a new preliminary model for chronic progressive multiple sclerosis

A Working Model for Chronic Progressive Multiple Sclerosis

This article is based on what has now been months of research in PubMed. I have reviewed hundreds of studies and can therefore substantiate a large proportion of the mechanisms presented here. A certain part still remains hypothetical, since chronic MS and the spinal cord in particular receive little attention in studies. I will link the studies when the article is completed (in a few months), because today it is very easy for interested readers to find the corresponding sources themselves using AI.

Why I View Chronic Progressive MS Differently Today

My personal involvement with multiple sclerosis (MS) goes back many years. For a long time, my therapeutic results were disappointing overall.

Until around 2017, in chronic progressive MS I saw relevant improvements in only a very small proportion of those I treated (10%), with the treatment of a proven or suspected heavy metal burden producing strikingly positive changes in individual cases.

Based on these experiences, the possible involvement of heavy metals played an important role in my disease model at that time.

Later, I additionally became interested in work discussing infectious or microbial factors in MS, especially through the work of US pathologist Alan MacDonald, who was able to specifically detect parasites using fluorescent antibodies in all 16 lumbar puncture samples he tested. This led me to ask whether, in addition to immunological processes, other factors might be involved in the development and maintenance of the disease.

However, another observation was decisive: relapsing-remitting MS and chronic progressive MS behave completely differently therapeutically in my practice.

My Experience with the Coimbra Protocol

In 2017, I was in Brazil with Prof. Cicero Coimbra. With the Coimbra Protocol, I have had very good clinical experience, particularly in patients with relapsing-remitting MS. In my own patient population, I observe exceptionally high clinical response rates when it is carried out carefully.

The situation is completely different in patients whose disease has progressed to a chronic progressive phase.

Here I see practically no efficacy with the Coimbra Protocol. This applies both to the Coimbra Protocol and to various other therapeutic approaches I have used.

A clinical constellation that I repeatedly observe is particularly striking:

• Motor function continuously deteriorates.
• Spasticity, gait disturbance and bladder dysfunction increase.
• At the same time, the cerebral MRI remains largely unchanged for years.
• Even neuromodulation directed exclusively at the brain can be considerably less effective in these patients than in disorders with predominantly cerebral network dysfunction.

This discrepancy was the starting point for a different disease model for me.

My Central Hypothesis

I consider it problematic to regard chronic progressive MS simply as a slower version of inflammatory relapsing MS.

Instead, my current working model is:

In some cases of chronic progressive MS, the dominant disease mechanism shifts from a primarily inflammatory-demyelinating disease increasingly toward a compartmentalized, self-sustaining neurodegenerative process, in which the spinal cord in particular may play a decisive role.

This explicitly does not mean that inflammation or autoimmunity are no longer present in progressive MS. These processes may continue to exist. Rather, my hypothesis is that in the advanced stage they no longer explain the clinical course on their own.

Four Observations That Led to This Model

1. Anti-inflammatory Treatment Alone Does Not Explain the Course

In chronic progressive MS, neurological deterioration can continue despite intensive anti-inflammatory or immunomodulatory treatment.

This does not mean that inflammation is absent. However, it suggests that additional mechanisms may autonomously perpetuate progression.

2. Immunomodulation Alone Is Often No Longer Sufficient

The fact that immunological therapies in progressive disease are often considerably less impressive than during highly inflammatory phases of the disease also suggests to me that the biological weighting of the disease process changes.

The decisive question is therefore no longer only:

“How do we suppress the autoimmune reaction?”

But additionally:

“Which mechanisms maintain neurodegeneration after the original inflammatory process has long since occurred?”

3. The Brain and the Clinical Course Can Become Decoupled

In some of my patients, neurological disability progresses considerably while the cerebral MRI no longer changes.

This is particularly interesting when spastic paraparesis, gait disturbance, pyramidal tract signs and neurogenic bladder dysfunction are simultaneously dominant.

For these patients, I consider an exclusively brain-centered view to be insufficient.

4. Only Since We Began Focusing Neuromodulation Therapy on the Spinal Cord Have We Achieved Real Success

With our early neuromodulation devices, we were able to treat only the brain and were actually able to achieve only temporary and, even then, only minor improvements. Only by focusing strongly on the spinal problem have we actually been able to get patients out of wheelchairs.

5. The Spinal Cord Moves to the Center

In a spinal-dominant phenotype of progressive MS, in my opinion, considerably greater attention must be paid to the spinal cord.

The functionally decisive changes may be located where motor, sensory and autonomic pathways run through a confined space. Even relatively small structural or functional changes can therefore have substantial clinical consequences.

My model of progressive MS is therefore much more strongly a brain-spine model than a purely brain-based model.

The Possible Role of the Gut Microbiome

Another building block emerged from my examination of the twin studies and the growing literature on the gut microbiome in MS.

Multiple Sclerosis and the Microbiome – the Twin Study

A particularly interesting question is whether certain Clostridia-related bacteria or their toxins can influence immunological or neurobiological processes.

This leads me to an important working hypothesis:

In progressive MS, a pathologically altered gut microbiome could act as a chronic biological amplifier.

The specific concept of direct toxin transport from the gut via venous connections to the spinal cord, however, is currently a hypothesis that should not be presented as an established mechanism.

Nevertheless, I consider the gut axis therapeutically relevant. For this reason, in appropriate patients we also investigate and treat dysbiosis and abnormal microbial patterns.

Progressive MS as Self-Perpetuating Neurodegeneration

For me, the decisive step is to stop viewing progressive MS exclusively from the perspective of demyelination.

After years of disease, a self-perpetuating neurodegenerative cycle may possibly develop, similar to what I was able to identify for Parkinson’s disease. In my opinion, this is a “milestone article” and should be read by all colleagues.

my Parkinson Research – Update 2023

This model also reflects the pathobiochemical reality of Alzheimer’s dementia and other tauopathies.

At the center are:

• microglia
• astrocytes
• oligodendrocytes
• damaged axons
• mitochondrial dysfunction
• oxidative stress
• impaired proteostasis
• impaired autophagy and lysosomal function
• alterations in lipid metabolism

Microglia and Lipid Droplets

Studies on lipid-laden microglial cells are particularly interesting.

Among other things, microglia remove cellular debris and damaged myelin. With chronic damage, however, there can be a striking and “abnormal” increasing intracellular accumulation of lipid droplets.

These lipid droplets are not equivalent to tau, beta-amyloid or alpha-synuclein. This is a distinct cell-biological process.

What is crucial, rather, is that lipid-laden microglia may be functionally altered. A cell that was originally reparative and responsible for clearing debris can develop into a cellular state that continues to sustain oxidative stress, inflammation and tissue damage.

This creates a possible vicious cycle:

Myelin damage -> phagocytosis of myelin -> lipid overload of microglia -> impaired cellular metabolism -> pro-inflammatory or neurodegenerative microglial phenotype -> further damage to myelin and axons.

This mechanism could explain precisely why, at some point, a disease process continues partly independently of its original trigger.

Therapeutic Considerations Derived From This

This model gives rise to several potential therapeutic targets. At present, these do not represent a finalized MS treatment protocol, but rather a mechanistically derived working model that I continue to develop on the basis of the scientific literature and my clinical observations.

1. Proteostasis and the Cellular Stress Response

In neurodegeneration, the balance between the production, folding, repair and degradation of proteins is disturbed.

I am therefore interested in therapeutic strategies that influence proteostasis, autophagy and lysosomal clearance.

2. Autophagy and Spermidine

One interesting approach is spermidine, which, among other things, has been associated with activation of cellular autophagy processes.

A simple natural source is wheat germ, as I learned from Prof. Emeritus Reinhard Jarrisch, Vienna General Hospital. Prof. Jarrisch was able to significantly stabilize and, in some cases, considerably improve Alzheimer’s patients with spermidine in the form of wheat germ. His best case was a female patient with a MOCA of 7 who improved to over 20, as he told me in 2023. His studies can be found in PubMed.

Scientific research into spermidine is particularly interesting in connection with aging processes and neurodegenerative diseases. However, a direct disease-modifying effect in progressive MS has not yet been demonstrated.

3. Nrf2 and Glutathione

Another central target is the body’s own antioxidant regulation via Nrf2.

Nrf2 regulates numerous cellular protective systems and influences, among other things, glutathione biosynthesis.

Therapeutically, I am therefore interested in substances or combinations such as:

• N-acetylcysteine (NAC)
• glycine
• sulforaphane
• diindolylmethane (DIM)

NAC and glycine provide essential starting substances for glutathione synthesis. Sulforaphane is one of the most interesting natural activators of the Nrf2-dependent stress response.

The new study shows that administration of NAC and glycine in this combination can achieve substantial rejuvenation of aging markers in the blood by as much as 30 years.

The aim is not to eliminate free radicals completely. Reactive oxygen species fulfill important physiological functions. Rather, the crucial point is to bring pathologically elevated oxidative and mitochondrial stress back into a physiologically controllable range. In addition, glutathione is the body’s own weapon against accumulated metals.

4. Lysosomal Function

Another possible bottleneck lies in the lysosomes, one of the cell’s essential recycling systems.

I find a recent study particularly interesting that investigates how poorly degradable intracellular materials (microplastics) can affect lysosomal function.

This raises the question for me of whether improving autophagy, lysosomal function and exocytosis of microplastics could also be used therapeutically in chronic neurodegeneration.

Sulforaphane is particularly interesting in this context because of its effects on cellular stress and detoxification systems.

The evidence on this is very sparse, essentially consisting of only one observation by a scientist, but it offers us for the first time a potential model for lysosomal dysfunction and thus for the accumulation of “toxic precipitates and lipids” in degenerative diseases.

5. The Unresolved Question of Lipid-Laden Microglia

One of the most interesting unresolved questions for me concerns:

How can pathologically lipid-laden microglial cells be returned to a more functionally favorable state?

I suspect that some of these lipids originate from phagocytosed myelin and degenerated neural tissue.

If the intracellular processing of these lipids no longer functions adequately, this could be precisely what stabilizes the degenerative microglial phenotype.

For me, this is where a particularly interesting field of research begins.

6. Peroxisomal Lipid Metabolism and Fibrates

From my earlier biochemical research, I am familiar with the pronounced metabolic effects of fibrates.

Substances such as fenofibrate activate PPAR-alpha in particular and can thereby substantially alter peroxisomal and mitochondrial fatty acid metabolism.

From my animal experimental experience at the time, I know how profoundly pharmacological activation of these metabolic pathways can alter lipid metabolism.

This leads to an interesting, but as yet not clinically proven hypothesis:

Could targeted modulation of lipid metabolism help to alter the pathological lipid phenotype of chronically activated microglia?

So far, I have not found any study on this. However, it appears biologically interesting enough to me to continue pursuing it conceptually.

Trazodone and the Apoptosis or Stress Switch

Another approach comes from my work on neurodegenerative diseases and trazodone.

There are interesting preclinical and clinical data on trazodone in connection with cellular stress responses and neurodegeneration. For this reason, years ago I began looking intensively at a possible neuroprotective or repurposed application; see my article on my Parkinson’s model linked above.

In my own practice, I have also observed remarkable clinical improvements in individual patients with cognitive decline under low doses.

Studies exemplifying what I am writing about Trazodone

For my current MS model, trazodone therefore remains an interesting pharmacological candidate, but not yet a proven component of therapy for progressive MS.

A Preliminary Multimodal Model

Based on the considerations above, the following therapeutic research architecture currently emerges for me:

• Regulate the gut microbiome and, in particular, reduce abnormal microbial burdens
• identify possible toxic burdens and treat them where appropriate
• reduce oxidative stress
• support glutathione synthesis
• activate Nrf2-dependent cellular protective systems
• support autophagy
• improve lysosomal function
• investigate microglial lipid metabolism as a potential therapeutic target
• stabilize mitochondrial and metabolic cellular functions
• simultaneously address the brain-spine-cerebellum axis functionally and through neuromodulation

This approach therefore differs fundamentally from the idea that chronic progressive MS simply requires “more immunotherapy” or “more brain stimulation.”

The Particular Importance of the Spinal Cord for Neuromodulation

My experience with neuromodulation has also changed my understanding of progressive MS.

In pronounced spastic paraparesis, I do not see the central dysfunction as a simple lack of cortical activity. Rather, as clinical practice shows, the loss of supraspinal and cerebellar control leads to increased spinal and reticulospinal gain that can only be influenced to a limited extent by cerebral neuromodulation.

What This Model Is – and What It Is Not

This concept is explicitly a preliminary pathophysiological working model.

It combines:

• published basic research
• findings from neurodegeneration research
• research on microglia, lipid metabolism and proteostasis
• microbiome research
• pharmacological repurposing approaches
• my own clinical observations
• my earlier experience in biochemical research

Not every connection within this model has yet been clinically proven.

Precisely for this reason, I consider the distinction between an established mechanism, a biologically plausible hypothesis and my own clinical observation important.

Why I Am Publishing This Model Already

The complete scientific elaboration of this model will still require considerable time. With a full clinical practice, such work is only possible step by step.

Nevertheless, I would like to make the basic ideas accessible now because they give rise to concrete and testable research questions.

In the long term, the decisive question in chronic progressive MS may not only be:

“How do we stop the inflammation?”

But rather:

“How do we interrupt an already self-perpetuating neurodegenerative cycle of myelin damage, microglial dysfunction, lipid accumulation, oxidative stress, impaired proteostasis, and spinal network failure?”

This is precisely the question I am currently working on.

For me, it may be one of the keys to a better biological understanding of chronic progressive multiple sclerosis.