7° Clinical case: Brainstem neoplasm in Orofacial pain

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7° Clinical case: Brainstem neoplasm in Orofacial pain

Abstract

The chapter begins by critiquing the traditional Efidence Based in Medicine (EBM) approach, which relies heavily on established scientific knowledge (denoted as $KB$). It argues that EBM's reliance on compatible and dependent variables is insufficient for capturing the full spectrum of clinical realities, especially in complex cases where quantum variables — which are independent and incompatible — play a crucial role. This critique is illustrated through the introduction of Masticationpedia, a platform intended to refine diagnostic processes in orofacial pain and temporomandibular disorders (TMDs) by integrating these new diagnostic paradigms.

The patient, referred to as 'Capsaicin', presented with bilateral diffuse orofacial pain affecting the temporal and occipital regions and burning mouth syndrome (BMS), persisting for over a decade. Despite long-standing dental treatments, including the use of a night guard, her pain persisted, leading to her classification under atypical orofacial pain (AOP) and TMD according to the Research Diagnostic Criteria (RDC). However, traditional diagnostic tools such as axiography and electromyography showed no abnormalities, suggesting that her symptoms might not be dental in origin.

Using the Masticationpedia protocol, the case was analyzed through various "contexts" — dental and neurological. Each context used specific diagnostic assertions ($\delta _{n}$ for dental and $\gamma _{n}$ for neurological), which were quantified and analyzed. Both contexts returned values indicating normality ($\delta _{n}=0$ and $\gamma _{n}=0$), which contradicted the patient's ongoing pain and symptoms, suggesting a gap in the traditional diagnostic model.

The chapter introduces the concept of the Coherence Demarcator (. 2003;362(9398):), a tool designed to weigh the clinical assertions more accurately within their respective contexts. In Capsaicin's case, r T. Neuroanatomy helped identify that the severity and implications of her symptoms were not adequately captured by traditional diagnostic categories, pointing towards a more serious underlying condition.

Faced with contradictory findings and persistent symptoms, further investigations were urged, leading to the discovery of a brainstem schwannoma via MRI — a finding that aligned with her symptoms but had been overlooked by standard diagnostic protocols. This case underscores the necessity of integrating advanced imaging and holistic diagnostic approaches when standard evaluations fail to explain severe symptoms.

The chapter concludes with reflections on the need for a paradigm shift in medical diagnostics, particularly in orofacial pain. It argues for the integration of quantum models that consider independent and incompatible variables, which can better account for the complexities of human pathology not adequately addressed by EBM.

The Masticationpedia initiative is positioned as a revolutionary step towards incorporating these new models into everyday clinical practice, aiming to improve diagnostic accuracy and patient outcomes in orofacial medicine. This approach not only challenges existing medical paradigms but also encourages a more nuanced understanding and treatment of conditions that transcend conventional medical categories.

Keywords

Evidence-Based Medicine (EBM):

• Description: Explore the limitations of traditional evidence-based medicine in diagnosing complex conditions like orofacial pain, where standard variables often fall short.

Quantum Diagnostic Model:

• Description: Understand how quantum diagnostic models use independent and incompatible variables to provide more accurate diagnoses of complex medical conditions, such as orofacial pain.

Orofacial Pain Diagnosis:

• Description: Investigate the challenges and advancements in diagnosing orofacial pain, highlighting the integration of new diagnostic paradigms through platforms like Masticationpedia.

Masticationpedia:

• Description: Discover Masticationpedia, an innovative platform designed to refine diagnostic processes in orofacial pain and temporomandibular disorders by utilizing quantum diagnostic models.

Temporomandibular Disorders (TMD):

• Description: Explore the complexities of diagnosing temporomandibular disorders and how new approaches like those presented in Masticationpedia can improve accuracy and patient outcomes.

Clinical Paradigm Shift:

• Description: Discuss the need for a paradigm shift in medical diagnostics, particularly in orofacial pain, to include models that handle the complexities of real-world clinical scenarios.

Brainstem Schwannoma:

• Description: Delve into the diagnostic journey of identifying rare conditions like brainstem schwannoma in patients presenting with symptoms that conventional diagnostics fail to explain.

Advanced Imaging Techniques:

• Description: Highlight the role of advanced imaging techniques in uncovering underlying serious conditions in patients with chronic orofacial pain, as part of a comprehensive diagnostic approach.

Neurological and Dental Diagnostics:

• Description: Examine the intersection of neurological and dental diagnostics in handling cases of orofacial pain and the methodologies that help distinguish between dental issues and more serious neurological conditions.

Capsaicin and Orofacial Pain:

• Description: Explore the relationship between dietary elements like capsaicin and exacerbation of orofacial pain, emphasizing the need for comprehensive patient assessment.

 

Article by  Gianni Frisardi

 

Introduction

The brain stem is the caudal portion of the brain that connects the diencephalon to the spinal cord and cerebellum. The brainstem mediates the sensory and motor pathways between the spinal cord and the brain and contains the nuclei of the cranial nerves, the ascending reticular activating system (ARAS), and the autonomic nuclei. It controls brainstem reflexes and the sleep-wake cycle and is responsible for autonomous control of the cardiovascular, respiratory, digestive and immune systems. Brainstem dysfunction can result from various acute or chronic insults, including stroke, infectious, cancer, inflammatory, and neurodegenerative diseases. In the context of critical illness, the brain stem can be susceptible to various insults that can be classified as structural and non-structural in origin. Brainstem dysfunction can therefore contribute to impaired consciousness, cardiocirculatory and respiratory insufficiency and therefore to increased mortality and especially manifest as orofacial pain (OP).Brainstem dysfunction in critically ill patients:

These important premises extracted from an interesting article by Sarah Benghanem are essential details, expression of a clinical experience which led the author of the chapter to scientific and epistemological reflections on the typology of language to be used in the creation of diagnostic models. and consequently to found Masticationpedia. One cannot, personal and responsible assertion of the author of the chapters, slavishly follow an axiom, a protocol such as the DRC or whatever and risk an error of differential diagnosis which can cost the life of a human being. If there is a gap in the model, which we will demonstrate during the implementation of Masticationpedia, then it should be noted as an anomaly, analyzed and eliminated or at least modified otherwise it is not a question of paradigmatic progress but only of intensive progress.

Presentation of the clinical case

It was the year 1995 when the 60-year-old female patient, who we will call with a fancy name 'Capsaicin' (we will understand the reason below) presented herself to our observation reporting bilateral diffuse orofacial pain in the temporal muscles region and in the occipital region , in addition, to the presence of burning mouth (BMS), for more than 10 years. The pain lasted for hours especially at night and did not occur cyclically. The patient was the bearer of a long-standing upper and lower ceramic fixed prosthetic rehabilitation with various fractures of the ceramic structure and wear veneers on the remaining natural teeth. However, no occlusal discrepancies were found in the prosthetic rehabilitation, but a release plate was performed by other health professionals to be used at night. The patient reported pain even with the plate inserted and was initially considered to be affected by Atypical Orofacial Pain (AOP) with a strong psychosomatic component and subsequently, according to the RDC protocol, affected by 'Temporomandibular Disorders'.

Having come to our observation, as per the Masticationpedia protocol, the main gnathological tests were performed, such as paraocclusal axiography of the condylar tracings and an interferential EMG of the masseter muscles. In this case, an ATM CT was not requested, much less an MR. We present in a schematic and representative way reporting some paragraphs exposed in the previous chapters the Masticationpedia protocol in its schematization as: assertions in the dental, neurological context and finally the diagnostic conclusion through the 'Demarcator $\tau$':

Significance of contexts

For the dental context we will have the following sentences and statements to which we give a numerical value to facilitate the treatment and that is $\delta _{n}=[0|1]$ where $\delta _{n}=0$ indicates 'normality' and $\delta _{n}=1$ 'abnormality and therefore positivity of the report:

$\delta _{1}=$ Paraocclusal axiographic tracing of the right condyle, negative in Figure 1, Normality, negative report

$\delta _{2}=$ Paraocclusal axiography tracing of the left condyle, negative in Figure 2, Normality, negative report

$\delta _{3}=$ Symmetric EMG interference pattern in Figure 5. Normality, negative report

• 

  Figure 1: Right consular paraocclusal axiographic tracing: a) Hinge axis center, b) orbital axis plane, c) protrusive tracing, d) mediotrusive tracing, e) mediotrusive masticatory cycle area, f) laterotrusive masticatory cycle area, g) laterotrusive backline , h) consular hinge axis in maximum intercuspidation,

• 

  Figure 2: $\delta _{2}$ Right consular paraocclusal axiographic tracing: a) Hinge axis center, b) orbital axis plane, c) protrusive tracing, d) mediotrusive tracing, e) mediotrusive masticatory cycle area, f) laterotrusive masticatory cycle area, g) laterotrusive backline.

• 

  Figura 3: $\delta _{3}$ Interferential EMG of right (top) and left (bottom) masseter muscles. Amplitude 200μV per division, time division 100 msec

The sentence $\Im _{o}$ (dental context) with a number $n\geq 1$ of other logically compatible statements $(\delta _{1},\delta _{2},.....\delta _{n}\ )$ determine the union and coherence between them $\Im _{o}\cup \{\delta _{1},\delta _{2}.....\delta _{n}\}$ and are represented with a mathematical formalism to facilitate the diagnostic dialectic in the following way $\Im _{o}\cup \{\delta _{1},\delta _{2}.....\delta _{n}\}\rightarrow \Im _{o}\cup \{0,0.....0\}=0$ which represents the average of the individual assertions reported. The average has been designed because it can often happen that some tests give answers with negative reporting to which to give the value $\delta _{n}=0$. The result in this case is $\delta _{n}=0$ and contextually derives the coherent affirmation of the sentence $\Im _{o}$ in which it is argued that the symptomatology of the 'Capsaicin' patient is not determined by the presence of a TMDs.

In the neurological context we will therefore have the following sentences and assertions to which we obviously give, as for the dental context, a numerical value to facilitate the treatment and that is $\gamma _{n}=[0|1]$ where i$\gamma _{n}=0$ indicates 'normality' and $\gamma _{n}=1$'abnormality' and therefore positivity of the report:

$\gamma _{1}=$ _bRoot-MEPs symmetrical in amplitude and latency in Figure 4, $\gamma _{1}=0\longrightarrow$ Normality, negative report

$\gamma _{2}=$ Jaw jerk symmetrical in amplitude and in latency in Figure 8, $\gamma _{2}=0\longrightarrow$ Normality, negative report

$\gamma _{3}=$ Symmetry in duration of the masseter silent period in Figure 6, $\gamma _{3}=0\longrightarrow$ Normality, negative report

Consequently even in sentence $\Im _{n}$ with a number $n\geq 1$ of other logically compatible assertions $(\gamma _{1},\gamma _{2},.....\gamma _{n}\ )$ they determine the union and coherence between them $\Im _{n}\cup \{\gamma _{1},\gamma _{2}.....\gamma _{n}\}$ and the formal representation will be similar to that of the dental context. $\Im _{n}\cup \{\gamma _{1},\gamma _{2}.....\gamma _{n}\}\rightarrow \Im _{n}\cup \{0,0.....0\}=0$with contextual coherent affirmation of the sentence $\Im _{n}$ in which it is argued that the symptomatology of the patient 'Capsiacin' does not electrophysiologically highlight any element that could indicate a correlation between orofacial pain and neuromotor damage.

• 

  Figura 4: $\gamma _{1}=$ Motor trigeminal roots evoked potentials bRoot-MEPs.

• 

  Figura 5: $\gamma _{1}=$ Mandibular tendon reflex (jaw jerk) recorded on the right (top) left (bottom) masseter muscles

• 

  Figura 6: $\gamma _{1}=$ Mechanical silent period recorded on masseter muscles right (top black corresponds to mean) left (bottom black corresponds to mean)

«In this scenario both the statements $\Im _{o}$ and $\Im _{n}$ are compatible, consistent and therefore true until a 'Consistency Demarcator 'τ' is found which highlights the greater weight in terms of clinical severity.»

Coherence Demarcator $\tau$

The $\tau$is a representative clinical specific weight, complex to research and develop because it varies from discipline to discipline and for pathologies, essential for not colliding logical assertions $\Im _{o}$ and $\Im _{n}$ in diagnostic procedures and fundamental for initializing the decryption of the machine code. Basically it allows to confirm the coherence of one union $\Im \cup \{\delta _{1},\delta _{2}.....\delta _{n}\}$ with respect to another $\Im \cup \{\gamma _{1},\gamma _{2}.....\gamma _{n}\}$ and vice versa, giving greater weight to the seriousness of the assertions and of the report in the appropriate context. Sometimes the doctor is faced with a series of positive reports to which he must give the right weight, he must consider the positivity of a report which highlights, for example, an osteoarticular renewal of the TMJ cannot have the same weight as a positivity of a report confirming latency delay of a trigeminal reflex. The demarcation $\tau$ weight, therefore, gives more significance to the more serious assertions in the clinical context from which they derive and therefore beyond the positivity of the assertions $\delta _{n}=1$ or which $\gamma _{n}=1$ in any case are always verified and respected, these must be multiplied by a $\tau =[0|1]$ where $\tau =0$ indicates 'Low seriousness ' while $\tau =1$ 'Severe Gravity'.

A consistency marker could be defined as a real number between 0 and 1 in the event that we have more than two reports and therefore a number close to zero would correspond to a report of 'low severity' while a number close to one to a reporting of 'severe severity'. But this is redundant. What is done is to compare the reports two by two and then use the values we have indicated to express the 'Gravity'.

So to recap we have:

$\Im _{o}\cup ({{\bar {\delta }}_{n})}\tau _{o}+\Im _{n}\cup ({{\bar {\gamma }}_{n})}\ \tau _{n}=\Im _{d}$

where

${{\bar {\delta }}_{n}}=$ average of the value of the clinical statements in the dental context which in our case in question is ${{\bar {\delta }}_{n}}=0$

${{\bar {\gamma }}_{n}}=$ average of the value of clinical statements in the neurological context and therefore ${{\bar {\gamma }}_{n}}=0$

$\tau _{o}=0$ reporting of low severity of the dental context

$\tau _{n}=0$ reporting of low severity of the neurological context

where the 'demarcator of coherence $\tau$ marker' will define the diagnostic path as follows $\Im _{o}\cup 0\cdot 0+\Im _{n}\cup 0\cdot 0=\Im _{d}\longrightarrow \Im _{d}=\Im _{n}\cup 0\cdot 0\longrightarrow \Im _{d}=0$

As we will see during the exposition of the clinical cases in Masticationpeida, one will be faced with similar clinical situations in which you are in the presence of orofacial pain but the reporting results in specialist contexts will be of low severity such as to cancel the discriminate value of $\tau$ .

«This formal logical syntax procedure has allowed us to verify how the clinical conclusion in the dental and neurological context is null and $\Im _{o}=0$ and $\Im _{n}=0$ . This means that the diagnosis is unknown $\Im _{d}=0$»
(The fact remains that the patient continues to experience orofacial pain and particularly with exacerbation after a spicy dinner.)

In the rare but real clinical cases in which the ' $\tau$ Demarcator' is reset, we are motivated to carry out an even more extensive and in-depth check, hypothesizing serious pathologies including head and neck tumors which simulate symptoms that can be superimposed on other pathologies. It is a serious mistake to consider the patient with such clinical manifestations and the simultaneous absence of systemic anomalies as a patient with psychosomatic disorders. Elements of psychophysical damage can certainly coexist but, if the 'Demarcator' fails, it is mandatory to deepen the diagnostics. In fact, head and neck cancer (HNC) affects over 890,000 people each year worldwide and has a 50% mortality rate. Aside from poor survival, HNC pain impairs eating, drinking and speaking, severely reducing quality of life. The different pain phenotype in patients (allodynia, hyperalgesia, and spontaneous pain) results from a combination of anatomical, histopathological, and molecular differences between tumors. Glial and immune modulation of the tumor microenvironment, as well explained in the article by Ye et al., influences not only cancer progression but also pain signaling among which transient receptor potentials contained in gustatory somatosensory systems are an example.

For the above reasons and for the persistence of the OP, the difficulty in concluding a certain diagnosis, the absence of organic-functional discrepancies and the zeroing of the '$\tau$ Demarcator', an MR of the brain was requested.

Imaging showed a neoplastic mass most likely a brainstem schwannoma with invagination of the occipital frame. (figure 7 and 8)

• 

  Figura 7: Axial section of the brain at the level of the medulla oblongata showing a mass (arrow) that partially invades the oval frame

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  Figura 8: Coronal section of the brain at the level of the medulla oblongata showing a mass (arrow) that partially invades the oval frame

«Unfortunately, the patient died a few years later of trochoencephalic neuroma.»
(.......leaving a doubt, that of the correlation between pain and capsaicin as reported by the patient on the occasion of a spicy diet.)

Thoughts and conclusions

The mammalian gustatory system is made up of taste buds, which are clusters of 50-100 taste cells found throughout the oral cavity. On the tongue, which is the central topic of the case report 'Capsaicin', the taste buds are located on circumvallate, foliate and fungiform papillae. Taste cells synapse with afferent fibers from branches of the cranial facial (CN VII), glossopharyngeal (CN IX) and vagus (CN X) nerves which, in turn, transmit information to the central nervous system (CNS) about gustatory attributes , intensity and hedonic nature. The taste buds are embedded in a stratified squamous epithelium, which contains somatosensory branches of the trigeminal (CN V), glossopharyngeal (CN IX), and vagus (CN X) cranial nerves. Information from these general sensory nerves provides information to the central nervous system about mechanical, thermal, and pain stimuli. Painful stimuli can result from strong or sharp mechanical stimuli, abnormally high or low temperatures, or chemical stimuli such as capsaicin, which is found in hot peppers and causes a burning taste sensation through the intervention of Transient Receptor Potentials (TRPs). These TRPs are divided into six subfamilies including TRPV1, which we are interested in to hypothesize the phenomenon of pain exacerbation of the patient 'Capsaicin' in spicy diet.

Figura 9: TRPV1, VR1, transient receptor potential cation channel subfamily V member 1. Wikipedia

TRPV1 and neuroinflammation

TRPV1s constitute a distinct subset of non-selective cation channels (Transient Receptor Potential) responsible for many cellular responses. They are activated by various stimuli such as acids, extracellular protons, high temperatures, plant toxins and vanilloid agonists. The TRPV1s present in mammals can be considered as sensors of chemical substances (capsaicin), thermal substances (heat) and/or harmful stimuli. The activation of TRPV1 leads to the depolarization necessary for the propagation of action potentials along the axons of the dorsal root ganglia (DRG) of neurons that project to the spinal cord and consequently also to the nociceptive trigeminal nuclei. What makes TRPV1 so critical for pain signaling is undeniably its ability to transduce inflammatory signals into electrical signals with the activation of both voltage-gated sodium and calcium channels located at the nociceptor level. The implication of TRPV1 in pathological pain prompted a careful study of these proteins. The limiting element in pharmacological research at the application level was the peculiarity of the TRPV1 channel, i.e. its polymodal mechanism of activation (heat, capsaicin, pH), which led to a high level of complexity in the design of a specific modality inhibitor.

The interaction between neurons and immune cells is a well-known phenomenon. TRPV1 plays its role, too, in neuroinflammation by being expressed in both neurons and immune cells. Significant importance should be given to the confirmed expression of TRPV1 in microglia and astrocytes, cells found in the vicinity of neurons. The neuro-immune axis is the site of production of neuroinflammatory molecules and receptors that interact between the two systems and ensure a complex response to external stimuli (or to the body's own pathologies). TRPV1 is said to contribute to microglia autophagy through its Ca²⁺ signaling, which leads to mitochondria-induced cell death. Basically, TRPV1 is a pro-apoptotic element.

Antagonists

Antagonists block the activity of TRPV1, thereby reducing pain. Antagonists identified include the competitive antagonist capsazepine and the non-competitive antagonist ruthenium red. These agents could be beneficial if applied systematically. TRPV1 antagonists have shown efficacy in reducing nociception from inflammatory and neuropathic pain models in rats. This provides evidence that TRPV1 is the sole receptor for capsaicin. In humans, drugs that target TRPV1 receptors could be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, or amputation, as well as pain associated with the inflammatory response of damaged tissue, such as in osteoarthritis.

Agonists

TRPV1 is activated by several agonists of natural origin. Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, after prolonged application, cause the decrease of TRPV1 activity (desensitization), leading to pain relief through the subsequent decrease of the TRPV1-mediated release of inflammatory molecules upon exposure to noxious stimuli.

An interesting study by the Tominaga group extends the list of TRPV1 interactions also to Anoctamin 1 (ANO 1) also known as Transmembrane member 16A (TMEM16A) a chloride channel which is usually activated by Ca2+. The authors demonstrate, in fact, that when TRPV1 interacts with the ANO1 channel it mediates the efflux of Chloride evoking depolarization (after stimulation by capsaicin) with increased excitability of the nociceptor. Tominaga highlighted a clear structural and functional crosstalk between TRPV1 and ANO1, which intervenes in the algogenic action of capsaicin.

These results demonstrate the importance of chloride homeostasis in the regulation of the excitability of the neuronal DRGs, i.e. of the dorsal root ganglia and obviously of the trigeminal somatosensory nuclei and in the pain phenomenon as a whole; one of the new approaches, therefore, where to intervene to mitigate painful hypersensitivity and neurogenic inflammation.

TRPV1 is activated by several agonists of natural origin. Agonists such as capsaicin and resiniferatoxin activate TRPV1 and, after prolonged application, cause the decrease of TRPV1 activity (desensitization), leading to pain relief through the subsequent decrease of TRPV1-mediated release of inflammatory molecules following administration. exposure to noxious stimuli.

An interesting study by the Tominaga group extends the list of TRPV1 interactions also to Anoctamin 1 (ANO 1) also known as Transmembrane member 16A (TMEM16A) a chloride channel which is usually activated by Ca2+. The authors demonstrate, in fact, that when TRPV1 interacts with the ANO1 channel it mediates the efflux of Chloride evoking depolarization (after stimulation by capsaicin) with increased excitability of the nociceptor. Tominaga highlighted a clear structural and functional crosstalk between TRPV1 and ANO1, which intervenes in the algogenic action of capsaicin.

These results demonstrate the importance of chloride homeostasis in the regulation of the excitability of the neuronal DRGs, i.e. of the dorsal root ganglia and obviously of the trigeminal somatosensory nuclei and in the pain phenomenon as a whole; one of the new approaches, therefore, where to intervene to mitigate painful hypersensitivity and neurogenic inflammation.

«Why, then, did the capsaicin taken in the food reported by the patient generate an exacerbation of pain?»
(....for chronic damage to the brainstem nerve fibers with consequent alteration of the neuro-immune homeostasis and contextual paradoxical effect of the analgesic action of capsaicin.)

In these cases, as stated in other chapters, we are dealing with an epistemological profile in which the basic knowledge, what we have called $KB$ (Knowledge Base) corresponds to a temporal limit of scientific information and consequently serious  difficulties of differential diagnosis. We had to wait 12 years to reach an ezipathogenetic conclusion overwritten from 1995, a period in which the patient 'Capsaicin' was being treated, to 2007 in which a research gave the elements to suspect the presence of an organic neurological damage with manifestations of pain and burning mouth. Burning mouth syndrome (BMS) is often an idiopathic, chronic intractable pain condition, affecting 1.5-5.5% of middle-aged and older women. We investigated heat and capsaicin receptor TRPV1, and its regulatory nerve growth factor (NGF), in BMS. BMS patients (n=10) and controls (n=10) were evaluated for baseline and post-topical capsaicin pain scores, and their tongue biopsies were immunostained for TRPV1, NGF, and neurofilament structural nerve markers and periphery. Nerve fibers penetrating the epithelium were less abundant in the BMS (p<0.0001), indicating small fiber neuropathy. TRPV1-positive fibers were overall significantly increased in BMS (p=0.0011), as were NGF fibers (p<0.0001) and NGF staining of basal epithelial cells (p<0.0147). There was a significant correlation between baseline pain score and TRPV1 (p=0.0143) and NGF (p=0.0252) fibers. A significant correlation was observed between baseline and post-capsaicin pain (p=0.0006).

«We are sure we know everything»

Bibliography & references