How a Malaria-like Protozoa may Trigger Micro-bleeds and Brain Lesions in MS (References)

The following references, taken together, point to a very different way of looking at MS. They show that MS lesions often form around tiny blood vessels, that people with MS can have more small brain bleeds and iron deposits around brain lesions, and that infections living inside red blood cells can cause exactly this kind of damage in the brain. They also highlight both old quinine reports and a modern hydroxychloroquine study where drugs originally designed to target malaria‑like parasites appeared to slow or improve MS‑type illness. All of this strongly suggests that infections in the blood and damage to small blood vessels may be playing a much bigger role in MS.

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References:

Hydroxychloroquine in PPMS

1. Koch M, Kaur S, Fransen NL, et al. Hydroxychloroquine for primary progressive multiple sclerosis. Ann Neurol. 2021;90(6):940-948. doi:10.1002/ana.26239.

Single‑arm, phase II futility trial (35 PPMS patients, 200 mg HCQ BID for 18 months) found that only 24% had ≥20% worsening on the Timed 25‑Foot Walk, which was less than the expected 40% threshold, suggesting HCQ reduced disability worsening and is a promising candidate needing randomized trials.
Link: https://pubmed.ncbi.nlm.nih.gov/34590328/​

2. Hydroxychloroquine in primary progressive multiple sclerosis. ClinicalTrials.gov identifier: NCT02913157.

Trial registry describing design: open‑label, single‑arm PPMS study testing whether 400 mg/day HCQ can prevent worsening of walking ability, excluding patients with enhancing lesions to focus on non‑inflammatory progression.​
Link: https://clinicaltrials.gov/study/NCT02913157​

3. Petracca M, Kaur S, Whitehouse L, et al. Serum neurofilament-light and glial fibrillary acidic protein levels in primary progressive multiple sclerosis treated with hydroxychloroquine. Mult Scler Relat Disord. 2023;68:104234. doi:10.1016/j.msard.2022.104234.

Biomarker analysis from the HCQ PPMS trial showing associations between treatment, neurofilament light, and GFAP, supporting a potential effect of HCQ on neurodegenerative processes in PPMS.​
Link: https://pubmed.ncbi.nlm.nih.gov/36214614/​

 

Central Vein Sign and Venocentric Lesions

4. Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722. doi:10.1038/nrneurol.2016.166.

Reviews evidence that MS lesions are characteristically venocentric, containing a small central vein, and proposes the central vein sign as an MRI biomarker to improve diagnostic specificity versus MS mimics.​
Link: https://www.nature.com/articles/nrneurol.2016.166​

5. Maggi P, Absinta M, Grammatico M, et al. Central vein sign differentiates multiple sclerosis from central nervous system inflammatory vasculopathies. Ann Neurol. 2018;83(2):283-294. doi:10.1002/ana.25154.

Demonstrated that when ≥50% of white matter lesions show a central vein, MS can be distinguished from inflammatory vasculopathies with very high diagnostic accuracy, reinforcing the perivenular origin of MS lesions.​
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC5901412/​

 

Blood–brain Barrier Evolution and Vascular Damage

6. Gaitán MI, Shea CD, Evangelou IE, et al. Evolution of the blood–brain barrier in newly forming multiple sclerosis lesions. Ann Neurol. 2011;70(1):22-29. doi:10.1002/ana.22472.

Using dynamic contrast‑enhanced MRI, showed that new MS lesions start with perivenular ring‑like enhancement that fills in centripetally, reflecting early, focal BBB breakdown around small veins, consistent with a vascular‑first lesion pattern.​
Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC3143223/​

7. Adams CW. Perivascular iron deposition and other vascular damage in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1988;51(2):260-265. doi:10.1136/jnnp.51.2.260.

Classic pathology paper documenting perivascular iron deposition, vessel wall damage, and evidence of red blood cell extravasation in MS plaques, supporting a role for micro‑bleeds and vascular injury in lesion development.​
(Access via iron chelation review) Link: https://www.tandfonline.com/doi/full/10.1042/AN20130037 (cites Adams 1988 extensively)​

 

Malaria‑like Infection and MS (Historical Research)

8. Kissler H. Is multiple sclerosis caused by a silent infection with malarial parasites? A historico-epidemiological approach: Part I. Med Hypotheses. 2001;57(2):180-187. doi:10.1054/mehy.2000.1171.

Link: https://pubmed.ncbi.nlm.nih.gov/11516218/

Part I reviews historical MS and malaria data and argues that the geographic and temporal patterns of MS (early clusters, latitude effects, and migration patterns) can be re‑interpreted as compatible with a long‑standing, often silent malarial or malaria‑like infection. It highlights early case descriptions where malaria and “disseminated sclerosis” overlapped and suggests that the spread of MS in Europe and North America may have followed the earlier spread and partial eradication of malaria, supporting the idea that at least some MS could reflect chronic intra‑erythrocytic parasitic infection rather than a purely spontaneous autoimmune disease.

9. Kissler H. Is multiple sclerosis caused by a silent infection with malarial parasites? A historico‑epidemiological approach. Med Hypotheses. 2001;56(3):329-335. doi:10.1054/mehy.2000.1182.

Part 2 reviews more than 100 years of observations (geography, seasonality, case reports, autopsies, quinine responses) and argues that silent malarial or malaria‑like infection could underlie MS in a subset of patients, citing data on antibodies and parasites found in MS cohorts.​
(Full text often behind paywall; your Live Disease Free website summary.)

Link: https://livediseasefree.com/the-lost-malaria-ms-link-over-140-years-of-forgotten-research-that-changes-everything/​

 

10. Spelman T, Gray OM, Trojano M, et al. Seasonal variation of relapse rate in multiple sclerosis is associated with sunlight exposure. J Neurol Neurosurg Psychiatry. 2017;88(11):1075-1079. doi:10.1136/jnnp-2017-315689.

Large registry‑based analysis showing significant seasonal variation in MS relapse rates, with peaks in spring and associations with monthly sunshine hours, supporting an environmental/infectious or seasonal trigger component.​
Summary: https://climahealth.info/resource-library/seasonal-variation-in-multiple-sclerosis-relapse/​

 

Malaria, Microvasculature, and Brain Injury

11. Pikor D, Hurła M, Banaszek-Hurła N, Drelichowska A, Paul M. Neurovascular pathophysiology and emerging biomarkers in cerebral malaria: an integrative perspective. Neurol Int. 2025;17(9):149. doi:10.3390/neurolint17090149.

This cerebral malaria review reinforces a neurovascular model that looks strikingly similar to what we see in MS. It shows how parasites inside red blood cells sequester in tiny brain vessels, activating the endothelium, disrupting the blood–brain barrier, and causing microvascular congestion, perivascular hemorrhages, and microinfarcts—lesions that closely resemble the perivenular damage, iron deposition, and microbleeds described in MS. It also highlights endothelial and inflammatory biomarkers (like adhesion molecules, Ang‑2/Ang‑1, and CXCL10) and argues that effective treatment must stabilize the microvasculature and protect the BBB, not just kill parasites—exactly the kind of vascular‑focused thinking that could be applied to MS as well.​

Link: https://pmc.ncbi.nlm.nih.gov/articles/PMC12472603/

12. Deplaine G, Safeukui I, Jeddi F, et al. The sensing of poorly deformable red blood cells by the human spleen can be mimicked in vitro. 2011;117(8):e88-e95. doi:10.1182/blood-2010-10-312801.

Shows that Plasmodium‑infected RBCs become less deformable and more likely to be sequestered or cause microcirculatory problems, providing a mechanistic basis for microvascular blockage in malaria.
Accessible review: https://pubmed.ncbi.nlm.nih.gov/21163923/​

 

Babesia and MS 

13. Haberli N, Coban H, Padam C, et al. Babesia microti infection in a patient with multiple sclerosis treated with ocrelizumab. Mult Scler Relat Disord. 2021;48:102731. doi:10.1016/j.msard.2020.102731.

Case report of severe babesiosis in an MS patient on anti‑CD20 therapy, highlighting how malaria‑like RBC parasites can cause significant hematologic and systemic disease in this population and the need for vigilance in endemic areas.​
Link: https://pubmed.ncbi.nlm.nih.gov/33450528/​

 

Early Clinical and Pathological Observations (MS–malaria Overlap)

14. Prince AD. Multiple sclerosis following malarial infection: report of nine cases observed in soldiers. J Nerv Ment Dis. 1889;16.

Neurologist Prince described at least six, later nine, cases in which malaria was followed by a chronic neurological illness compatible with disseminated sclerosis, suggesting a temporal association between malaria and MS‑like syndromes.​
(Details summarized in: Kissler H. Med Hypotheses. 2001.)​

15. Spiller WG. A case of malaria simulating disseminated sclerosis. Univ Penn Med Bull. 1897;10.

Reported a malaria case with unilateral spastic weakness and other signs closely resembling disseminated sclerosis, explicitly noting how similar the neurological picture was to MS.​

16. Spiller WG. Disseminated sclerosis with unsuspected malarial infection: report of an autopsy case. J Nerv Ment Dis. 1900;27.

Autopsy case of an 8‑year MS‑like illness in a man with no history of malaria attacks, where motile malarial parasites were found post‑mortem in small vessels of brain and spinal cord, implying long‑standing, clinically silent malarial infection.​

17. Mannaberg J. Ueber die Beziehungen zwischen Malaria und multipler Sklerose. Wien Klin Wochenschr. 1899;12.

Argued, based on clinical and pathological similarities, that disseminated sclerosis could be caused by malarial parasites, and that MS‑like symptom complexes played an important role in malaria.​

18. Müller F. Ueber die Pathogenese der multiplen Sklerose und ihre Beziehung zur Malaria. Dtsch Med Wochenschr. 1904;30.

Proposed that both malaria and MS involved obstruction of small brain vessels by parasitized red blood cells, and recommended quinine as a useful remedy in all cases of MS, particularly when vertigo was a major symptom.​

19. Dürck H. Ueber die pathologische Anatomie der Malaria: Granulome und Leptomeningitis. Beitr Pathol Anat. 1917;62.

Described malaria granulomas and leptomeningitis in cerebral malaria and compared them to similar granulomatous and meningeal findings reported in MS brains, suggesting these could represent early stages of MS plaques.​

20. Frerichs F. Ueber multiple Sklerose mit kapillaren Blutungen. Arch Pathol Anat Physiol Klin Med. 1849;2.

One of the earliest MS pathology descriptions, noting multiple small hemorrhages in association with demyelinating lesions, supporting the idea of capillary hemorrhages as part of MS lesion formation.​

21. Dawson JW. The histology of disseminated sclerosis. Trans R Soc Edinb. 1916;50:517‑740.

Classic MS pathology monograph; included description of small capillary hemorrhages and perivenular demyelination in MS, which later authors compared to hemorrhagic changes seen in cerebral malaria.​

22. Unnamed authors (two neuropathologists). Cerebral malaria lesions producing multiple areas of sclerosis. Arch Neurol Psychiatry. 1942;47.

Reported that hemorrhages, necrotic foci, and granulomatous nodules in cerebral malaria all healed as “patches of sclerosis,” and concluded that multiple scattered areas of sclerosis from malaria could disturb brain function similarly to MS.​

 

Early Quinine Treatment Reports

23. Unnamed authors. On three cases of coexisting malaria and multiple sclerosis treated with quinine. Med Klin Wochenschr. 1892;9.

Described three clinical situations where malaria and MS‑like disease overlapped (symptoms during fever, after fever, or without fever) and noted that quinine treatment was beneficial in two MS cases.​

24. Marburg O. Über die Behandlung der multiplen Sklerose mit Chinin. Wien Klin Wochenschr. 1920s;33.

Reported that small doses of quinine improved overall health and neurological function in MS patients, especially in early stages, and recommended its continued use.​

25. Brickner RM. The treatment of multiple sclerosis with quinine: results in forty‑nine patients over five years. Arch Neurol Psychiatry. 1935;33.

Systematic 5‑year observation of 49 MS patients treated with quinine; concluded that quinine therapy was beneficial, particularly in early MS, based on global clinical impressions and functional outcomes.​

26. Conklin SD. Multiple sclerosis treated with quinine hydrochloride: report of a complete functional recovery. J Nerv Ment Dis. 1937;85.

Detailed case of a 27‑year‑old woman diagnosed with MS who received continuous quinine hydrochloride from 1934–1937 and experienced rapid, near‑complete, and sustained recovery of neurological function, with only nystagmus remaining.​

27. Castellani A. Malaria closely simulating disseminated sclerosis: four cases cured by quinine. 1917;190(4911).

Reported one Balkan and three tropical cases of a malarial condition with scanning speech, intention tremor, nystagmus, spastic gait, and hyperreflexia—clinically indistinguishable from MS—all completely cured with quinine; Castellani concluded they were not “true MS” precisely because they responded to antimalarial therapy.​

28. Craig CF. The diagnostic value of quinine reaction in chronic malaria with neurological manifestations. Am J Trop Med. 1917;1.

Observed that administration of quinine in suspected chronic malaria could provoke fever and clinical reactions even when no parasites were seen, using this as evidence to attribute central nervous system lesions to malarial infection.​

29. Mühlens P. Die Chininprobe zur Aufdeckung latenter Malariainfektionen. Dtsch Med Wochenschr. 1921;47.

Described the “quinine test” method: small quinine doses triggering reappearance of parasites or fever, used as a diagnostic tool to unmask latent malaria when blood smears were repeatedly negative.​

30. Perret‑Gentil M. Beobachtungen über Malariaplasmodien bei Beginn der Chinintherapie. Schweiz Med Wochenschr. 1945;75.

Recommended examining blood specifically at the start of quinine therapy, when he most often observed malarial parasites and fever in chronic or silent malarial infections.​

 

Cerebral Micro-bleed Studies

31. Zivadinov R, Ramasamy DP, Benedict RHB, et al. Cerebral microbleeds in multiple sclerosis evaluated on susceptibility-weighted images and quantitative susceptibility maps: a case-control study. 2016;281(3):884-895. doi:10.1148/radiol.2016160060.

445 MS patients, 45 CIS, 51 other neurological disease, 177 healthy controls; using SWI and QSM, they found a higher prevalence of cerebral microbleeds in MS/CIS than in healthy controls, especially in older patients, and more microbleeds were associated with worse physical and cognitive disability.
URL: https://pubmed.ncbi.nlm.nih.gov/27308776/​

32. Subramanian K, Haacke EM, Li X, et al. Longitudinal magnetic resonance imaging of cerebral microbleeds in multiple sclerosis patients. Brain Sci. 2020;10(11):815. doi:10.3390/brainsci10110815.

In 2 MS cohorts (100 RRMS; 112 MS + 25 controls) scanned with SWI and QSM, 14–19% of MS subjects had at least one microbleed; new microbleeds appeared over time, and longer disease duration and older age increased the chance of developing microbleeds, confirming that CMBs can accumulate and change over time in MS.
URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC7697968/​

33. Cerebral microbleeds in MS patients are associated with increased risk for physical, cognitive disability. News release. University at Buffalo press summary of Zivadinov et al.

Summarizes the Radiology case‑control study: “20% of MS patients over the age of 50 have cerebral microbleeds compared to 7% of healthy controls;” among those under 50, 14% of CIS patients had microbleeds vs 3% of healthy controls, and microbleeds were associated with increased physical and cognitive disability.
URL: https://www.buffalo.edu/news/releases/2016/06/022.html​

There are real solutions to recover from parasites today!

To restore health, we must focus on treating the cause of inflammation, which are parasites. First, identify the enemy (parasites), then support the body and treat the parasites while following a holistic approach. When parasitic infections are treated effectively, we can overcome inflammation or disease.

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