Post 5: The better explanation – Explanatory Models

Blog post 5: The better explanation

“There is always a clue”

Gill Grissom

Jan Willem, with whom I have been debating various science topics for over more than a decade, introduced me to Occam’s Razor. The razor states that the better explanation is not complexed beyond necessity(Tatham 1987). In philosophy the razor is usually interpreted as:

“an explanation should consist of the fewest possible new assumptions.”

I believe however there is more to Occam’s razor than is currently appreciated. Occam apparently never formulated the razor in Latin himself:

“Lex parsimoniae”

It means nothing more than ‘Law of parsimony’. To me, this formulation transforms the law in a double edged razor. The second edge has to do with the number of questions the explanation actually solves. This double edge is most obvious when conceiving God himself as a scientific explanation, just in the way I believe Occam did. I believe Occam intended to show us that God is the most powerful explanation to the natural world known to science. The first edge of his razor is keeping down the number of new assumptions required to explain. Nothing new here, no single explanation can be simplified beyond consisting of just one factor: God.

But the true force of God as an explanation is that God is not one single explanation. God is the explanation to every conceivable question. This would be the second edge of the razor. The second edge cuts down the number of remaining questions after this one question has been solved. The better explanation is the one that answers many questions. Like “God” can be the answer to just any question.

More so, the amount of questions solved by a single explanation might confer more power to an explanation than its sheer simplicity. In other words, the better explanation is the one containing the fewest possible new assumptions while answering a maximum number of questions.

Still, an explanatory model should be reasonably concise and feel as ‘one’. It would be pointless to explain the whole by an infinite number of explanations or an infinitely lengthy one.

In my opinion, an explanation that answers a lot of questions, even a somewhat complicated one, has more explanatory power than one simple explanation to each question. I could not find any philosophical work backing up this double edged interpretation of Occam’s Razor. Regardless I will use the second edge of Occam’s Razor as the leading principle in finding better explanatory models in medicine. As we have seen this model should solve as many questions as possible. So,:

“What are the questions?”

Well, medicine is full of questions. Each disease is a collection of questions. Obvious questions like “what is the cause of this or that disease” have been around for a long time. The odds for finding answers to obvious questions is however slim since many already tried for so long to solve them. Let us try the opposit and ask weird questions. Quite weird would be asking whether a symptom is ‘one’. Like we did in the previous episode. Are diseases really independent from each other? Are their causes really independent from each other? How sharply can the borders in between diagnostic entities really be defined? How sharply can their causes be set apart?

Why is a modern lifestyle associated with disease? Why do the odds for contracting new diseases seem to go up with every new diagnosis an individual receives? How comes disease is depending on age, race, gender and socioeconomic aspects? What is stress? Why is it making us so sick? What is the nature of our mind and what is its place in medicine? What is fatigue? Why do we need rest? What is the nature of symptoms? Are symptoms to be explained from ‘the disease’? Or are symptoms ‘explained’ from ‘the cause’ of this disease? Or are symptoms to be explained from the body of the individual perceiving these symptoms? Or should the perceived symptoms be explained from the mind of this individual? Or does every single symptom in every single disease have its own explanation? Do symptoms, in classical medical logic, require some sort of ’cause’ at all to ‘happen’? Or are symptoms allowed to be just magically there?

What is the nature of complaints? How do complaints relate to ‘normal’ symptoms’ and psychosomatic symptoms? How comes these ‘symptoms in the mind’ seem having a relation with stress and fatigue? Can the distinction of functional and organic symptoms and conditions be made at a biochemical level? Is medicine responsible for explaining medically unexplained symptoms? In other words: does a patient, who is telling he cannot stand on one leg once in while, deserve a medical explanation?

I think they do and to find new ways to at least explain something, we are going to follow Paul Feyerabend and bring anarchy into medicine. Feyerabend, an influential philosopher of science of the XX^e century, believed that in order to explain, “anything goes”. Hence, we are going to disrupt the borders of medical specialities and explain diseases from (the cause of) their symptoms. Instead of the more ‘obvious’ other way round: explaining symptoms from the (cause of) disease. Most of what follows just shows why there is sense to this reversed approach of explaining diseases from symptoms.

It was around the 1970’s that philosophy of science traded in its endeavour for explanations to settle for the less challenging and until then despised ‘causal attribution’. As seen previous episodes, it lead to the huge success of ‘Evidence-based medicine’. A success totally driven by ‘medical practice’ at a moment where medical philosophers had to admit their defeat in clearly defining ‘disease’. In my opinion this is when ‘medicine as a whole’ became a ‘medical practice driven’ endeavour looking for ’causes’ people get sick or get better. I firmly believe that despite any number of causes one finds to a particular disease:

“Only ‘explanation’ can reveal how a disease is caused”

To get to this explanation we might just need to look at things differently. Like taking another perspective. Or vantage point. Maybe we need to trade in classical medical assumptions for new ones. Previous episodes have been about one of these assumptions in particular:

“One cause, one disease”

Although essential to medical practice, philosopher of science Karl Popper tells us it is nothing more than a hypothesis that has not been falsified. Therefore we cannot admit “One cause, one disease” within the explanatory part of medicine. Nor can we completely reject it either. Therefore we will, only in the explanatory part of medicine, replace “One cause, one disease” by a mitigated/derogated assumption. The new assumption is that a disease as well as its cause both are ‘more or less one’ instead of being ‘absolutely one’. This reduced ‘truth value‘ of “One cause, one disease” comes with a down side. Causes that are ‘more or less one’ and are leading to diseases that are ‘more or less one’ are just lacking the ability to connect the observed data into …. one …. ? Into one concept? Into one story? One narrative connecting the observed data together?

In the previous paragraph we have demoted disease to mere narrations where the characters and forces at play are the various aspects of cause and disease. Not unlike different versions of a tale still are one narrative.

As said in previous episodes we cannot throw “One cause, one disease” out of ‘medical practice’ since it is the logical justification for virtually every treatment. In the explanatory part we now know very little since causes and diseases are only ‘more or less one’. This is the consequence of having kicked “One cause, one disease” from the explanatory part. But it needs to be replaced by some other bold and inspiring assumption. After all scientific knowledge and explanations need to be tentative. So, we need to assume certain ‘things’ are ‘really’ the ‘same’, assume a reason must exist for these ‘things’ to be ‘the same’ and subsequently prove those assumptions make any sense. But, what are we going to assume now?

”We are to admit no more causes of natural things than such as are both true and sufficient to explain their appearances. Therefore, to the same natural effects we must, so far as possible, assign the same causes.”

Isaac Newton

The explanatory part of medicine has been emptied of all firm assumptions about of things like cause and disease to be the ‘same’. To fill this void with, what is there left in medicine we might consider to be ‘real’ and assume to be ‘the same’? Well, besides symptoms there is nothing much left to go on. So, let us consider symptoms to be the “natural things” and “natural effects” Newton was referring to in the above citation. In our new view for the explanatory part we just substitute symptoms for diseases. Thus we look into the cause of symptoms and prove this makes more sense than looking for the cause of diseases. Even more, or more precisely, we will explain how symptoms are caused and subsequently new pathways to the origin of disease.

What we just did is changing our focus upon Newton‘s natural world. We still see the same unhealthy individuals. But now we zero down on the symptoms of these unhealthy individuals to perceive them as “natural things” and “natural effects”. The diseases of these individuals are no longer our focus and therefore are somewhat blurred, a bit less ‘one’, a bit less real, a bit less of a factual account of what is happening in Newton‘s natural world. In this new view upon the medical world we assume that when symptoms are looking alike (look alike) they just are ‘the same’ and have the same cause. No questions asked. Even the ‘only in the mind symptoms’, or no matter what other name might be used to designate ‘medically unexplained symptoms’, they are all true.

You might think: “This is fundamentally wrong, no one in his right mind would ever consider this!”. My reply here is that this cannot be fundamentally wrong since it is precisely this fundament that has been changed. According to philosopher of science Thomas Kuhn, we have created a second account of reality. Albeit one that is irreconcilable with the traditional medical view. In western medicine the dominant and only view on reality is that diseases are undoubtedly true. Our new account of reality considers symptoms as the indisputable truth. Even the sketchy, mental and unreal ones.

To solve the incommensurability regarding/of these two rather opposed accounts of reality, as Kuhn puts it, we assign a specific domain to either view. To either worldview if you like. Two worldviews that both are true. From the point of view of deciding which treatment is best to be administered: diseases are true. This is the worldview of ‘medical practice’. From the point of view of explaining: symptoms are true. This is the worldview of our newly formed ‘explanatory part’ of medicine.

In my opinion these two accounts of reality do not compete for ‘the truth’ in the way Thomas Kuhn saw it. Instead of competition, these two equally true accounts of reality coexist in a way more in accordance with Nietzsche’s perspectivism. Friedrich Nietzsche, an influential modern times German philosopher, argues that the reality unfolding itself right in front of your eyes depends heavily on your chosen vantage point. For example, one can choose to see waves compatible with relativity theory, or choose to see particles compatible with quantum physics. A schism of two perfectly real/true worldviews that are as yet incompatible but are expected to be reconciled in the future.

As for waves versus particles, as well as for symptoms versus diseases, either perspective upon the natural world will give a different account of reality, both of which are true. Now we just need to find proof our new worldview makes any sense. Hereto we need to find solid arguments to the following claim:

“One symptom, one cause”

In the next section I only rephrase and repeat what has already been said. Feel free to pick up again at the next ћ sign. By the way, this ћ sign has been introduced by Paul Dirac, a French mathematician, pioneer of quantum physics. It is his abbreviation of Planck’s constant divided by 2π. Max Planck, a theoretical physicist, introduced the idea of ‘quanta’ into physics to explain the peculiar form of the black-body radiation spectrum.

Back to medicine. We have created two domains in it: ‘medical practice’ and ‘the explanatory part of medicine’. Each domain beholds a different account of reality. These realities do

not exclude each other but are different perspectives upon the same world. Two equally true worldviews. Two perspectives, one on symptoms and the other one, the traditional one, on diseases. From the point of view of deciding which treatment is best to be administered: diseases are true. This is the worldview of ‘medical practice’. Conversely, from the vantage point upon finding new ways towards explanatory models in medicine: symptoms are true.(or maybe better put it this way Andy?: …. from the vantage point of explaining what is happening inside a human body while being affected by disease: symptoms are true) Thus, the worldview of our yet to be defined explanatory model shall be that symptoms are true and diseases are narratives based on facts that allow to predict what is going to happen.

To be utterly clear, where medicine is currently seeing individuals with diseases that eventually require an explanation, in our new worldview we choose to see individuals with symptoms. Also requiring an explanation. We still look at the same individuals with the same health issues, the same symptoms, the same complaints etc. In respect to these individuals each worldview has its own fundamental question. In the traditional conception of the medical world this question is: “What is the cause of their disease(s)?”. In the new worldview we now wonder: “What is the cause of their symptoms?”. Our hope is that, since symptoms are somehow related to diseases, the cause of the symptoms might inform us about the cause of the diseases. If the (world)view of the symptoms being absolutely true does improve explanations of diseases in the other worldview, than we are all good and the new worldview proved itself to be not fundamentally wrong at all.

To get to the ‘better explanation’ it might therefore take as little as shifting our focus from ‘diseases’ to ‘symptoms’. Change our vantage point from which we try to make sense out of what seems to be happening in the natural world. Nietzsche’s perspectivism suggests there are as many causes to a phenomenon as there are vantage points upon it. As we have seen in earlier episodes, medicine generally takes a distant view and observes groups of individuals contracting diseases that are regarded as events caused by other events. In our quest for better explanations we will go for the closest possible vantage point. A vantage point inside an individual’s biochemical processes. When zooming in this closely on biochemical processes we no longer clearly ‘see’ diseases, nor their respective causes, as ‘one’. But it will be the closest we can get to an explanation. Meanwhile, Occam’s double edged razor tells us we should consider one single explanation for diseases, symptoms and every imaginable question. All in one.

”But how are we going to find clues to what should be in that biochemistry based explanation?”

One last point before getting to the clue finding strategy:

“When it comes to explanations there is no reason to distinguish symptoms from complaints.”

When it comes to diagnose diseases, this distinction does matter. When it comes to explaining diseases, it does not. For example, there is no reason to believe a specific type of headache is caused in a substantially different way when it is called a symptom instead of complaint. Newton tells us that when the headache really looks the same, either as a complaint or as a symptom, than only one single cause should be assigned.

Subsequently, we follow Occam’s second principle. The double edged razor one: reduce the total number of explanations required as far as possible. Together Occam and Newton show us that one explanation for similar phenomena is stronger than each phenomenon having its own explanation. Especially Occam’s second principle of cutting down the total number of explanations incites us to use the same biochemical origination model for symptoms and complaints, provided that symptom and complaint are really similar. Let us take the example of the headache again: If in one person a specific headache is a symptom and this exactly same type of headache is called a complaint in another person, than Occam and Newton tell us that we should look for only one (biochemical) explanation for this headache until proof exists this combined explanation for symptom and complaint cannot be. Ergo, the strongest explanation is a combined one for symptoms and complaints.

Let us recapitulate the different ideas discussed in this episode:

The double edged razor of Occam: an explanation should be concise and address as many questions as possible.
Feyerabend and his “Anything goes” when it comes scientific progress, in our case ‘explanation’.
Newton told us that when we encounter the same symptom(s) in different diseases we should look for the same causes that explain this.
Nietzsche showed us that different vantage point upon a system will lead to different accounts of reality.
Kuhn told us that different accounts of reality can co-exist in science until one proves to be the truth.
We proposed there would be two worlds, both are true, two worldviews: one where diseases are real, one where all symptoms are real, even the psychosomatic and other ones.
And again based on Newton: when it comes to explaining there is no point in distinguishing symptoms from complaints.

If we now may speak of medicine as a doctrine than the core idea would be that symptoms do not mean anything by themselves. It is this idea we challenge full force:

“One symptom, one cause”

From here we will start to build the ‘better explanation’. The strongest explanatory model is the one that is:

Reasonably concise while fully explaining symptoms as well as complaints
Provides new insights into several diseases
Answers or unlocks a lot of other questions

The problem we now run into is that “explaining the symptoms” does not offer insight into how to proceed towards this explanation. This approach does not offer any information to work with since in medicine information is enclosed within diseases. So, as absurd as it might seem to first attack the idea of disease as unreal (not really an entity, not really real, not really one), to subsequently turn back to it for information, that is exactly what we will do. We take diseases, decompose them into information, take out their symptom sets and for the moment at least we will ignore the rest.

The next problem to solve is: What symptoms and diseases are we going to select?

Just some more repetition of ideas here: Our new world view, the one inextricable linked to the explanatory part of medicine, is built under the assumption that symptoms and complaints are equal and real. Even the most doubtful complaint from patients diagnosed with the most sketchy psychiatric condition affecting ‘the mind’, every complaint, every symptom, is real. But one single explanatory model for every know symptom in every disease and condition it is known to be encountered in probably leads to a sheer endless explanation based on a endlessly complexed model. This conflicts with the point of the whole operation: an explanatory model that feels as ‘one’ and is reasonably concise. So, we need to narrow down.

Let us include in our model just three diseases. Let these three be diseases that are known for having a huge amount of symptoms and complaints. Let us include one ‘real’ medical condition and one of those psychiatric conditions that are shrouded in doubt. Let the third one be an ‘intermediate’ condition, with ‘intermediate’ referring to the extend with which this condition is regarded as real from the point of view of current medical practice.

Let us not only limit the scope of the explanatory model to three diseases. Let us also limit the amount of symptoms we need to explain by treating the symptoms as a group. In other words, we need to find one reason for a set of symptoms to be ‘the same’ in three different conditions. Ideally, we select the three diseases in such a way the set of symptoms shared amongst all three of them is as large as possible. Since a large set will reduce the odds for symptoms being ‘the same’ for no reason at all.

Thus, despite this large set of symptoms being a member of different diseases, we will treat it as one. One group. One set actually. Look at this shared set as the centre, called intersection, of a Venn-diagram. A Venn-diagram consisting of three overlapping circles. Each circle accommodates the set of symptoms most likely to be found in its respective condition. The overlapping part of the three circles, the intersection, harbours the set of symptoms shared amongst the three conditions.

After extensive digging I found a quite large group of identical symptoms being shared by:

Multiple sclerosis: an auto-immune disease affecting the central nervous system
‘Chronic fatigue syndrome’ / ‘Myalgic Encephalomyelitis’ (both terms are in use: ME/CFS)
Somatization disorder: the actual archetype of conditions where ‘symptoms are in the mind’

The shared symptoms and complaints are:

Weakness
Fatigue
Cognitive impairment
Abdominal pain
Bloating
Nausea
Vomiting
Constipation or diarrhoea
Headache
Impaired touch or pain sensations of the skin, itchiness or tingling
Various posture and gait related issues
Muscle jerks that may present like seizures
Chronic cough, sore throat, dysarthria or dysphonia, swallowing issues, painful throat
Eye pain, rectal pain, pain in the extremities, chest pain, back pain,
Sexual dysfunction or pain
Various sensitivities, allergies or intolerances
Mood problems
Visual disturbances, sensitivity to light, dry eyes, double vision, visual loss
Urinary symptoms: retention, incontinence, pain

Symptoms and complaints for ‘Chronic fatigue syndrome/Myalgic Encepalomyelitis'(ME/CFS) were taken from a free book recommended by Centre for Disease Control(CDC) and published by the ‘Institute of medicine'(Institute of medicine 2015). For a structured insight into the symptomatology of ME/CFS I also recommand articles on the symptomatology of ME/CFS(Bateman 2021, Lim 2020).

Symptoms and complaints for ‘Multiple sclerosis’ were taken from an overview redacted by the ‘National Institute of Neurological Disorders and Stroke’ and presented on the CDC-website as an overview for ‘Multiple sclerosis'(NINDS’ summary of Multiple sclerosis). I did include several more articles that extensively review the symptomatology of ‘Multiple sclerosis'(Teasell 1993, Frohman 2011, de Sa 2011, Hubbard 2021).

Somatization disorder symptoms were taken from the ‘Diagnostic and Statistical Manual of mental disorders (DSM), version 4-TR. ‘TR’ stands for ‘totally revised’. If I remember correctly, in earlier versions of the DSM the phenomenon of ‘functional symptoms’ was diagnosed as ‘Somatization disorder’, which is currently redefined under the name of ‘Somatic symptom disorder’ in the DSM-5 with very little attention being paid to the actual nature of the symptoms themselves. Since it is the symptoms we are interested in, it is the structured overview of symptoms in the 4-TR edition we have been using. In the DSM-4-TR ‘Somatization disorder’ is referred to as ‘Briquet’s syndrome‘ after the French doctor who in my eyes did a most excellent job as an observer as well as in the meticulous definition of diagnostic criteria for the syndrome(Morrison 1978, Stone 2008). In respect to the same phenomenon but now referred to as ‘Medically unexplained Illness’, the CDC recommands an article by Emily Kendall that I highly recommand for demonstrating the elusive nature of this condition by simply outlining the various perspectives onto this condition(Kendall 2012). Further, Stone et al. did some remarkable work in describing what the syndrome looks like in medical practice in the absence of judgement on the reality of whatever is brought under the doctor’s attention(Stone 2008). Of course, a historical overview is most valuable to seize the phenomenon of ‘functional symptoms’ (or complaints), somatization, hysteria, ‘psychosomatic symptoms’ (or complaints), ‘Medically unexplained symptoms’, … , or whatever designation might be used. Over time, the phenomenon has gone by many names. I recommend the following article by Julie Maggio(Maggio 2020). I further recommand articles by RA Cleghorn and Shahar Arzy to appreciate how ‘the medically unexplained’ got lost in between ‘medicine as a whole’ and psychiatry as one of its sub specialities(Cleghorn 1961, Arzy 2014). Also, the first chapter by Don R. Lipsitt of Michael Blumenfield’s ‘Psychosomatic medicine’ might be instructive in this respect. It however might be more difficult to find on the internet as compared to all other references that are accessible as free full text.

Each of the above three condition and their symptoms will be discussed in more detail in further episodes. For now, we just retain that there is one set of symptoms that is present in each of these three conditions that is large and virtually identical among the three of them. Some people might feel urged to point out Multiple sclerosis is a real disease, an organic disease, while the others … . I’ll interrupt you right here because: “It does not matter”. In our newly adopted worldview where all symptoms are real anyway, diseases are more like stories about things that happen. Narratives about facts and events that we will try to relate to a biochemical reality. For this moment however we just have a bunch of equally real symptoms present within three different conditions and no clue to anything.

To move forward to ‘a better explanation’ we just take the above listed set of symptoms and do nothing more than try to explain them as one single phenomenon. Not as three different phenomena called diseases. We assume, although belonging to three different diseases, it must mean something in respect to the human body for this set to be large identical. In other words, we assume that the mechanism by which the human body expresses this particular set of symptoms must in some way be ‘the same’ in respect to Multiple sclerosis, Chronic fatigue syndrome and Somatization disorder. I suppose there is only a limited amount of mechanisms by which a human body can express or become aware of the same set of symptoms.

To proceed to the next step, depict symptoms as being on ‘the field of all symptoms’. A bit like the field of all real numbers in Maths. But here it is the ‘field of all real symptoms’ (I really had to make this joke). From the perspective of this field a disease is nothing more than a set of symptoms. (The field does not understand disease is also about suffering, treatment, uncertain outcome, … .) On this ‘field of all symptoms’ there is this large set of symptoms that is parts of our three conditions: Multiple sclerosis, Chronic fatigue syndrome and Somatization disorder. This set is represented by the orange part in the Venn-diagram depicted at the top of this text. The circles in this Venn-diagram represent the set of symptoms characteristic of respectively Multiple sclerosis, Chronic fatigue and Somatization disorder. With their shared symptoms in the orange middle section. This orange intersection is the phenomenon we are going to provide an explanation for. Exactly as in Newton‘s quote above: ”We are to admit no more causes of natural things than such as are both true and sufficient to explain their appearances. ….”

As said earlier however, we have no clue to what happens in that orange intersection. To find clues to what happens in this part of the Venn-diagram we are going to use Epicurus’ Principle of multiple Explanations:

“If several theories are consistent with the observed data, retain them all”

Epicurus

Epicurus was a Greek philosopher convinced of the atomic nature of things. By the sheer power of his mind, Epicurus conceived the mind itself aught to be atomic in nature. Believe it or not, this is exactly where my story is heading too, in some way.

Okay, the orange stands for the data and Epicurus is telling us that our three conditions are to be combined into one single explanation for the whole data set. The problem however is that we still have no clue to what is triggering these orange symptoms. Now this is where Epicurus tells us that if we come across other conditions the orange symptoms are also integrally part of than these conditions should also be included into the explanatory model. This is how we are going to use Epicurus’ principle to find clues to this explanatory model. We will include three more conditions but this time there must be a distinct clue to the biochemical origination of the condition. The mechanism, so to speak. The cause, if like.

After some more extensive digging I came up with the following three conditions that all have a distinct clue to their biochemical origination and also present with the same orange symptoms. Two deficiency syndromes and one intoxication:

Cobalamin deficiency: Cobalamin is another name for vitamin B₁₂
Sarin intoxication: Sarin is a nerve blocking agent interfering with reuptake of the vital neurotransmitter acetylcholine, hence them being referred to as cholinergic neurons.
Copper deficiency: Copper, required in numerous enzymes for their specific activity, has its allocation to specific subcellular compartments heavily regulated to match specific cellular activities(Witt 2020, Hasan 2012)

The symptoms of ‘Cobalamin deficiency’, ‘Sarin intoxication’ and ‘Copper deficiency’ do fit the orange intersection as tightly as the first three conditions. Especially when including ‘Copper deficiency’ symptoms as they are observed in cattle. I am not saying that the orange symptoms are equally common in all 6 conditions. Some of these symptoms might even be fairly uncommon in one or several of these conditions. How often symptoms occur is a major concern in diagnostics and hence the domain of medical practice, it is however not a problem affecting the explanatory part of medicine. The explanatory part of medicine has to explain symptoms even if they occur only once. Of course it would be rather uncertain whether symptoms that occur only once are really real symptoms. S they might as well be totally unrelated complaints. However, we have decided that this does not matter, all symptoms (or complaints) are real. In other words:

We cannot allow medical practice to define a disease in terms of diagnostic criteria and than impose this definition upon the rest of medicine. The diagnostic criteria are only a list of key features and most common symptoms of the disease. As I see it, the diagnostic criteria might no longer contain all the of the information required to find the most plausible explanation for the disease.

In the next episode we will present symptoms and known biochemical facts of the three chosen syndromes, Multiple sclerosis, Somatization disorder and Chronic fatigue syndrome.

Arzy S, Danziger S. The science of neuropsychiatry: past, present, and future. J Neuropsychiatry Clin Neurosci. 2014 Fall;26(4):392-5.

Barlow RM, Recent advances in swayback. Proc R Soc Med. 1958 Sep;51(9):748-52.

Bateman L, Bested AC, Bonilla HF, Chheda BV, Chu L, Curtin JM, Dempsey TT, Dimmock ME, Dowell TG, Felsenstein D, Kaufman DL, Klimas NG, Komaroff AL, Lapp CW, Levine SM, Montoya JG, Natelson BH, Peterson DL, Podell RN, Rey IR, Ruhoy IS, Vera-Nunez MA, Yellman BP. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Essentials of Diagnosis and Management. Mayo Clin Proc. 2021 Nov;96(11):2861-2878.

Benkirane A, Warlop T, Ivanoiu A, Baret P, Wiame E, Haufroid V, Duprez T, Hantson P. Case report: Motor neuron disease phenotype associated with symptomatic copper deficiency: Challenging diagnosis and treatment. Front Neurol. 2023 Jan 4;13:1063803.

Chalmers GA. Swayback (enzootic ataxia) in Alberta lambs. Can J Comp Med. 1974 Apr;38(2):111-7.

Chami HA, Hall MAK. Copper Deficiency and Polyneuropathy: A Case Report. Cureus. 2022 Aug 22;14(8):e28261.

Cleghorn RA. A comparison of the historical roots and developments in medicine and psychiatry as they affect research. Can Med Assoc J. 1961 Jul 1;85(1):18-27.

Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015 Feb 10.

Frohman TC, Castro W, Shah A, Courtney A, Ortstadt J, Davis SL, Logan D, Abraham T, Abraham J, Remington G, Treadaway K, Graves D, Hart J, Stuve O, Lemack G, Greenberg B, Frohman EM. Symptomatic therapy in multiple sclerosis. Ther Adv Neurol Disord. 2011 Mar;4(2):83-98.

Gasimova U, Jayanth P, Kafaie M. A Case Series of Patients With Polyneuropathy Due to Copper Deficiency. Cureus. 2023 Apr 9;15(4):e37329.

Grzeszczak K, Kwiatkowski S, Kosik-Bogacka D. The Role of Fe, Zn, and Cu in Pregnancy. Biomolecules. 2020 Aug 12;10(8):1176.

Hasan NM, Lutsenko S. Regulation of copper transporters in human cells. Curr Top Membr. 2012;69:137-61.

Hubbard AL, Golla H, Lausberg H. What’s in a name? That which we call Multiple Sclerosis Fatigue. Mult Scler. 2021 Jun;27(7):983-988.

Institute of Medicine. 2015. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press.

Jaiser SR, Winston GP. Copper deficiency myelopathy. J Neurol. 2010 Jun;257(6):869-81.

Kaler SG, DiStasio AT. ATP7A-Related Copper Transport Disorders. 2003 May 9 [updated 2021 Apr 15]. In: Adam MP, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023.

Kaler SG. Inborn errors of copper metabolism. Handb Clin Neurol. 2013;113:1745-54.

Kendall EA, Zaman RU, Naved RT, Rahman MW, Kadir MA, Arman S, Azziz-Baumgartner E, Gurley ES. Medically unexplained illness and the diagnosis of hysterical conversion reaction (HCR) in women’s medicine wards of Bangladeshi hospitals: a record review and qualitative study. BMC Womens Health. 2012 Oct 22;12:38.

Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010 Mar 12;86(3):343-52.

Lim EJ, Son CG. Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Transl Med. 2020 Jul 29;18(1):289.

Maggio J, Alluri PR, Paredes-Echeverri S, Larson AG, Sojka P, Price BH, Aybek S, Perez DL. Briquet syndrome revisited: implications for functional neurological disorder. Brain Commun. 2020 Sep 23;2(2):fcaa156.

Morrison JR. Management of Briquet syndrome (hysteria). West J Med. 1978 Jun;128(6):482-7.

Ojha R, Prasad AN. Menkes disease: what a multidisciplinary approach can do. J Multidiscip Healthc. 2016 Aug 17;9:371-85.

Puchkova LV, Babich PS, Zatulovskaia YA, Ilyechova EY, Di Sole F. Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin as a Nutritive Source of Copper: Overview of the Current Data. Nutrients. 2018 Oct 30;10(11):1591.

de Sa JC, Airas L, Bartholome E, Grigoriadis N, Mattle H, Oreja-Guevara C, O’Riordan J, Sellebjerg F, Stankoff B, Vass K, Walczak A, Wiendl H, Kieseier BC. Symptomatic therapy in multiple sclerosis: a review for a multimodal approach in clinical practice. Ther Adv Neurol Disord. 2011 May;4(3):139-68.

Stone J, Hewett R, Carson A, Warlow C, Sharpe M. The ‘disappearance’ of hysteria: historical mystery or illusion? J R Soc Med. 2008 Jan;101(1):12-8.

Tatham PH. J R Soc Med 1987 Jun;80(6):331-2.

Teasell RW. Managing advanced multiple sclerosis. Can Fam Physician. 1993 May;39:1127-30, 1133-4, 1137-41.

Witt B, Schaumlöffel D, Schwerdtle T. Subcellular Localization of Copper-Cellular Bioimaging with Focus on Neurological Disorders. Int J Mol Sci. 2020 Mar 28;21(7):2341.

Holmes JM. Cerebral manifestations of vitamin-B12 deficiency. Br Med J. 1956 Dec 15;2(5006):1394-8.

Sahoo MK, Avasthi A, Singh P. Negative symptoms presenting as neuropsychiatric manifestation of vitamin B12 deficiency. Indian J Psychiatry. 2011 Oct;53(4):370-1.

Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood. 1990 Sep 1;76(5):871-81.

Shulman R. Psychiatric aspects of pernicious anaemia: a prospective controlled investigation. Br Med J. 1967 Jul 29;3(5560):266-70.

Shorvon SD, Carney MW, Chanarin I, Reynolds EH. The neuropsychiatry of megaloblastic anaemia. Br Med J. 1980 Oct 18;281(6247):1036-8.

Toru S, Yokota T, Inaba A, Yamawaki M, Yamada M, Mizusawa H, Hayashi M. Autonomic dysfunction and orthostatic hypotention caused by vitamin B12 deficiency. J Neurol Neurosurg Psychiatry. 1999 Jun;66(6):804-5.

Vasconcelos OM, Poehm EH, McCarter RJ, Campbell WW, Quezado ZM. Potential outcome factors in subacute combined degeneration: review of observational studies. J Gen Intern Med. 2006 Oct;21(10):1063-8.

Calderón-Ospina CA, Nava-Mesa MO. B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin. CNS Neurosci Ther. 2020 Jan;26(1):5-13.

Badar A. Neuropsychiatric Disorders Associated With Vitamin B12 Deficiency: An Autobiographical Case Report. Cureus. 2022 Jan 21;14(1):e21476.

Serin HM, Arslan EA. Neurological symptoms of vitamin B12 deficiency: analysis of pediatric patients. Acta Clin Croat. 2019 Jun;58(2):295-302.