Post-Malaria Neurological Syndrome (PMNS): a rare case report with brain biopsy findings

doi:10.21203/rs.3.rs-2762320/v1

Download PDF

Case Report

Post-Malaria Neurological Syndrome (PMNS): a rare case report with brain biopsy findings

https://doi.org/10.21203/rs.3.rs-2762320/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 19 Dec, 2023

Read the published version in BMC Infectious Diseases →

You are reading this latest preprint version

Post-malaria neurological syndrome (PMNS) is a rare, self-limiting condition that presents with a wide range of neurological manifestations after clearance of malarial infection, especially Plasmodium Falciparum, most patients recover without residual deficits. Here we present a case of a 29-year-old, male with a recent history of malaria treated successfully, who presented due to a generalized tonic-clonic seizure, without any other neurological symptoms, the examination and labs were unremarkable, he underwent a computer tomography (CT) scan and Magnetic resonant imaging (MRI) which both showed two areas of vasogenic edema involving the subcortical white matter of left frontal and right posterior parasagittal regions, all autoimmune screens, infection workup from blood and CSF were negative, he underwent a brain biopsy that showed intense perivascular inflammation with neuronal loss and gliosis, findings are nonspecific and can be seen in a variety of condition. The patient’s condition improved, and he was discharged without any complications.

Post Malaria neurological syndrome (PMNS)

Malaria

brain biopsy

Acute disseminated encephalomyelitis (ADEM)

Malaria is an endemic disease with high morbidity and mortality if not treated, Malaria can present with de novo neurological symptoms, and can lead to sequelae, especially with cerebral malaria. PMNS on the other hand is the development of new neurological manifestations in patients who had recent malaria infection with successful treatment, PMNS is a relatively new phenomenon [1], with low incidence, the presentation has a wide range of neurological signs and symptoms from headache to seizure, confusion, and loss of consciousness, a set of criteria was suggested to aid in the diagnosis of PMNS; requiring a recent infection with malaria that successfully treated proven by malaria negative smear, and a symptoms-free period after malaria cure [2]. Before considering PMNS all effort must be done to rule out all other causes that can explain the patient presentation, The presence of abnormal brain imaging findings was reported in up to half of the cases with PMNS with no specific pattern or distribution [3], almost all of the cases showed neurological improvement and resolution of all symptoms without remaining deficit, although steroid was used in some severe cases to fasten the recovery. However, its use is still debated whether it has a role in the improvement of these cases [1, 4]. Herein, we present a case of new seizure disorder in a patient with a recent Malaria infection, The importance of our case is to highlight the PMNS brain biopsy findings, which have not been reported before, this can lead to a better understanding of the disease. We report this case to highlight PMNS as one of the deferential diagnoses for any patient present with neurological manifestation after cured malarial infection.

A 29-year-old male from Ghana with no history of chronic diseases, recently came to Qatar, 2 months earlier he was diagnosed with malaria and treated successfully in his home country, the patient presented to the hospital because of a generalized tonic-clonic seizure occurred for the first time at home and witnessed by his friend, followed by postictal confusion which resolved when the patient arrived to the hospital, the patient was complaining of a mild headache, otherwise he denied weakness, numbness, history of seizure, blurred vision, hearing loss, or loss of consciousness before.

Vitally was stable, and labs including CBC, electrolyte, Renal, and liver function were within normal, two malaria blood test films came negative, and the patient had high creatinine kinase, and myoglobulin on admission related to seizure which improved after, CT head (Fig. 1) showed two areas of vasogenic edema involving the subcortical white matter of the left frontal and right posterior parasagittal location with subtle increased adjacent leptomeningeal enhancement, MRI head with contrast (Fig. 2A, B, C, and D) showed heterogenous area seen mainly in subcortical and abutting cortical noted on right occipital parietal and anterior para-flacine left frontal lobe with surrounding marked vasogenic edema. CSF analysis showed WBC: 2, Glucose: 3.4 mmol/l, protein: 0.41 gm/l, no oligoclonal bands, culture: negative, TB smear, culture: negative, viral PCR: (HSV1,2, varicella zoster, enterovirus, and mumps) came negative, negative for oligoclonal bands, and cytology negative for malignancy, CSF IgG index 0.5 (within normal range), tests for brucella, syphilis, Schistosoma, HIV Ag/Ab came negative, autoimmune screen including ANA, ANCA, RF, C3, and C4 came all negative, QuantiFERON, blood culture also negative, the patient was started on phenytoin and was doing well all the hospital course without any complain.

Given the patient’s age and imaging findings, serious conditions like primary malignancy, metastasis, or hidden infection needed to be excluded, brain biopsy was done as advised by the neurology team, The biopsy showed lymphohistiocytic inflammation and areas of parenchymal injury as well as destruction. The inflammatory infiltrate is composed predominantly of macrophages, activated microglia, and small lymphocytes, predominantly small T cells highlighted by CD3 (Fig. 3) with a reversed CD4/CD8 ratio. Only a few small B cells are identified. Areas of parenchyma destruction show cavitation and cystic changes with extensive reactive gliosis characterized by astrocytes with eccentric nuclei and abundant eosinophilic cytoplasm (Gametocytes) (Fig. 4). The vessels show prominent perivascular inflammatory infiltration with greater involvement of veins–venules than arteries and arterioles (Fig. 5A, B). There is no definite evidence of vascular necrosis, granulomas, acute inflammation, emperipolesis, viral inclusions, parasites, Plasmodium, fungal elements, demyelination, or malignancy. Immunohistochemical stains are negative with BRAF V600E, HSV-1, HSV-2, and CMV.

The patient was discharged home after the brain biopsy and had a follow-up after one month with repeated MRIs head that showed the same previous change, the patient otherwise was stable without any complaint. He continues to attend our regular follow-ups.

Post-malaria neurological syndrome (PMNS) is a relatively rare transient clinical entity, post malaria neurological symptoms were first reported in early 1990 [1] but the definition of the post-malaria neurological syndrome was first presented by Nguyen et al in their study as a collection of new neurological or psychiatric features that occur after full recovery of severe Falciparum Malaria infection [2] Since then cases of PMNS were reported sporadically, mostly after Malaria Falciparum but also after infection with Vivax species [3], it is more notably after severe Malaria infection [5], the time frame requires a symptoms-free period varying from days after recovery to months [6, 7], the latency period can extend to more than 100 days post-infection [8]. Followed by complete resolution of the symptoms without sequelae [5].

The relative risk for the development of PMNS ranges between 0.7 to 1.8 per 1000 cases [2, 9] while Malaria is a quite prevalent disease in endemic areas (500 million annually) this may suggest that PMNS is underreported as only severe or serious manifestations were encountered [10].

The symptoms of PMNS encompass a wide spectrum of neurological or psychiatric symptoms, most commonly with acute psychosis like confusion 66–72% [1, 10], and seizures (~ 30%) [11]. In order to correctly identify PMNS a negative blood smear showing clearance of the parasitemia is a must for the diagnosis [2, 12]. Workup should be undertaken to rule out any other possible explanation like viral, bacterial, autoimmune, or malignancy. Cerebral spinal fluid CSF analysis could show pleocytosis with lymphocyte predominance with increased protein levels [7, 8]. However, no relation could be drawn between the symptoms’ severity and worsening CSF findings [2].

The exact mechanism of PMNS remains elusive, and few theories tried to explain it, one of the first suggested etiologies is that of molecular mimicry in which antibodies directed towards the malaria antigens would cross-react with autoantigen [3, 5]. However, this would require a prolonged persistent infection or relapse which by default would not fit under the definition of PMNS [8], another theory about structural aberrations caused by the recent malaria infection could explain the pathogenesis. However, the hallmark of rapid and complete resolution of the symptoms and the time frame makes it unlikely [3, 11]. Other possibilities like co-infection with a viral agent that precipitates encephalitis or neurotoxicity as an adverse drug reaction [5].

Interestingly, all the reported cases seem to adopt an immunological process as the main pathogenesis mechanism [6, 11] supported by the symptoms-free period, and markers of immune system activity during the disease, Poulet described multiple possible antibodies implicated in the development of PMNS like voltage-gated potassium channels (VGKC). The proposed management lines would further support this theory [3, 8].

Imaging modalities like magnetic resonance imaging (MRI) were reported to be abnormal in less than 50% of the cases [7]. Findings showed nonspecific changes with increased uptake in the grey and white matter [5]. Although it is not clear how long the changes will persist when MRI is abnormal. To the best of our knowledge, no previous case of PMNS underwent a brain biopsy, though the biopsy characteristics revealed a nonspecific neuronal injury and inflammatory response, it was crucial to eliminate possibilities of an underlying malignancy or an autoimmune process like vasculitis or ongoing infection. No final conclusion can be drawn from the biopsy findings, but it seems that the dense infiltrate with lymphocytes and macrophages – most likely in settings of immunological activation – and their interaction with the brain parenchyma are the leading cause in the pathogenesis of the symptoms.

The PMNS has common features with ADEM and AIP; the symptomology, time frame, lab, imaging findings, and prognosis would place PMNS in between ADEM and AIP [1] with possible overlapping traits from both syndromes. PMNS is self-limiting and spontaneous full recovery is the rule. However, the use of steroids in prolonged or severe cases was proposed as the first line, with intervenors immunoglobulins (IVIG) and plasmapheresis coming next in line [8, 11].

Post-malaria neurological syndrome is an important complication of Malaria infection, characterized by a post-infection symptoms-free period followed by de novo neuropsychiatric manifestations that would subside completely in a few days to weeks without residual symptoms, the syndrome is quite rare and may be underreported, further reports are needed to cast a light on the possible etiologies, the natural course of the disease, interventions, and long-term prognosis.

Acknowledgments

The authors acknowledge Dr. Issam Albozom for the pathological interpretation

Conflict of Interest Statement:

The authors declare no conflict of interest.

Funding Sources:

This work was not funded. Open access fees are provided by Qatar National Library

Author Contribution:

Dr. Mouhammad J Alawad wrote and edited the manuscript; Dr. Mustafa Almayoof edited the manuscript, Dr. Adel Al bozom performed the literature review, Dr. Taha provided clinical follow-up, Dr. Khalifa Farfar supervised the work, provided mentorship & edited the manuscript. All authors have approved the final manuscript.

Data Availability Statement:

Data and materials are available on request.

Ethical approval:

This case was approved by the Medical Research Centre of Hamad Medical Corporation, MRC 04 – 22 – 640

Consent to publish statement:

Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Guarantor:

Mouhammad J Alawad

Tamzali Y, Demeret S, Haddad E, Guillot H, Caumes E, Jauréguiberry S. Post-malaria neurological syndrome: four cases, review of the literature and clarification of the nosological framework. Malar J. 2018;17(1). 10.1186/s12936-018-2542-8.
Mai NTH, Day NP, Chuong LV, et al. Post-malaria neurological syndrome. The Lancet. 1996;348(9032):917–21. 10.1016/s0140-6736(96)01409-2.
Panda PK, Sharawat IK, Panda PK. Case Report: An Adolescent Girl with Isolated Neuropsychiatric Features and Apparent Post-Malaria Neurological Syndrome. Am J Trop Med Hyg. 2020;102(5):1030–2. 10.4269/ajtmh.19-0791.
Caetano A, Mendonça MD, Ferreira NR, Alves L. Post-malaria neurological syndrome or viral encephalitis? BMJ Case Reports Published online January. 2016;7:bcr2015213591. 10.1136/bcr-2015-213591.
Yadava SK, Laleker A, Fazili T. Post-malaria neurological syndrome: a rare neurological complication of malaria. Infection. 2019;47(2):183–93. 10.1007/s15010-019-01267-9.
Nayak R. Post-malaria neurological syndrome: a rare manifestation of common disease. Trop Doct. 2013;43(2):86–7. 10.1177/0049475513486643.
Bellazreg F, Slama D, Ben Lasfar N, et al. Neurological manifestations following cured malaria: don’t forget post-malaria neurological syndrome. Afr Health Sci. 2021;21(1):273–6. 10.4314/ahs.v21i1.35.
Poulet A, Bou Ali H, Savini H, Kaphan E, Parola P. Post-malaria neurological syndrome: Imported case series and literature review to unscramble the auto-immune hypothesis. Travel Med Infect Dis. 2019;29:16–20. 10.1016/j.tmaid.2018.09.003.
Mizuno Y, Kato Y, Kanagawa S, et al. A case of postmalaria neurological syndrome in Japan. J Infect Chemother. 2006;12(6):399–401. 10.1016/s1341-321x(06)70902-3.
Markley JD, Edmond MB. Post-Malaria Neurological Syndrome: A Case Report and Review of the Literature: Table 1. J Travel Med. 2009;16(6):424–30. 10.1111/j.1708-8305.2009.00349.x.
Castaldo N, Tascini C, Della Siega P, Peghin M, Pecori D. Clinical presentation and immunological features of Post-Malaria Neurologic Syndrome: a case report and review of literature. Malar J. 2020;19(1). 10.1186/s12936-020-03476-2.
Carreira J, Casella MI, Ascenção BB, et al. Acute disseminated encephalomyelitis, a rare post-malaria neurological complication: Case report and review of the literature. Travel Med Infect Dis. 2019;28:81–5. 10.1016/j.tmaid.2018.03.005.

No competing interests reported.

Download PDF

Journal Publication

published 19 Dec, 2023

Read the published version in BMC Infectious Diseases →

Editorial decision: Major revision
20 Jun, 2023
Reviews received at journal
20 Jun, 2023
Reviewers agreed at journal
13 Jun, 2023
Reviews received at journal
11 Apr, 2023
Reviewers agreed at journal
11 Apr, 2023
Reviewers agreed at journal
10 Apr, 2023
Reviewers invited by journal
10 Apr, 2023
Editor assigned by journal
10 Apr, 2023
Editor invited by journal
07 Apr, 2023
Submission checks completed at journal
07 Apr, 2023
First submitted to journal
31 Mar, 2023

You are reading this latest preprint version

Post-Malaria Neurological Syndrome (PMNS): a rare case report with brain biopsy findings

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Case Presentation

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1