Involuntary Movement Disorders in Central Nervous System Fungal Infections: A Systematic Review

Abstract

Background

Central nervous system fungal infections, though rare, may lead to various movement disorders either due to direct fungal invasion or as adverse effects of antifungal drugs.

Objectives

This systematic review aimed to consolidate all published cases and characterize the clinical patterns, mechanisms, and outcomes.

Methods

A systematic review was conducted in line with PRISMA 2020 guidelines and registered with PROSPERO (CRD420251088348). Published case reports, series, and cohorts describing movement disorders in CNS fungal infections were identified from PubMed, EMBASE, Scopus, and Google Scholar.

Results

Forty‐five studies with 50 cases were included. Movement disorders directly attributed to fungal infection (n = 22; 44%) occurred predominantly in males (86.4%) with a mean age of 48 years. The most common pathogens were Cryptococcus neoformans (68.2%) and Coccidioides (13.6%). Chorea (45.5%), parkinsonism (27.3%), and tremor (13.6%) were frequent. Basal ganglia involvement was seen in 77.3% of patients. Antifungal drugs used included amphotericin B (77.3%), fluconazole (50%), and flucytosine (54.5%). Outcomes included full recovery (18.2%), partial improvement (36.4%), persistent symptoms (22.7%), and death (22.7%). Drug‐induced movement disorders (n = 11; 22%) were linked mainly to amphotericin B (81.8%), with tremor (45.5%), myoclonus (18.2%), and dystonia (18.2%). Mortality was 45.5%. Ataxia with cerebellar involvement (n = 17; 34%) presented as gait (58.8%), truncal (29.4%), or limb ataxia (17.6%), with cerebellar abscesses (52.9%) and leptomeningeal enhancement (23.5%) on imaging. Recovery occurred in 64.7%, while 17.6% died.

Conclusion

CNS fungal infections can lead to diverse variety of movement disorders. Early recognition of clinical patterns and neurotoxic drug effects is essential for optimal management.

Central nervous system (CNS) fungal infections, though relatively rare, represent a significant cause of neurological morbidity and mortality, particularly in immunocompromised populations. These infections, caused by pathogens such as Cryptococcus neoformans, Aspergillus spp., Histoplasma capsulatum, and other endemic or opportunistic fungi, are traditionally associated with raised intracranial pressure, meningitis, and altered mental status. ¹ , ² However, isolated case reports and small series have documented a wide spectrum of movement disorders arising in the context of CNS fungal infections, including parkinsonism, chorea, dystonia, tremor, myoclonus, and ataxia. These manifestations may result either from direct fungal invasion of motor circuits, immune‐mediated processes, vascular infarcts, or adverse effects of antifungal therapy. ³ , ⁴ Despite this emerging clinical observation, the literature remains scattered, and no systematic synthesis currently exists that characterizes the full range, patterns, mechanisms, and outcomes of such movement disorders in fungal CNS infections.

The aim of this systematic review is to comprehensively analyze all available published cases describing movement disorders in patients with CNS fungal infections. In terms of the PICO framework: the Population (P) includes patients of any age and immune status diagnosed with a confirmed CNS fungal infection; the Intervention/Exposure (I) is the occurrence of any movement disorder, either as a direct manifestation of fungal infection or secondary to antifungal treatment; there is no Comparison group (C) given the descriptive nature of the data; and the Outcomes (O) include the type and timing of movement disorder, associated clinical features, diagnostic findings, treatment approaches, and eventual neurological outcomes. This review seeks to assess clinical patterns, highlight pathophysiological mechanisms, and outcome.

Methods

This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) 2020 guidelines. A detailed review protocol was prepared prospectively and registered with the PROSPERO database under the registration ID [CRD420251088348], prior to beginning the search and data extraction process. ⁵

Eligibility Criteria

We included published reports that described human cases of movement disorders in association with confirmed or clinically presumed central nervous system fungal infections. Eligible studies comprised individual case reports, case series, and cohort studies. There were no restrictions based on age, sex, immune status, or geographic location. The fungal infection had to be confirmed either through cerebrospinal fluid culture, cryptococcal antigen testing, histopathological examination, imaging evidence of fungal abscesses or enhancement patterns, or the identification of fungal species from sterile sites. Movement disorders were required to occur during the active phase of infection, as a delayed complication, or in the context of antifungal drug exposure. Studies were excluded if they lacked a confirmed diagnosis of fungal infection, if the movement disorder could not be attributed to the infection or treatment, or if co‐existing infections obscured attribution. Reviews, editorials, and conference abstracts without primary patient data were also excluded. Subtypes of the movement disorders were classified using the criteria set by the Movement Disorder Society. ⁶

Search Strategy and Information Sources

A comprehensive literature search was conducted using the PubMed, EMBASE, and Scopus databases, as well as the first 50 pages of Google Scholar. The search strategy used Boolean operators and adapted controlled vocabulary appropriate to each database, including MeSH terms for PubMed and Emtree for EMBASE. The core search string used was: (“Movement disorders” OR “parkinsonism” OR “dyskinesia” OR “chorea” OR “dystonia” OR “tremor” OR “ataxia” OR “myoclonus” OR “tics” OR “stereotypy” OR “extrapyramidal” OR “involuntary movements”).

AND (“CNS fungal infections” OR “central nervous system fungal infections” OR “fungal meningitis” OR “cryptococcal meningitis” OR “aspergillosis” OR “candidiasis” OR “histoplasmosis” OR “coccidioidomycosis”). The final search was completed on July 6, 2025. No restrictions were applied regarding language or publication date.

Study Selection

Two reviewers (RKG and SP) independently screened all titles and abstracts for relevance, followed by full‐text review of potentially eligible studies. Discrepancies in study selection were resolved through discussion with a third reviewer (RAM). Duplicate records were removed using EndNote 21 (Clarivate Analytics, USA). The study selection process, including the number of records identified, screened, included, and excluded, was documented in a PRISMA flow diagram (Fig. 1).

Figure 1.

PRISMA 2020 flow diagram illustrating the selection process for studies included in the systematic review.

Data Extraction

Data were independently extracted by two reviewers (RKG and RAM) using a standardized extraction form. From each report, we collected demographic information including age, sex, and immune status; type of fungal organism (when identified); diagnostic methods (such as CSF‐based tests, histopathology, or imaging); and presence of any pre‐existing conditions. The nature of the movement disorder was described in detail, including classification based on Movement Disorder Society criteria and timing in relation to infection or antifungal treatment. Neuroimaging features, CSF findings, and other laboratory or autoimmune markers were recorded where available. Treatment‐related data included antifungal regimens, adjunctive therapies, surgical procedures, and medications used specifically for movement disorder management. Outcomes were categorized as complete recovery, partial improvement, persistent symptoms, or death. Proposed pathophysiological mechanisms were documented as described in the original reports. Any disagreements during data extraction were resolved through discussion and consensus among the authors.

Quality Assessment

The quality of included case reports and case series was assessed using the tool developed by Murad et al, which evaluates risk of bias across four domains: selection, ascertainment, causality, and reporting. ⁷ Two reviewers (SS and SP) independently assessed each study and resolved any disagreements by consensus. Reports meeting all four domains were rated as “good,” those fulfilling three were rated as “fair,” and those meeting only one or two domains were considered “poor.” No formal risk of bias assessment was conducted for cohort studies. ⁸

Data Synthesis

Extracted data were synthesized descriptively. Categorical variables were summarized as counts and percentages, while continuous variables were reported as medians or means, along with ranges when available. A narrative synthesis was used to describe the spectrum, onset, and distribution of movement disorders among patients with CNS fungal infections. Findings were grouped under three main clinical categories: movement disorders directly caused by fungal infection, drug‐induced movement disorders due to antifungal therapy, and cerebellar ataxia or other cerebellar involvement.

Results

In the present systematic review, we analyzed 45 reports comprising a total of 50 individual cases of central nervous system fungal infections associated with movement disorders and/or cerebellar involvement (Tables S1–S3). Of these, 22 cases featured movement disorders directly attributable to fungal infections, 11 cases involved drug‐induced movement disorders linked to antifungal therapy, and 17 cases demonstrated cerebellar ataxia or related cerebellar features. The case distribution and relevant clinical, radiological, and therapeutic details are presented in tables (Tables S1–S3). A PRISMA flow diagram (Fig. 1) outlines the study selection process, and the methodological quality of all cases was assessed as good (Item S1). PRISMA checklist has been provided as Item S2.

Movement Disorders Due to Fungal Infections

This group predominantly comprised adult males (86.4%) with a mean age of 48 years (range 20–90). Most were immunocompetent (59.1%), but 72.7% had underlying conditions—hypertension (six cases) and diabetes (five cases) being most common. Cryptococcal infections accounted for 68.2% of cases; others included coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis.

Chorea/hemichorea/ballismus was the leading movement disorder (45.5%), followed by parkinsonism (27.3%) and tremor (13.6%). The movement disorder had a subacute onset in most (59.1%). MRI showed basal ganglia lesions in 77.3%, often associated with thalamic or midbrain involvement. CSF cultures (40.9%) and cryptococcal antigen testing (31.8%) were common diagnostics. Amphotericin B (77.3%), flucytosine (54.5%), and fluconazole (50%) were the main antifungal agents. Treatments included antipsychotics (27.3%), benzodiazepines/baclofen (22.7%), and levodopa (9.1%). Outcomes were mixed4 (18.2%) had full recovery, 8 (36.4%) improved partially, and 5 (22.7%) died. Proposed mechanisms included direct basal ganglia invasion (45.5%), vasculitic ischemia (18.2%), and inflammatory damage (Tables S1 and S5). Among the 22 cases of CNS fungal infections presenting with movement disorders, 3 (13.6%) occurred in patients with HIV/AIDS (Tables S1 and S4).

Drug‐Induced Movement Disorders

In this subset, patients were younger (mean age 34.2 years, range 8–74), with 81.8% males. These disorders followed antifungal therapy, especially amphotericin B (9/11 cases); one case each was associated with itraconazole and liposomal amphotericin B. Most had serious comorbidities‐leukemia/lymphoma (six cases), renal transplant (1), and aplastic anemia (1). The movement disorders were mostly tremor (45.5%), dystonia (18.2%), and myoclonus (18.2%), typically with delayed onset (1–8 weeks). Neuroimaging often showed white matter changes (27.3%), hydrocephalus (27.3%), or was non‐significant (27.3%). Mechanistically, amphotericin B‐induced leukoencephalopathy was the leading hypothesis (54.5%), with basal ganglia/extrapyramidal toxicity in 27.3%. Treatments involved drug withdrawal (18.2%), supportive care (45.5%), and antiparkinsonian therapy (27.3%). The prognosis was poor—5 patients (45.5%) died, and only 2 (18.2%) fully recovered. Duration of follow‐up was mostly short, with 3–6 months in 27.3% and >6 months in another 27.3%. This group underscores the neurotoxic potential of antifungal agents, especially amphotericin B, in immunocompromised individuals receiving intensive therapy (Tables S2 and S4).

Ataxia and Cerebellar Involvement

This group showed a predominance of older males (mean age 54.5 years, 70.6% male). Most patients were immunocompetent (70.6%), and 12/17 had comorbidities, including hypertension (3), diabetes (2), HIV/AIDS (1), and lymphoma post‐rituximab (1). Fungal etiologies were diverse: cryptococcal infections (seven cases), cerebellar abscesses (4), paracoccidioidomycosis (3), aspergillosis (2), and histoplasmosis (1). Causative species included C. neoformans (6), P. brasiliensis (3), and A. fumigatus (3). Gait ataxia was the most common manifestation (58.8%), followed by truncal and limb ataxia. Imaging showed ring‐enhancing cerebellar lesions (52.9%), leptomeningeal enhancement (23.5%), and infarcts/edema (29.4%). The cerebellum was involved in 16 of 17 cases (94%), affecting the vermis (three cases), bilateral hemispheres (4), and posterior cerebellum (2). CSF‐based tests (52.9%) and histopathology (41.2%) confirmed the diagnosis. Treatment included antifungal drugs alone (3), surgery with antifungals (4), and immunomodulation or shunting (4). Recovery was seen in 11 patients (64.7%), while three died (17.6%). Proposed mechanisms included direct cerebellar invasion (53%), leptomeningeal inflammation or infarcts (18%), and pressure effects (18%). Follow‐up extended beyond 1 year in 8 patients (47%), suggesting ataxia may have a relatively favorable prognosis with appropriate intervention (Tables S3 and S4).

This systematic review highlights several salient and previously underrecognized aspects of movement disorders associated with central nervous system fungal infections. It is the first to delineate clinical patterns across three distinct subgroups: movement disorders due to direct fungal involvement, antifungal drug‐induced disorders, and cerebellar ataxia syndromes. Cryptococcal species were the most frequently implicated pathogens, particularly in immunocompetent individuals, challenging the traditional view that such infections are limited to immunosuppressed hosts. Notably, many of these immunocompetent cases originated from tropical and subtropical regions, including Brazil, India, Malaysia, and Mexico, where environmental exposure is high. Cryptococcus gattii, in particular, is known to infect immunocompetent hosts and is strongly associated with environmental reservoirs such as decaying eucalyptus trees, soil, and avian droppings. Geographic clustering of such cases underscores that local ecological factors, rather than overt immune deficiency alone, may determine disease risk. This highlights the importance of environmental exposure in the pathogenesis of CNS cryptococcosis among apparently healthy individuals.

Chorea was the most frequent movement disorder in our review, yet basal ganglia involvement was the predominant neuroimaging correlate, reflecting the central role of basal ganglia–thalamocortical circuits in motor control. Lesions in the subthalamic nucleus or striatum often produced chorea or hemiballismus, while substantia nigra or putaminal involvement was more often associated with parkinsonism. Cryptococcal and histoplasma lesions localized mainly to the striatum, caudate, or subthalamic nucleus, explaining the predominance of choreiform presentations. Basal ganglia thus represent a common pathway linking fungal neuropathology to abnormal involuntary movements, while cerebellar abscesses and leptomeningeal inflammation were dominant correlates of ataxia. Amphotericin B, the cornerstone of antifungal therapy, was the main drug implicated in treatment‐induced movement disorders, typically via leukoencephalopathy and extrapyramidal toxicity. Underlying disease strongly influenced susceptibility and outcomes: profound immunosuppression from HIV/AIDS, malignancy, or transplantation predisposed to disseminated disease, whereas metabolic illnesses such as diabetes, renal or hepatic failure, and environmental exposures facilitated infection in apparently immunocompetent hosts. In such patients, advancing age, subtle immune dysregulation, and systemic comorbidities likely interacted with direct fungal invasion to shape neurological manifestations, including ataxia and cerebellar involvement (Tables S1 and S4).

Movement disorders and cerebellar ataxia in fungal infections of the central nervous system arise through multiple overlapping mechanisms. These mechanisms vary depending on the fungal species, immune status of the patient, and anatomical location of the infection. One important mechanism is direct invasion of brain structures involved in motor control. Fungi such as Cryptococcus neoformans, Histoplasma capsulatum, and Aspergillus species can penetrate the blood–brain barrier and reach deep brain regions such as the basal ganglia, thalamus, and midbrain. When these structures are affected, disorders like chorea, parkinsonism, and dystonia may appear. A study examined 11 AIDS patients with CNS cryptococcosis and found that cryptococcal involvement of the dentate nuclei was common but underrecognized. CT failed to detect infratentorial lesions, while MRI identified dentate and supratentorial lesions more reliably. All patients had dilated Virchow‐Robin spaces, and most had gelatinous pseudocysts. ⁹ Another possible mechanism is vascular. Fungal infections can cause vasculitis or small‐vessel thrombosis. This leads to infarcts in motor pathways. For example, fungal invasion of perforating arteries supplying the basal ganglia may result in ischemic injury. This can produce sudden or subacute movement disorders. In some cases, cerebellar arteries may be involved, leading to ataxia. ¹⁰ , ¹¹ Inflammation is also a key contributor. Fungal infections cause immune activation within the brain. This inflammatory response may damage neurons and supporting cells. When the inflammation involves the cerebellum or its connections, patients may develop gait disturbance, limb incoordination, or truncal instability. A post‐infectious immune‐mediated response is sometimes observed even after the fungal infection is controlled. Additionally, post‐infectious immune dysregulation may trigger autoimmune encephalitis, such as anti‐NMDA receptor encephalitis, compounding neurological symptoms. ¹² , ¹³ The occurrence of ataxia and cerebellar involvement in “immunocompetent” hosts likely reflects not only direct fungal invasion but also the interaction of advancing age, subtle immune dysregulation, and comorbid systemic illnesses, which together increase susceptibility to CNS fungal pathology and influence the pattern of neurological manifestations.

Some patients develop movement abnormalities due to raised intracranial pressure or hydrocephalus. This mechanical pressure can affect cerebellar and midbrain structures, causing ataxia or tremor. In addition, antifungal drugs themselves may be neurotoxic. Agents such as amphotericin B can damage white matter, leading to leukoencephalopathy and extrapyramidal symptoms. ¹⁴ , ¹⁵ Central nervous system mycoses produce movement disorders through overlapping mechanisms. Direct fungal invasion damages basal ganglia or cerebellar circuits, while vascular injury from angioinvasion causes infarcts in motor pathways. Inflammatory dysregulation, hydrocephalus, and antifungal drug neurotoxicity further shape symptoms. Age, diabetes, renal or hepatic dysfunction, and genetic factors subtly compromise immunity even in “immunocompetent” hosts, making pathogenesis multifactorial and explaining the diverse neurological manifestations observed in reported cases.

This review has several limitations. Most included data were derived from case reports and small series, introducing potential publication and selection bias. Heterogeneity in reporting limited standardized comparisons across cases, particularly regarding diagnostic methods, imaging details, and treatment responses. The absence of a control group precludes inference of causality or incidence estimates. Many reports lacked long‐term follow‐up, hindering assessment of sustained outcomes. Additionally, reliance on clinical judgment for attribution of movement disorders to fungal infection or antifungal therapy may have introduced subjectivity. Finally, the exclusion of non‐English articles may have led to the omission of relevant cases from non‐indexed regional literature.

Conclusion

In conclusion, movement disorders in CNS fungal infections are diverse, underrecognized, and may arise from infection or antifungal therapy. Basal ganglia and cerebellar involvement are common. Early recognition, targeted imaging, and prompt intervention are essential.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Study design, B. Study execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique.

R.K.G.: 1A, 1B, 1C, 2B, 2C, 3A, 3B

P.S.: 1A, 1B, 1C, 2B, 2C, 3A, 3B

R.A.M.: 2B, 2C, 3A, 3B

S.S.S: 2B, 2C, 3A, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work.

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

Financial Disclosures for the Previous 12 Months: RKG received honoraria/ royalty for writing book chapters for UpToDate (Wolters Kluwer Health) and MedLink Neurology USA. The other authors declare that there are no additional disclosures to report.

Informed Consent

This is a systematic review of previously published studies. As it did not involve direct patient participation or collection of new data, informed consent was not required.

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.

Supporting information

Data S1. Item S1: Evaluation of the methodological quality of case reports and case series.

Data S2. Item S2: PRISMA checklist.

Supplementary Table S1. Case‐wise Summary of Movement Disorders Attributable to Central Nervous System Fungal Infections: Etiology, Presentation, and Outcomes.

Supplementary Table S2. Drug‐Induced Movement Disorders Following Antifungal Therapy in Central Nervous System Fungal Infections: A Case‐Based Analysis.

Supplementary Table S3. Clinical Characteristics of Ataxia and Cerebellar Involvement in Central Nervous System Fungal Infections: A Case‐Based Review.

Supplementary Table S4. Summary Table of Clinical Patterns and Outcomes of Movement Disorders and Ataxia in Central Nervous System Fungal Infections.

Data Availability Statement

The data that supports the findings of this study are available in the supplementary material of this article.