A patient suffering from the syndrome of Wallenberg, due to a stroke in the brainstem, lateral side, with severe neuropathic pain, visus difficulties, gait abnormalities and all this in combination with symptoms of colitis ulcerosa, was treated with palnitoylethanolamide (Normast®). To the patients surprise, the severe pain, which was Lyrica insensitive, reacted vary positively, and decreased 50%. And, as a very special bonus, the diarrhoea and fecal incontinence also decreased 50% in frequency...

As the joint finding of a clear significant decrease in central neuropathic pain hand in hand with a decrease in bowel movements and fecal incontinence in this patients points out to a common pathogenesis, we will outline the role of the mast cell in inflammatory bowel disease such as colitis ulcerosa, and its relation to neuropathic pain.

Mast cell hyperactivity in inflammatory bowel disease, neuropathic and pain symptoms and the effect of Normast® 

Inflammatory bowel disease (IBD), which is comprised of two main types, ulcerative colitis (UC) and Crohn's disease (CD), affects approximately 3.6 million people in the United States and Europe.  IBD is characterized by chronic or relapsing immune activation and inflammation within the gastrointestinal (GI) tract that markedly alters GI function, and withinn the whole process the mast cell plays an important role.

Other chronic inflammatory diseases of the gastrointestinal system, including celiac disease, an autoimmune reaction to gluten in wheat and other grains, and irritable bowel syndrome (IBS). All these disorders are charactaized by abdominal pain and GI dysfunction. Furthermore, both IBS and IBD are linked to each other, not only in symptoms, as IBS-like symptoms frequently occur in patients before the diagnosis of IBD, and a high percentage reports of IBS symptoms are detected in patients in remission from established IBD.

Importantly data suggest that chronic inflammation in the gut could lead to persistent changes in the GI nervous system, which is extensive, as well as in smooth muscle function, resulting in colonic dysmotility, hypersensitivity, and dysfunction; various of these symptoms bear resemblance to neuropathic symptoms.

Biopsies from patients with IBD have indicated a clear role of inflammatory effects on enteric neurons in the generation of a whole variety of symptoms of IBD. ^[1][2] The enteric nervous system (ENS) is sometimes called the brain of the gut, and these important nerve circuits forming the intrinsic innervation of the entire bowel, controls also virtually all GI functions. So we speculate many of the symptoms in IBD, such as chronic pain, frequent bowel movements, hypersensitivity are all at least in part symptoms of a dysfunctioning nervous system, triggered by overactive mast cells. One clearly sees the link between neuropathic pain, glia hyperactivation and interleukine cascades, mast cell over activity and the IBD cascade of events.

In our patient these two syndromes occured together, and treatment with the mast cell stabilizor palmitoylethanolamide decreased both symptoms of neuropathic pain as well as symptoms of IBD!

And we quote:

Enteric ganglia are organized into two major ganglionated plexuses, the myenteric (Auerbach's) and submucosal (Meissner's) plexus. They contain a variety of functionally distinct neurons, including primary afferent neurons, interneurons, and motor neurons, synaptically linked to each other in microcircuits. In addition, enteric neurons are supported by glial cells, the ENS counterparts of astrocytes of the CNS, that can modulate enteric neuron function. Neurons of the ENS also exist in close apposition to cells of the mucosal immune system and the intestinal epithelium and bi-directional communication is known to occur at both of these interfaces. 

Signaling between immune cells and enteric neurons can also evoke alterations in gut function. 

Evidence in animal models of IBD shows that, in addition to gross changes in the morphology and architecture of neural ganglia and nerve cell bodies, subtle changes in the expression of neurotransmitters or their receptors at synapses within the gut wall are a prevalent and important aspect of intestinal inflammation. Inflammatory cells in the intestine, such as dendritic cells, lymphocytes, macrophages and mast cells, express receptors for small molecule neurotransmitters and neuropeptides, and enteric neurons are responsive to cytokines that inflammatory cells secrete. 

And in addition to that a phenomena very much close to central wind-up has been found in the gut nervous system:

Maintained neuronal excitation, observed only in neurons from the inflamed bowel, may contribute to the dysmotility, pain, and discomfort associated with intestinal inflammation and IBD in particular. The mechanisms responsible for the changes in excitability are not yet understood, but they may involve a persistent alteration in channel expression and/or a continuous release of inflammatory mediators due to low-grade inflammation. ^[3]

The mast cell in IBD 

Changes in number and electronmicroscopic appearances of mast cells in the mucosa of large intestine of patients suffering from colitis ulcerosa either in its active or remission period have been documented. In the active phase of the disease the increase in number of mast cells is significant. The cells show pronounced degranulation. These morphological findings corroborate current hypotheses and suggest that the increase in number of mast cells in the active stage of coliitis ulcerosa mediates an hyperergic reaction.^[4] 

In e separate study the changes in the number of mast cells were studied in 37 colonoscopical biopsies from patients with ulcerative colitis. We quote: Accumulation of mast cells accompanied by intense degranulation was found to be significant in the active stage of the disease. Two forms of degranulation were observed: discharge of the individual granules and protrusion and detachment of the cytoplasmic processes containing granules. The latter was a sign of rapid degranulation, as described earlier in animal experiments. Mast cells were closely associated with capillary blood vessels, Schwann cells, neural fibres, myofibroblasts and collagenous fibres, and were also present between epithelial cells. ^[5] Other publications reach the same conclusion. ^[4]

Very recently it was again pointed out that in patients with inflammatory bowel disease (IBD)increased numbers of human tryptase-β (hTryptase-β)-positive mast cells (MCs) can be found in the gastrointestinal tract. In an animal model the amino acid sequence of mouse mast cell protease (mMCP)-6 is most similar to that of hTryptase-β. Experimental data show that mMCP-6 is an essential MC-restricted mediator in chemically induced colitis and that this tryptase acts upstream of many of the factors implicated in IBD.^[7] 

Inflammatory bowel disease (IBD) are now hypothesized to result from stimulation of immune responses against resident intestinal bacteria within a genetically susceptible host. Mast cells most probably play a critical role in IBD pathogenesis, since they are typically located just beneath the intestinal mucosal barrier and can be activated by bacterial antigens.^[8]  

We take the liberty to quote verbatim from a free article on the internet:

Mast cells, central neuropathic pain and IBD, treated with Normast

Thus, our patient suffering from both symptoms of IBD as well as pain due to a stroke in the brain stem, the syndrome of Wallenberg, promted us to explore the role of the mast cell in IBD. We saw a clear role in the pathogenesis of the mast cell, as well as the hypersensitivity and winding up of enteric neurons and glia, with a close resemblance to the entire central and peripheral wind up hypersensitization process in neuropathic pain.

The treament with Normast helps to downregulate the overactive mast cells, as well as glia cells and thus to downregulate the hypersensitization process. We could prove in an ex juvantibus way, in our patient, the importance of the mast cell pathology in both indications, and the therapeutic role of palmitoylethanolamide.

As Normast is proven to be safe and effective in various chronic pain states, treating pain and IBD in patients having no other treatment options seems a wise thing to do. ^{[10] [11] [12] [13][14][15][16][17] [18][19][20][21][22][23]} 

March 2011, prof. dr. Jan M. Keppel Hesselink 

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