Dear Editor,

Cortical tremor, also known as rhythmic cortical myoclonus, is a small amplitude, rhythmic oscillation involving the distal upper limbs during posture and action and is rarely present at rest [1]. The pathophysiology of cortical tremor is believed to be associated with increased excitability in the sensorimotor cortex, similar to cortical myoclonus [1]. Cortical tremor is a common symptom observed in several conditions, including celiac disease, corticobasal syndrome, autoimmune encephalopathy, and druginduced disorders. Here, we report a patient presenting with cortical tremors in the bilateral hands after 1 month of recovery from initial Plasmodium falciparum infection.

A 65-year-old Korean male patient visited the outpatient clinic in the Department of Neurology and reported new-onset bilateral hand tremors that had developed 1 week prior. He presented fine, distal, semirhythmic contraction of his hands that was observed during forward outstretching posture and when performing hand movement tests and finger-to-nose tests, consistent with cortical tremor. He also had myoclonus in his hands during the resting state. He denied other symptoms, such as headache, dizziness, and cognitive decline. He had a past medical history of malaria treatment 2 months prior to the present visit. A detailed past medical history showed episodic high fever after returning from the Republic of Uganda 3 months earlier, after which he had been initially diagnosed with P. falciparum infection. He showed only transient confusion but other neurological examinations were unremarkable. After anti-malarial medications, his medical condition gradually improved, and he recovered fully without any neurological complaints at the time of discharge. Final malaria examination revealed no malarial parasites.

At the present visit, the patient was initially planned for admission to further evaluate his cortical tremor. However, during the 2-week waiting period after the outpatient clinic visit, he experienced worsening hand tremor (Supplementary Video 1 in the online-only Data Supplement). Along with the onset of new symptoms such as confusion, disorientation, and memory impairment, his condition necessitated an immediate visit to the emergency center. Initial enhanced brain magnetic resonance imaging (MRI) revealed diffuse leptomeningeal enhancement in only the contrast-enhanced fluid-attenuated inversion recovery (CE-FLAIR) sequence, with no definite leptomeningeal enhancement observed in the T1 sequence (Figure 1). Blood tests revealed no malarial parasites. Cerebrospinal fluid (CSF) analysis was performed, revealing lymphocytic meningitis with a white blood cell count of 37 μL with 66% lymphocytes, an elevated protein level of 190.6 mg/dL, and a glucose level of 81 mg/dL. Based on the overall clinical profile and evaluation, a diagnosis of post-malaria neurologic syndrome (PMNS) was made. Thereafter, the patient was initially started on intravenous acyclovir, which was subsequently discontinued after CSF results all were negative except one paraneoplastic antibody test (anti-recoverin 1+). Ophthalmologic evaluation for retinal involvement and enhanced chest/abdomen computed tomography for malignancy workup showed unremarkable results. Followup brain MRI showed a decreased extent of diffuse leptomeningeal enhancement on the same sequence. He showed a partial response to intravenous methylprednisolone 1 g/day for 5 days and a greater response to subsequent intravenous immunoglobulin 400 mg/kg for 5 days. At the 6-month follow-up after discharge, he experienced complete recovery from his symptoms, including cortical tremor.

Since it was first reported in 1996, PMNS is well known for its characteristic development of neurological symptoms after full initial recovery from malaria infection and clearance of parasitemia following treatment, most commonly with complicated P. falciparum [2]. It is associated with various neurological symptoms, including confusion, seizure, tremor, behavioral abnormities, impaired consciousness, and myoclonus [2,3]. However, cortical tremor has not been reported in patients with PMNS. Among those patients, tremor was reported as occurring in less than 20% of cases [2]. However, cortical tremor, also known as rhythmic cortical myoclonus, has not been previously reported in PMNS. In our case, the patient exhibited semirhythmic (8–10 Hz), small amplitude (1–2 cm) oscillations in the distal upper limbs during postural and kinetic movement. The rhythmicity of cortical tremor is thought to be influenced by the cortical loop, subcortical structures, and the cerebello-motor cortical loop [1]. In this case, diffuse leptomeningeal involvement in the bilateral cerebral and cerebellar cortex can contribute to the manifestation of cortical tremor via unstable cerebello-motor cortical loop mechanisms [1]. Even without corroborative electrophysiological study data, the rhythmicity, duration, amplitude, and exacerbating patterns aligned with the typical manifestations of cortical tremor.

The pathogenesis of PMNS is not fully understood, but delayed onset after a median 14-day (range 0–60 days) symptomfree period and beneficial effects of intravenous corticosteroids and immunoglobulin are suggestive of the immunological mechanism of this disease [2]. In our case, the patient experienced complete recovery following immunotherapy without any additional complications, further supporting the involvement of an immunological process. PMNS’s subacute neurological progression resembles autoimmune encephalitis, suggesting a potential diagnosis. The antineuronal antibody test was positive for anti-recoverin, often linked with cancer-related retinopathy [4]. However, no clinical evidence of underlying cancer or ophthalmologic abnormalities was found. Moreover, the patient’s history of malaria and the typical time interval between symptom onset and malaria infection suggested a false-positive result for anti-recoverin antibodies. A total of 71.3% of patients show false positivity for paraneoplastic antibodies [5]. This underscores the necessity for careful interpretation of positive antineuronal antibody results [4-6].

In PMNS, brain MRI scans typically appears normal but may reveal signal changes in areas such as the periventricular zones, brain stem, and cerebellum [2]. Our case presented diffuse leptomeningeal enhancement on the CE-FLAIR sequence but not on the T1 sequence. In addition, there was no evidence of parenchymal involvement on either of two executive brain MR images. The CE-FLAIR sequence, owing to its higher diagnostic accuracy and stronger correlation with CSF parameters compared to T1-based sequences, has been widely used as a part of the routine MRI protocol and could be a better imaging choice for the early identification of infectious meningitis [7]. Previous studies reported that more than 50% of PMNS patients showed unremarkable brain MRI results but did not perform the CE-FLAIR sequence [2]. We recommend that the CE-FLAIR sequence be included in brain MRI for suspected diagnosis of PMNS.

In conclusion, we presented a rare clinical manifestation of PMNS characterized by cortical tremor, which demonstrated a positive response to immunotherapy. As PMNS can be misdiagnosed as paraneoplastic encephalopathy, a detailed medical history is important, and the possibility of false-positive antineuronal antibody results should be considered.

Supplementary Material

Notes

Ethics Statement

This study was approved by the Institutional Review Board of Samsung Medical Center (IRB No. SMC 2023-07-038). Written informed consent was obtained from the patient for anonymous use of demographic data, medical conditions, images, videos, treatment, and prognosis.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Author contributions

Conceptualization: Jong Hyeon Ahn. Data curation: all authors. Investigation: all authors. Methodology: all authors. Project administration: Jong Hyeon Ahn. Supervision: Jinyoung Youn, Jin Whan Cho, Jong Hyeon Ahn. Visualization: Jun Seok Lee, Jong Hyeon Ahn. Writing—original draft: Jun Seok Lee, Jong Hyeon Ahn. Writing—review & editing: Jun Seok Lee, Jong Hyeon Ahn.

Figure 1.

Brain magnetic resonance imaging (MRI) findings of the patient. Initial brain MRI showed diffuse leptomeningeal enhancements in cerebral sulci and cerebellar folia on the axial contrast-enhanced fluid attenuated inversion recovery (CE-FLAIR) sequence (A). On the other hand, the axial contrast-enhanced T1 sequence imaged on the same day as the CE-FLAIR presents unremarkable enhancements at similar levels (B). In the follow-up brain MRI, there was a significant reduction in the degree of leptomeningeal enhancement in the axial CE-FLAIR compared to the initial brain MRI (C). The contrast-enhanced T1 sequence of follow-up brain MRI shows no signs of leptomeningeal enhancement (D).

REFERENCES

• 1. Latorre A, Rocchi L, Magrinelli F, Mulroy E, Berardelli A, Rothwell JC, et al. Unravelling the enigma of cortical tremor and other forms of cortical myoclonus. Brain 2020;143:2653–2663.ArticlePubMedPDF
• 2. Yadava SK, Laleker A, Fazili T. Post-malaria neurological syndrome: a rare neurological complication of malaria. Infection 2019;47:183–193.ArticlePubMedPMCPDF
• 3. Trivedi S, Chakravarty A. Neurological complications of malaria. Curr Neurol Neurosci Rep 2022;22:499–513.ArticlePubMedPMCPDF
• 4. Lee SK, Lee ST. The laboratory diagnosis of autoimmune encephalitis. J Epilepsy Res 2016;6:45–50.ArticlePubMedPMC
• 5. Ebright MJ, Li SH, Reynolds E, Burke JF, Claytor BR, Grisold A, et al. Unintended consequences of Mayo paraneoplastic evaluations. Neurology 2018;91:e2057–e2066.ArticlePubMedPMC
• 6. Kim G, Hong HL, Kim SY, Lee HR, Kim DG, Park S, et al. Mixed infection with Plasmodium falciparum and Plasmodium ovale in a returned traveller: the first case in Korea. J Korean Med Sci 2019;34:e23. ArticlePubMedPMCPDF
• 7. Azad R, Tayal M, Azad S, Sharma G, Srivastava RK. Qualitative and quantitative comparison of contrast-enhanced fluid-attenuated inversion recovery, magnetization transfer spin echo, and fat-saturation T1-weighted sequences in infectious meningitis. Korean J Radiol 2017;18:973–982.ArticlePubMedPMCPDF

Figure & Data

References

Citations

Citations to this article as recorded by  

Comments on this article