, and L occipital lobe, with contrast enhancement	Resolution in 2 months after initiation of anti‐TxT/chorea present until death	Resolution (1 month)/NA
Nath, 1993 5	1, male	L hemi‐chorea‐ballismus involving the hemi‐face	L brisk reflexes	32	MD (hemi‐facial chorea) 1 month before CTx diagnosis	HIV	CT: ring‐enhancing lesion in R GPi, R parietotemporal, and L temporal regions	Some response to TxT and haloperidol	Considerable improvement (10 days)
Provenzale, 1994 32	1, male	R hemic‐chorea‐ballismus	Disinhibited behavior	65	0	HIV	MRI: ring‐enhancing mass in L STN	Resolution within a few weeks after initiation of anti‐TxT	Reduction
Linazasoro, 1994 15	2, 1 male/1 female	2 R hemi‐chorea‐ballismus	NA	25/25	NA	HIV	CT: lesions in LN and STN	NA	NA
Krauss, 1996 33	1, male	R hemi‐ballismus	NA	32	NA	HIV	MRI: enhancing lesions with edema, 1 in L STN	No response to pharmacological therapy; resolution with chordotomy	NA
Manji, 1995 34	1, female	R choreoathetosis, R hand dystonia	Headache, R hemiparesis, R brisk reflexes, dysphagia	28	0 (dystonia 5 months)	HIV	CT: low‐density lesions in bilateral thalamus, LN, and R frontal and L parietal lobes	Significant improvement 5 weeks after initiation of anti‐TxT	Almost complete resolution
Maggi, 1996 3	3, male	L hemi‐coreoathetosis	Aphasia, R hemiparesis/−/confusion	27/31/32	0	HIV	MRI: multiple supratentorial lesions, including R STN	Resolution within 10–30 days of anti‐TxT	NA/reduction (4 months/resolution (3 months)
Mattos, 2002 11	6, male	6 hemi‐chorea‐ballismus	2 HIC	27–40	NA	HIV	CT: ring‐enhancing lesions in BG and frontal lobe	NA	NA
Rabhi, 2011 35	1, female	L hemi‐chorea‐ballismus	Headache, nausea, L hemiparesis	59	0	HIV	MRI: ring‐enhancing lesion in R capsule‐thalamus with edema	Resolution within 2 weeks of anti‐TxT	Resolution
Reyes, 2016 36	1, male	R hemi‐coreoathetosis, R foot dystonia	Cognitive decline	22	0	HIV	MRI: T2 hyperintensities in bilateral BG, thalamus and frontal lobe, and R parietal and temporal lobes	Resolution 10 days after initiation of anti‐TxT and haloperidol	Improvement (2 months
Dimal, 2021 37	1, male	L hemi‐chorea‐ballismus	L hemiparesis	24	0	HIV (cerebral TB)	MRI: T2 hyperintensities in R STN, R CP, and ring‐enhancing lesion in L frontal lobe	Dramatic improvement with anti‐TxT and risperidone; almost complete resolution at 9‐month follow‐up	Resolution (4 months)

^a 0 means MD was simultaneous with other CTx‐related manifestations.

^b Death is indicated when it happens as a direct result of the acute CTx infection.

^c No neurological manifestations prior to the transplantation.

Abbreviations: MD, movement disorder; CN, cranial nerve; CTx, cerebral toxoplasmosis; CNS, central nervous system; MRI, magnetic resonance imaging; CT, computed tomography; L, left; CMV, cytomegalovirus; BG, basal ganglia; NA, not available; R, right; HIV, human immunodeficiency virus; UL, upper limb; HIC, intracranial hypertension; TB, tuberculosis; LL, lower limbs; anti‐TxT, anti‐toxoplasmosis treatment; CP, cerebellar peduncles; DaTSCAN, dopamine transporter scan; LN, lenticular nucleus; GPi, globus pallidus internus; STN, subthalamic nucleus; HH, homonymous hemianopsia; XHIGM, X‐linked hyper immunoglobulin M syndrome; SCP, superior cerebellar peduncles; HOD, hypertrophic olivary degeneration; WH, white matter.

Discussion

We reported a case of HIV‐related CTx in which (1) 3 types of MDs developed subacutely after successful infection control (ie, right upper limb tremor combined with right‐sided hemiparkinsonism and right hand dystonia), (2) the strictly unilateral MDs were topographically related to the sequelae of CTx brain MRI lesions (ie, contralateral [left] anterior midbrain involving the substantia nigra [SN] and contralateral [left] thalamus), (3) DaTscan demonstrated absent dopaminergic uptake in the left BG (a finding at times observed in the presence of ipsilateral midbrain lesions), ⁶ and (4) the introduction of l‐dopa mildly improved tremor combined with parkinsonism and led to the development of dyskinesia, in accordance with documentation of presynaptic dopaminergic deficit.

Although MDs in CTx are more frequently of the choreic type, other forms have been described, and the clinical picture of our patient is in line with those reports. Reduced putaminal uptake in the DaTscan was previously reported in 1 case of HT ¹² and none of parkinsonism, and l‐dopa efficacy was shown in 3 cases of HT ⁸ , ¹⁰ , ¹² and 2 of parkinsonism. ¹ , ²⁶

Although one could consider calling the patient's tremor HT, we think that according to the consensus statement on the classification of tremors of the Movement Disorder Society, ³⁸ “tremor combined with parkinsonism” is the most accurate syndromic classification because (1) both postural and kinetic tremor may coexist with rest tremor in patients with parkinsonism; (2) although the frequency of the tremor was not confirmed by electromyography, with naked‐eye observation it was superior to the 5 Hz cutoff set for HT; and (3) the anterior midbrain lesion in the MRI did not involve the red nucleus (RN). Moreover, the MRI of the patient exhibits multiple CTx lesions in the bilateral hemispheres of the cerebellum, and albeit mild cerebellar features in this patient, such as limb dysmetria and intentional tremor, cannot be completely excluded, due to spasticity and dystonia overlaps, we do not think that the cerebellar lesions are causing the tremor, as they not involve the nuclei or pedunculi. HT is a clinical syndrome but pathophysiology heterogenous, requiring the disruption of at least 2 of the following systems: cerebello‐thalamo‐cortical, dentate‐rubro‐olivary, and dopaminergic nigrostriatal. ³⁹ In this last system, the proximity of the RN and SN in the midbrain may explain the improvement observed with l‐dopa in 3 reported cases of CTx‐related HT. ⁸ , ¹⁰ , ¹²

Regarding the pathophysiology of CTx‐related parkinsonism, the first report, from Carrazana et al, ²³ postulated that parkinsonism can be caused by direct (by toxoplasma abscesses) or indirect (through edematous mechanical pressure) destruction of the pre‐ or postsynaptic dopaminergic cells, at the level of the SN or striatum, respectively; interruption of the nigrostriatal dopaminergic pathways traveling through the internal capsule; and transient vascular disturbances of the anterior choroidal artery. Later on, other studies provided additional evidence on the interplay between T. gondii and parkinsonism, although this probably accounts for the perpetuation of MD rather than its emergence in the setting of acute CTx: (1) 1 study of animal models infected with T. gondii discovered tyrosine hydroxylase, the rate‐limiting enzyme for dopamine synthesis, in the intracellular tissue of brain cysts and increased dopamine metabolism in neuronal cells, ⁴⁰ and (2) a higher prevalence of toxoplasmosis seropositivity was demonstrated in Parkinson's disease patients, but this was an inconsistent finding across studies. ⁴¹

In view of that, our study reinforces that CTx‐related parkinsonism can be cause by direct SN damage, rather than BG (which would cause a post‐synaptic dopaminergic deficit), as it was demonstrated by brain MRI (T2 hyperintensity of left midbrain, involving partially the SN) and DaTscan (absent dopaminergic uptake in left BG). Of note, we cannot exclude that a previously involuted toxoplasmosis abscess, or even residual tissue necrosis at the level of the left caudate or putamen, might contribute to the absence of tracer uptake in the left BG.

Notably, not all patients with parkinsonism and HT have improved with l‐dopa (2 cases), ⁷ , ²³ and other therapeutic options have been effective (treatment of the CTx itself, and for HT, clonazepam, trihexyphenidyl, primidone, and isoniazid), ⁷ , ⁸ , ¹⁰ , ¹¹ , ¹³ , ²³ emphasizing that other mechanisms also interfere in the pathophysiology of these MDs (as noted previously by Carrazana et al). ²³

Similar to CTx, cysticercosis, tuberculosis, and cryptococcosis have also been associated with parkinsonism either as a consequence of lesions (granulomas or abscesses) involving the BG or SN or secondarily to direct pressure of the SN from ventriculitis and obstructive hydrocephalus. Although a positive response to l‐dopa and postmortem neuropathological evidence of nigrostriatal damage were described in some cases, findings from presynaptic dopaminergic imaging have never been reported. ⁴² , ⁴³ , ⁴⁴

The persistence or appearance of an MD, despite improvement of MRI/computed tomography lesions, as in our case and others in the literature, does not mean toxoplasmosis treatment failure, but it is probably due to residual injury from coagulative necrosis. ⁹ Alternatively, HIV coinfection may contribute to perpetuating the MD. ⁵ Neuropathological studies have shown damage to the BG and reduced levels of dopamine in HIV encephalopathy, which in turn is clinically supported by the observations of greater neuroleptic sensitivity in HIV patients and a higher proportion of MDs in patients with CTx/HIV coinfections than in patients with CTx without HIV. ⁴⁵ Moreover, in 1 study of simian immunodeficiency virus–infected monkeys, dopamine was reduced by 44% at 2 months of infection, ⁴⁶ and another demonstrated 25% of nigral neuronal loss in HIV‐positive patients, even if asymptomatic. ⁴⁷ Importantly, HIV‐induced parkinsonism was shown to be successfully treated with l‐dopa. ⁴⁸

In conclusion, our case provides evidence that SN damage and hence presynaptic dopaminergic deficit may occur in CTx‐related parkinsonism. Its presence should be searched in MDs (especially in “tremor combined parkinsonism” syndromes) related to CTx or other causes of structural lesions affecting the midbrain, allowing prompt initiation of l‐dopa and thus avoiding unnecessary trials of other drugs. Practically all types of MDs can be observed in CTx, and although the latter is expected to decrease in the era of HIV antiretroviral therapies, it remains an important cause of acquired MDs.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Data Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

M.J.M.: 1B, 1C, 3A

F.M.: 1B, 1C, 3B

A.Q.: 1A, 3B

R.J.N.: 1A, 3B

A.L.: 1A, 3B

E.M.: 1A, 3B

K.P.B.: 1A, 3B

Disclosures

Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval by the ethics committee of UCL Queen Square Institute of Neurology was not required for this work. Patient consent was obtained for video recording and publication.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: M.J.M., A.Q., R.J.N. and E.M. have nothing to declare. F.M. is supported by The Michael J. Fox Foundation Edmond J. Safra fellowship in movement disorders. A.L. has received honoraria for speaking at meetings from the International Parkinson's Disease and Movement Disorders Society. K.P.B. has received grant support from Welcome/Medical Research Council, National Institute for Health Research, Parkinsons's UK, and EU Horizon 2020. He receives royalties from publication of Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), Marsden's Book of Movement Disorders (Oxford University Press, 2012), and Case Studies in Movement Disorders–Common and Uncommon Presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as a consultant/scientific board member from Ipsen, Allergan, and Merz and honoraria for speaking at meetings from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals, and the American Academy of Neurology and the International Parkinson's Disease and Movement Disorders Society.