Is it that bad?

Is it that bad?

When I got sick, about 20 years ago, for the first time I started thinking about diseases and loss of health. And I remember coming to the conclusion of how fortunate I was, from a physical standpoint. Not of how fortunate I had been in the past (that was obvious), when I could conquer mountains, running on rocks with my 15 Kg bike on the shoulders; no, of how fortunate I was in that very moment, while confined at home, mostly lying horizontally. I was fortunate, I could still move my hands, I had still all my body, even if I couldn’t use it in the outside world, even if most of the usual activities of a 20 years old man were far beyond reaching, I realized how fortunate I was. And after 20 years I still say that, as for the physical functioning, I am a very lucky man. There are even some years, during the core of the summer, in which I can run for some minutes in the sun. I am blessed.

I am aware that this might offend some patients, but I think that those who have ME/CFS in the vast majority of cases are fortunate too, from a physical standpoint. Yes, it is annoying to need help from others for so many things, but with assistance and some arrangements, you can go on with a productive life… unless you have cognitive impairment.

Actually, I never felt fortunate concerning my cognitive functioning. That has been a true tragedy, I have lost my entire life because of the cognitive damage, by any means because of the limitations of my body. I would have had a meaningful life (according to any standard) even with physical limitations way worse than mine if I had had a functioning brain. But I lost it when I was 20 before I could get the best from it and that is the only real tragedy.

As an example of what I am saying, consider a person like Stephen Hawking: he has been a prolific scientist, he had a stellar career (literally), he shaped our culture with his books for the general public, he was a father of three, and so forth. And yet for most of his life, while he was doing all these things, his physical functioning was way worse than the one of the average ME/CFS patient (worse even of a very severe patient, probably). For many years he could use only the muscles of the head. That’s it. Think about that. Was he missing or invisible? Definitely not!

Was he a disabled man? Yes, technically speaking he was, but in fact, he has never really been disabled, if we judge from his accomplishments. He once said that the disease somehow even helped him in his work, because he could concentrate better on his quantum-relativistic equations¹.

So what I am saying is that if we consider the physical functioning in ME/CFS, it is a negligible problem in most of the cases. The only thing that matters is the impairment in cognition (in the cases in which it is present), especially if it starts at a young age (consider that after you reach your thirties there is very little chance that your brain will give a significant contribution to humanity, even if you are perfectly healthy, so it is not a big loss if you get sick after that age). That is disastrous and there is no wheelchair you can use for it. For all the other symptoms you can find a way to adjust, just as Hawking did in a far worse situation.

This might be one of the reasons for the bad reputation of ME/CFS: there isn’t awareness about cognitive issues, no one talk about them (and in some cases, they are in fact not present at all). But I am pretty sure that the real source of disability in these patients, the lack of productivity, is due to their cognitive problems (when present). Also because in a world like ours, you can work even without using most of your muscles. It is not impossible, I would say it is the rule for a big chunk of the population.

The following one is an interview with Norwegian neurologist Kristian Sommerfelt, in which he points out some analogous considerations. He has done some research on ME/CFS with the group of Fluge and Mella, including the well-known study on pyruvate dehydrogenase. From the subtitles of the video (minute 3:38):

“This [the cognitive problem] is a very typical ME symptom and some of what I believe causes the main limitation. I don’t think the main limitation is that they’re becoming fatigued and exhausted by moving around, walking, running, or having to sit still. If it were just that, I think many ME-patients could have had a much better life. But the problem is that just actively using the mind leads to problems with exactly that, using the mind. It comes to a stop, or slow down, depending on how ill they are.”


¹ It seems that Stephen Hawking had a very unusual presentation of Amyotrophic Lateral Sclerosis (ALS): one half of those with this disease die within 30 months from the first symptom; moreover one out of two ALS patients has a form of cognitive impairment which in some cases can be diagnosed as frontotemporal dementia [R]. So, Stephen Hawking was somehow lucky, in his tragedy, and he doesn’t represent the average ALS patient. I mentioned his case as an example of a person with very severe physical impairment and no apparent cognitive decline, not as an example of the average ALS patient. 

About me

About me

The following video is meant to be a presentation of both the blog and of myself. As I started improving again, some days ago, I decided to record this monologue, so that there could be a video memory of my struggle.

This winter I have spent almost three months in South America, to see if I would have improved during the austral summer, as I usually improve during the Italian summer; and in fact, I did improve. When I came back to Italy (in March) I had a relapse, though. For the last three months, I have been mostly horizontal, without reading or thinking for most of the time.

Now I am climbing the mountain again: I started my rehabilitation reading novels some days ago, then I switched to simple calculations and now I have written my first small code since March. And when I will reach the cognitive level I had about 20 years ago just before I got sick, I will lose everything for months (or years) and I will have to wait without thinking much (despite my best efforts) until I can start all over again…

The myth of Sisyphus has been shaped after me.

 

 

My saviour

One of my short-lived summer improvements (2013). During all these years, as soon as I started feeling better, I opened my books, even before taking a shower and having my hair cut. Happy as a child for most of the time, but also profoundly saddened for the time lost, especially at the beginning of the improvement, when I could realize how much time had passed from the previous positive phase.

97284908_10220774536729711_4708150532923981824_n

Each time I had to start exactly from where I had left many months or even years before (the longest gap has been 5 years without studying). I had to do a cognitive rehabilitation each time, learn again how to read properly, how to do math, how to discipline my thoughts, how to code. It is a hard process each time. And then, a few weeks after, when I recovered enough to function mentally, I relapsed again.

I am pretty sure that only this complete, obsessive devotion to studying has saved me from very bad cognitive disability.

Before getting sick, coding and math had taught me how to think. Then, when I became ill, each equation I wrote, each drawing and code, all those efforts made to bring my soul back from wherever it was, they kept me alive for all these years.

The time machine

I am aware that these are just messages floating in the silence, stored somewhere in the planet as binary numbers. I am writing to myself, mainly, from my remote hiding place.

I have travelled through ages, without really being part of them. All alone with my problem. As a patient with a rare disease that doesn’t even have a proper description, I do not belong to humankind.

But humans have paradoxical behaviours, they care more about a man who lived five thousand years ago in the north of Italy, trapped in the ice of our highest mountains, than of clochards that live right now in pain and loneliness in their community. So it might be that generations from now, someone will find these notes, an archaeologist who will try to build my story, from fragments of what I left behind: drawings and calculations. Mathematics is a universal language, after all, and to some extent, even art is universal; not always but often, good art is forever.

If I fail my mission, history will never record my existence. But it might be that at some point in the future someone will find these notes frozen in the ice of a planet long forgotten by humans themselves, as we now have forgotten Africa, the place we all come from.

 

Why I study my own disease

Why I study my own disease

A lot of patients have asked me why I use my little energies to study my disease, instead of just waiting for science to conquer it.

There are many reasons, the first one being that I am desperate because of the cognitive disability that is worse than death. I am not concerned about the physical limitations, at all, even though I have been mostly housebound for the last 20 years. Another reason is that I like computational biology, and I started studying engineering before getting sick with the idea of switching to bioengineering after graduating. So, this is my job.

The other point is that even though I fit the criteria for ME/CFS, I have a rare disease, granted that ME/CFS is not a rare disease: it has a prevalence of 0.4% according to some studies, so it is relatively common. Then why am I a rare patient? Let’s do some calculations: since the median age at onset is 36.6 years with a standard deviation of 12.3 years, the proportion of males is 19% and the proportion of those who are housebound for most of their disease is 25% (R), the probability for a ME/CFS patient of having my same characteristics is (assuming that these are all independent random variables) given by p=0.0075. So, less than 1 out of 100 ME/CFS patients has my type of illness. If we consider also that pain or aching in muscles is present in 59% of patients and it is mostly absent in my case, the above-mentioned probability is even lower: p=0.0031. Which means that only 3 ME/CFS patients out of 1’000 have my illness.

Taken all these data together, the prevalence of my disease in the general population becomes 1/100’000, which means that I have a rare disease, according to the European definition (where a disease is defined rare if it has a prevalence ≤1/2’000) [R]. In the US a disease is defined rare only if it has a prevalence ≤1/200’000, though [R].

And besides that, it is pretty obvious that I am a unique case. I have never found a patient like me, so far. It can also be noted that in Italy, given a population of 60 million inhabitants, those who have my condition are only 600. This might be the reason why I haven’t met them, yet.

This means that I am probably the only one who is studying my disease, on the planet! This is why I’m doing what I’m doing.

91569815_10220268929849855_9111778109215997952_o

Above, my personal book of immunology, built page by page, paper by paper. I have three other books about this discipline. One of them was a gift from a neurologist that perhaps thought that gift was the only thing she could do to save me. Another one is a very sophisticated text on cutting edge immunology. But this one is the best one because I have selected and read each one of its pages. It is by no means a complete book, it is mainly focused on B cells and B cell autoimmunity, but it has been very useful.

I have built several other books like this, on computational methods in immunology, on metabolism, on neurosciences, on microbiology, and on some diseases: Lyme, ME/CFS, mast cell activation, POTS…

I have learned a great deal, even though outside academia. But I had no choice, I have been too sick and too slow to study at university: I had only a few weeks in which I could study, and then months or years in which I had to wait. This has been my routine. Moreover, given the lack of energy and time, I had to study only what was truly important for my health. Because my goal was to cure myself and save me from a lifetime of cognitive disability.

Testing hypotheses

Testing hypotheses

Introduction

My ME/CFS improves during summer, in the period of the year that goes from May/June to the end of September. I don’t know why. I have several hypotheses. One possible reason for the improvement in summer is an interaction between the light from the Sun and some parts of my physiology, the immune system for instance. We know that ME/CFS tends to have an oscillating course in most of the patients (Chu L. et al. 2019), but the presence of a seasonal pattern in this patient population has not been investigated so far, to my knowledge. And yet, if you ask directly to patients, many of them say that they feel better in summer. Unfortunately, we don’t have scientific data on that, this is an area worth investigating with some carefully done survey.

Seasonal variation of the immune system

The immune system has a high degree of variation for several reasons (Brodin P et Davis MM 2017). In particular, there are studies about the seasonal fluctuations in the expression of some crucial genes of the immune response (Dopico XC et al. 2014).

How does this regulation happen? Different mechanisms are possible, some of them might be related to changes in the light we receive from the Sun as the Earth rotates around it. We know that the length of the day has an effect on innate immunity: the more the hours of light, the lower the power of the innate immune system (Pierre K. et al. 2016). We also know that ultraviolet radiation, particularly UVB, is an agonist for the aryl hydrocarbon receptor (AhR) (Navid F. et al. 2013). This receptor seems to reduce the expression of the major histocompatibility complex II (MHC II) in dendritic cells (DCs), thus reducing their antigen-presenting activity (Rothhammer V. et Quintana F.J. 2019). UVB might be able to reach dendritic cells when they are circulating near the skin, during summer, thus inhibiting their antigen-presenting activity. Infrared radiation, on the other hand, seems to have an effect on energy metabolism: in Fall we lose a significant amount of infrared radiation in a wavelength range (0.7-1.0 nm) that is known to have an effect on mitochondrial activity (Nguyen L.M. et al. 2013) and it might perhaps have an indirect effect on immunity too.

As further proof of seasonal fluctuation in immunity, some immunological diseases have this kind of seasonality: Rheumatoid arthritis (Nagamine R. et al. 2014) and Rheumatic fever (Coelho Mota C.C. et al. 2010) are two examples. Moreover, the prevalence of Multiple Sclerosis is directly proportional to the latitude (Simpson S. et al. 2011). We also know that there is seasonal fluctuation in serum autoantibodies (Luong T.H. et al. 2001).

Of course, sunlight might be just one of the variables into play. The other aspect I am considering is the seasonal distribution of some common pathogens. Streptococcus, Enteroviruses and Fungi of the genus Penicillium are known to have a seasonal distribution with a peak in Fall and/or Winter (Ana S.G. et al. 2006), (Salort-Pons M et al. 2018), (Coelho Mota C.C. et al. 2010). Common influenza has this pattern too. Rheumatic fever, a disease due to an abnormal immune response to Streptococcus, has its flares in Fall because Streptococcus is more common in that period of the year (Coelho Mota C.C. et al. 2010). Even the composition of the gut microbiota has a seasonal pattern (Koliada A. et al. 2020). I am currently investigating my immunosignature, measured with an array of 150.000 random peptides, to see if I can find some relevant pathogen in my case. You can find this study here.

(A few months after I wrote these notes a pivotal study has been published on these same topics, avalilable here).

An experiment

I moved from Rome (Italy) to Rosario (Argentina) at the beginning of January. I was very sick and I steadily improved after about 40 days. I became a less severe ME/CFS patients and I could work several hours a day and care for myself, granted that I did not exceed with aerobic exercise. At the end of March, I started deteriorating as it usually happens at the end of September, when I am in Rome. In order to study this phenomenon, I have built a complete model of solar radiation at sea level, which considers the inclination of sunrays in function of the latitude and of the day of the year. It takes into account the effect of the atmosphere (both diffusion and absorption) and the eccentricity of the orbit (Maccallini P. 2019). If you look at the figure below (a byproduct of my mathematical model) you can see that when I started deteriorating in Rosario, the power of sunrays at noon in that city was still as high as it is in Rome during the summer solstice (this is due to the fact that the Earth is closer to the Sun in this period and to the fact that Rosario is closer to the Equator than Rome is).

Rome_vs_Rosario

So I have to discard the original idea that the power within the infrared range, or the ultraviolet radiation, or the visible one is responsible for my improvement in summer. If I still have to consider that sunlight has something to do with my improvement, I must conclude that it is the length of the day the relevant parameter: I may need more than 12 hours of light to feel better. Why? Because the longer the day, the lower the strength of the innate immunity. This is now my working hypothesis and I will start from the following mathematical model to pursue this research: (Pierre K. et al. 2016).

I will also use full-spectrum lamps early in the morning and in the evening to reproduce a 15 hours day, so to dampen down my innate immune system in a safe, drug-free way. I have to reproduce a day of 15 hours and see what happens. In the figure below the hours of the day at dawn and at dusk and the length of the day for Rome, for each day of the year (this is also a plot from my model).

ore di luce

What follows is the script I have coded in order to plot the first figure of this post. More details on this model of solar radiation are here: (Maccallini P. 2019). As a further note, I would like to acknowledge that I started pursuing this avenue in the summer of 2009: I was building the mathematical model of solar radiation (see figure below, made in 2009) but as the summer finished, I turned into a statue and I had to stop working on it. When I improved, about a year later I started working on the systematic analysis of the mechanical equilibrium of planar structures (it is a chapter of this book). I am proud of that analysis, but it has not been very useful for my health…

trigonometria sferica 2

% file name = sun emissive power sea level Rosario vs Roma
% date of creation = 07/11/2019
% sun emissive power per unit area, per unit wavelength at sea level
clear all
% three parameters of the orbit
A = 6.69*( 10^(-9) ); % 1/km
B = 1.12*( 10^(-10) ); % 1/km
delta = pi*313/730;
% the two parameters of Plunk's law
C_1 = 3.7415*( 10^(-16) ); % W*m^2
C_2 = 1.4388*( 10^(-2) ); % mK
% Stefan-Boltzmann parameter ( W/( (m^2)*(K^4) ) )
SB = 5.670*( 10^(-8) );
% radius of the photosphere (m)
R_S = 696*(10^6); % m
% temperature of the photosphere (K)
T_S = 5875;
% conversion of units of measurments
N = 20; % dots for the equator
R = 3.8; % radius of the orbit
ro_E = 1.3; % radius of the earth
lambda_Rosario = -32*pi/180; % latitude of Rosario (radiants)
lambda_Roma = 41*pi/180; % latitude of Rome (radiants)
delta = 23.45*pi/180; % tilt angle
% the array of theta
theta(1) = 0; % winter solstice (21/22 December)
i_ws = 1;
day = 2*pi/365;
days = [1:1:366];
for i = 2:366
theta(i) = theta(i-1) + day;
if ( abs( theta(i) - (pi/2) ) <= day )
i_se = i; % spring equinox (20 March)
endif
if ( abs( theta(i) - pi ) <= day )
i_ss = i; % summer solstice (20/21 June)
endif
if ( abs( theta(i) - (3*pi/2) ) <= day )
i_ae = i; % autumn equinox (22/23 September)
endif
endfor
% the array of the radius (m)
for i=1:1:366
o_omega (i) = (10^3)/[ A + ( B*sin(theta(i) + delta ) ) ]; % m
endfor
% the array of the wavelength in micron
N = 471;
L(1) = 0.3;
L(N) = 5.0;
delta_L = ( L(N) - L(1) )/(N-1);
for j = 2:N-1
L (j) = L(j-1) + delta_L;
endfor
% the array of beta*L
load beta_int.mat S
% the array of L in metres
L_m = L*( 10^(-6) );
% angle psi
psi(1) = 0;
minute = pi/(12*60);
for i = 2:(24*60)+1
psi(i) = psi(i-1) + minute;
endfor
% -----------------------------------------------------------------------------
% Rosario
lambda = lambda_Rosario
% angle between n and r at noon in Rosario
for i= [i_ws, i_ae, i_ss, i_se]
for j=1:(24*60) + 1
% scalar product between n and r
scalar_p(j) = [cos(lambda)*sin(psi(j))*cos(delta) + sin(lambda)*sin(delta)]*( -cos(theta(i)) )+ [(-1)*cos(lambda)*cos(psi(j))]*( -sin(theta(i)) );
endfor
% value of psi at noon
for j=1:(24*60) + 1
if ( ( scalar_p(j) ) == ( max( scalar_p ) ) )
j_noon = j;
psi_noon (i) = psi(j);
endif
endfor
% angle between n and r at noon
cos_gamma (i) = scalar_p(j_noon);
endfor
% the array of the emissive power (W/(m^2)*micron) in Rosario
for i = i_se:i_se
for j=1:N
num = C_1*( (R_S)^2 );
den = ( (L_m(j)^5)*( (e^(C_2/( L_m(j)*T_S ))) - 1)*( (o_omega(i))^2 ) )*10^6;
power(j,i) = ( num/den )*( e^(-S(j)/cos_gamma (i)) );
endfor
% plotting
plot (L (1:N), power(1:N,i), '-r', "linewidth", 2)
xlabel('wavelenght ({\mu})');
ylabel('W/m^{2}{\mu}');
axis ([0.3,5,0,1500])
grid on
endfor
hold on
% -----------------------------------------------------------------------------
% Rome
lambda = lambda_Roma
% angle between n and r at noon in Rosario
for i= [i_ws, i_ae, i_ss, i_se]
for j=1:(24*60) + 1
% scalar product between n and r
scalar_p(j) = [cos(lambda)*sin(psi(j))*cos(delta) + sin(lambda)*sin(delta)]*( -cos(theta(i)) )+ [(-1)*cos(lambda)*cos(psi(j))]*( -sin(theta(i)) );
endfor
% value of psi at noon
for j=1:(24*60) + 1
if ( ( scalar_p(j) ) == ( max( scalar_p ) ) )
j_noon = j;
psi_noon (i) = psi(j);
endif
endfor
% angle between n and r at noon
cos_gamma (i) = scalar_p(j_noon);
endfor
% the array of the emissive power (W/(m^2)*micron) in Rosario
for i = [i_ae, i_ss]
for j=1:N
num = C_1*( (R_S)^2 );
den = ( (L_m(j)^5)*( (e^(C_2/( L_m(j)*T_S ))) - 1)*( (o_omega(i))^2 ) )*10^6;
power(j,i) = ( num/den )*( e^(-S(j)/cos_gamma (i)) );
endfor
endfor
hold on
plot (L (1:N), power(1:N,i_ae), '-k', "linewidth", 2)
plot (L (1:N), power(1:N,i_ss), '--k', "linewidth", 2)
legend ('spring equinox in Rosario', 'autumn equinox in Rome', 'summer solstice in Rome', "location",'NORTHEAST')
hold on
plot ([0.4,0.4], [0,1500], '--k', "linewidth", 1)
plot ([0.7,0.7], [0,1500], '--k', "linewidth", 1)

Back home

Back home

Continuation of this post.

Forty-four hours of travelling, in total, from Rosario to Rome, by pullman, by plane, and by train. With 40 kilos of books and papers.

I had a flight for Rome that was programmed to take off from Ezeiza, the International airport of Buenos Aires, on April 13th, but I decided to take the one organized by the Italian government for March 23th, a special flight set up to bring back home Italian citizens abroad, before a complete shut down of international flights from Argentina to our country. There were no flights from Rosario, my city, to Buenos Aires, though, but I managed to find a company that organizes transportations by pullman from one city to the other, in Argentina: Tienda Leon.

So, on March 22nd, I moved to Ezeiza where I waited several hours before sitting on my chair, on a brand new Boeing 787 bearing the colours of the Italian company Neos.

While at the airport, I met most of the Italians that were going to get the same flight, all wearing their masks. Some of them with some very fancy models, that made them look like a Star Wars character. I was there, well aware that I was going far beyond the limit set by my disease. I had to lay down continuously and I could see how frail I was in comparison with the other passengers waiting for the flight. No one knew how sick I was, I told nobody. No one knew that I have been living in my bedroom for most of the last 20 years. And that this was the very first long travel abroad for me.

I have just received the notification that my flight for April 13th has been cancelled, so my choice to come back as soon as possible has been a wise one. I took that decision also because of the advice from the diplomatic offices of the Italian Consulate in Rosario.

A friend has crafted the picture above, not knowing how much Indiana Jones has meant for me when I was a teenager. But, even though an appealing adventure, the tragedy behind it is real, it is not a movie. Once in Milan, I could start seeing the effects of the pandemic in the eyes of the staff of the airport of Malpensa: the fear and the concern. Then I moved from Milan to Fiumicino, where I found a train for Rome, my city. A city that I left two and a half months ago full of life and noise, now empty as in a dream.

 

From Argentina to Italy, during a pandemic

From Argentina to Italy, during a pandemic

It has been a great ride, my almost-three-month period here in Rosario, next to the huge slowly flowing river of Paranà. This is a city full of life, embraced by the warmest summer I have ever seen. Populated by wonderful citizens.

WhatsApp Image 2020-03-09 at 09.37.08

I have been living in an apartment where the sun awakes me very early in the morning, through a wide window next to my bed. I could see the roofs of the centre of the city as I opened my eyes, including the top of the Monumento National a la Bandera, a gigantic building that celebrates this great nation. For the second half of the day, I had the light from the opposite window and I could follow its changes, while I was working, as the hours passed by; I saw every day the same magic ritual: as the photons from our star went through thicker layers of the atmosphere, they changed their frequency, turning redder and redder, culminating in a warm explosion, just before the night.

And in the meanwhile, news from Italy was scarier and scarier and the hypothesis that the new coronavirus could reach this continent was more obvious as the weeks passed by. Now we have the virus here, and president Alberto Fernandez has declared the state of quarantine from March 20th.

At that point, the connection between Argentina and other countries (including Italy) has become uncertain; my flight planned for March 28th has been cancelled and I have decided to get one of the special flights organized by the Italian government to bring back its citizens from Argentina, before a complete shut down of international travels. So I had about 48 hours to find a means of transport from Rosario to the airport in Buenos Aires, where the flight will take off tomorrow, at 1:00 AM.

But there was no way I could find a flight from Rosario to Buenos Aires in such a short time, also because of the shut down of Argentina, and no trains were available. Fortunately enough I have found a Pullman, and I am going to leave this apartment in a few hours.

My come back to Italy is becoming more and more adventurous also because I will land in Milan, one of the places most hit by the infection in the whole planet. There I have to reach Rome. I have been able to find a plane from Milan to Rome, so it will be possible to be at home on the evening of March 23rd. I have to avoid getting the virus though, during this travel. I will be exposed to it for sure, so I am taking any possible measure to ensure my safeness.

This travel to Argentina has been a success. My health has improved, even though now I am deteriorating again, as was expected, as the light of the summer of the southern hemisphere becomes weaker. But I have been able to use my new energies to write and submit a paper on the cingulate cortex in ME/CFS, I have gone further with my studies on the analysis of the immunosignature (measured using random peptides) in my own serum (R), I have started the study of a mathematical model for the diffusion of Coronavirus 19 among the Italian population (R). I have learnt a great deal about computational neuroanatomy (R) and neurosciences in general. I have finished a complete model for solar radiation at sea level (R) and I might have found one of the environmental parameters that determine my improvement during summer. And yes, I have also been able to draw a portrait.

WhatsApp Image 2020-03-18 at 10.07.35

The adventure in the realm of science and art has been great, now I have to live the adventure of coming back home going through a world that is facing one of the greatest health challenges of the last century.

I cannot die

I cannot die

“I can’t say whether it is a titanic patience or endless desperation. What are they waiting for? Have they given up waiting? Which is the present they are immersed in?”

Italo Calvino, Palomar

For most ME/CFS patients (about two thirds), the disease has an oscillating course, with some periods of improvements followed by worsening of symptoms. Some of them can even experience recoveries, only to find themselves trapped again, weeks or months later (Stoothoff J et al. 2017), (Chu L. et al. 2019). Some anecdotes suggest that there might be a correlation with seasons, with improvements in summer, but there are no systematic surveys on that, to my knowledge.

As for me, in the last 20 years of pitiful combat with this monster, I experienced some substantial short-lived improvements, mainly during the core of summer. At the very beginning of the disease, I also recovered for one whole year. It was the year 2001, I was 21 and that year has been the only period of normality in my whole adult life. I spent these 12 months studying desperately and what I am as a person is mainly due to what I learned back then. I had already been very sick for about two years and when I recovered, it was as if I were born again. It was a second chance and I was determined to do all right from day one. I decided what was really important to me and I devoted myself to my goal: learning quantitative methods to use in engineering and – one day – in biology.

When darkness caught me again, I was, among other things, reviewing all the main theorems of calculus (particularly those about differential equations) with my new skills and I remember thinking that I was becoming good at developing my own proofs. I had become good at thinking and so, I reasoned, I could finally start my life! But in a few weeks, my mind faded away, and there was nothing I could do to keep a grip to all my beloved notes and books. They became mute and closed as monolithic gravestones. I remember clearly that along with this severe and abrupt cognitive decline, I developed also orthostatic intolerance, even though I hadn’t a name for it back then. But I couldn’t keep sitting, and I didn’t know why. I was forced to lay as if the gravitational acceleration had suddenly increased. My brain had changed to a lifeless stone, and so did my body.

From that very moment, my only thought has been how could I go back to my books and my calculations. And this still is my first thought, when I wake up in the morning. After almost 20 years.

I have experienced some short improvements in these years, during which I had to learn again how to study, how to do calculations, how to code. I never went back to what I was, though. And my brain is ageing, of course, as anyone else’s brain does. But in these short periods of miraculous come back I experience a rare sense of joy (along with anger and fear). Something that you can experience only if you have been facing death.

I was born and I died dozens of times in the last 20 years, and this gives me the perception that, in fact, I cannot die: I feel as if I were immortal and I had lived for a thousand years while at the same time still being in my twenties, since I have no experience of life.

In fact, I lived only when I crossed these short bridges from one abyss to the following one.

A leap of faith

A leap of faith

Soy un aventuriero en busca de un tesoro

Pauolo Coelho, El Alquimista

During last summer, I’ve pursued a lot of things. I delivered a speech in Turin, after the screening of the documentary Unrest, about the OMF-funded research on the use of the measure of blood impedance as a possible biomarker for ME/CFS (video, blog post, fig. 1, fig. 2).

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Figure 1. Group photo after the screening of Unrest in Turin, Italy, with the organizer of the event (Caterina Zingale, second from the right) and representatives of two Italian ME/CFS associations.

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Figure 2. Question time after the screening of Unrest. On the screen, a drawing of mine.

Then I flew to London to attend the Invest in ME conference, the annual scientific meeting that gathers researchers from all over the world who shared their latest work about ME/CFS. There I met Linda Tannenbaum, the CEO of the Open Medicine Foundation, whom I had the pleasure to encounter for the first time about a year before in Italy, and I introduced myself to Ronald Davis (fig. 3), the world-famous geneticists turned ME-researcher because of his son’s illness. I presented to him some possible conclusions that can be driven from the experimental results of his study on the electrical impedance of the blood of ME/CFS patients, with the use of an electrical model for the blood sample (R, paragraph 6).

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Figure 3. Talking to Ron Davis about a possible explanation for the increase in electrical impedance in the blood of ME/CFS patients in London, during the last Invest in ME conference (blog post).

In London, I was able to visit the National Gallery and while I was passing by all these artistic treasures without being able to really absorb them, to get an enduring impression that I could bring with me forever, I decided to sit down and to copy one of these masterpieces (I can’t draw for most of the time, and when I improve for a few weeks in summer, I usually have to carefully choose where to put my energies). I sat probably beside one of the least important portraits collected in the museum (Portrait of a young man, Andrea del Sarto, figure below) and I started copying it with a pen. When I finished, the museum was closing, so that I missed all the works by Van Gogh, among many other things.

We were at the beginning of June, I was experiencing my summer improvement, a sort of substantial mitigation of my illness that happens every other summer, on average. But because of these travels, I elicited a two-month worsening of symptoms, during which I had to stop again any mental and physical activity: I just lay down and waited. At the beginning of August, I started thinking and functioning again and I almost immediately decided to quit what was my current project (a 600-page handbook of statistics that I commenced in 2017) and I started studying mathematical modeling of enzymatic reactions (figures 4 and 5).

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Figure 4. The plot of the reversible Michaelis-Menten equation for ribulose-phosphate 3-epimerase. The intersection of the surface with the plane is the state of equilibrium of the reaction (the rate of production of X5P is the same as the rate of its transformation into Ru5P) (R).

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Figure 5. The plot of the concentrations of S, P, ES and E for the transformation of L-tryptophan into N-formylkynurenine by IDO-2. This is a semianalytical solution that I found using the approximation of the Lambert function. I also pursued numerical solutions, of course (R).

I knew that these reactions were described by ordinary differential equations and that I could solve them numerically with the methods that I studied just before I got sick, about 18 years ago. I was interested in the metabolic trap theory by Robert Phair, an OMF-funded researcher. So I downloaded a chapter of one of the most known books of biochemistry and a thesis by a Turkish mathematician on metabolic pathways simulation and I started my journey, working on the floor (I have orthostatic intolerance even when I get better in Summer, so I can’t use a desk, figure 6). I ended up learning the rudiments of this kind of analysis, also thanks to a book by Herbert Sauro and to some suggestions by dr. Phair himself! Some of the notes I wrote in August are collected here.

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Figure 6. In August I was studying mathematical modeling of metabolic pathways, sitting on the floor: because of my orthostatic intolerance, I can’t sit for long, especially when I need to think. You can see the book by Sauro opened in the foreground, the thesis by a Turkish mathematician (red cover), and the handbook of Octave (blue/red cover).

At the beginning of September, I was absorbed by the problem of how to study the behavior of the steady states of tryptophan metabolism in serotoninergic neurons of the midbrain as the parameters of the system change. This kind of analysis is called bifurcation theory and I literally fell in love with it… In figure 6 you can also see a drawing: I was drawing a picture I have been thinking about for the last 20 years. It is a long story, suffice it to say that in 1999, just before my mind faded away for 18 months, I started studying the anatomy of a man who carries a heavyweight on his back (see below). That was my first attempt at communicating what was happening to me, at describing my disease.

Only recently I considered not representing the weight, which is a more appropriate solution since this is a mysterious disease with no known cause, and I made a draft (the one in figure 2) that I then used as a starting point for the drawing below. I finished this new drawing at the beginning of September, in a motel room of San José, in California, just in time for donating it to Ronald Davis (figures below) when I moved to the US to attend the third Community Symposium at Stanford (see here). In California, many surprising things happened: I met again Linda Tannenbaum and Ronald Davis, and yes, I encountered also Robert Phair! But this is another story…

resilience 2

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In the following pictures, you can see how the drawing evolved. Notably, the figure in the center changed his face and some part of his anatomy. The three figures are meant to be a representation of the same figure from three different points of view. It is more like a project for a sculpture, a monument that is much deserved by these patients.

At Stanford, I had the chance to be face to face with one of my preferred sculptures ever: The Thinker, by Rodin, in both its version: the model molded first, on the top of The Gates of Hell, and the big one (crafted later), now considered the iconic symbol of Philosophy, but likely originally meant to be a metaphor for creative thinking (I say this because the original sculpture included in The Gates of Hell is a representation of the Italian poet Dante Alighieri, depicted in the act of imagining his poem).

At the end of September, my mind started fading away again. I knew that would have happened, even though I had an irrational hope that this year would have been different. At that point, I was in Italy and I asked some friends to help me organize a trip to the southern hemisphere, in order to live another summer. It required more time than I would have hoped. I am going to leave Italy only tomorrow. My goal: Argentina. I have been able to do something, at a highly reduced speed, in October, though. I have developed a model for solar radiation at sea level, in function of the day of the year, of the latitude, and of the distance from the Sun (I have considered the actual elliptic orbit of our planet). The main problem has been the modeling of absorption and of diffusion of radiant energy from our star by the atmosphere, but I solved it. Part of these notes are here, but I want to self-publish the end product, so I keep the rest to myself. In that period, I was also able to find the exact solution of the improper integral known as the Stefan-Boltzmann law, something I tried to do in the summer of 2008, in vain, in one of my recovery-like periods. In figure 6 you can see one of the results of my model for solar radiation: the monochromatic emissive power at sea level in function of the day of the year, for the city of Buenos Aires.

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Figure 7. The monochromatic emissive power of the sun at noon, at sea level, at a latitude of -32° N, in function of the wavelength and of the day of the year. Note that the vertical axis is expressed in W on microns multiplied by square meters.

My intention was to use that model to choose the perfect place where to move in order to have environmental conditions that closely resemble the ones that we have in Rome from June to September (the period in which my improvements happen). I also wanted to quantitatively study the effect of both infrared radiation and ultraviolet radiation on my biology. There are several interesting observations that can be made, but we will discuss these subjects another time, also because I had to quit this analysis given my cognitive deterioration. The video below is a byproduct of the geometric analysis that I had to pursue in order to build my model for solar radiation at sea level.

Dawn and dusk at a latitude of 42 degrees north, during three years of the silent rolling of the Earth on its silken ellipse. Three years of adventures, suffering, joy and death.

So, by November my mind was completely gone and my physical condition (namely orthostatic intolerance and fatigue) had worsened a lot. This year I have been able to try amphetamines: I had to go from Rome to Switzerland to buy them (they are restricted drugs that can’t be sold in Italy and can’t be shipped to Italy either). One night I felt good enough to take a train to Milan and then to take another transport to the drug store. And back. I managed to do the travel but I pushed my body too far and I had to spend the following month in bed, 22 hours a day, with an even worse mental deterioration. It is like having a brain injury. Amphetamines have been useless in my case, despite two studies on their potential beneficial effect in ME/CFS.

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Right now, I am collecting all the books and the papers that I need with me in Argentina (figure above), in case I will improve enough to study again. But what am I going to work on?

  1. I want to finish my model of solar radiation, with some notes on the effect of infrared radiation, ultraviolet radiation, and length of the day on the immune system. There is a mathematical model published recently that links the length of the day to the power of the innate immune system, and I want to write a code that calculates the relative activity of the innate immunity in function of latitude and day of the year. I would like to self-publish it as a booklet.
  2. I want to finish my handbook of statistics.
  3. I need to correct a paper submitted for publication (it has been accepted, but some corrections have been required).
  4. I want to deepen my understanding of the bifurcation theory for metabolic pathways and to continue studying tryptophan metabolism with this new knowledge.
  5. I want to complete my work on autoantibodies in ME/CFS (see this blog post) and to submit it to a journal. I have been working on that for a while, inventing new methods for the quantitive study of autoimmunity by molecular mimicry.

Should I improve again in Argentina, several avenues can be followed in order to understand the reason why summer causes this amelioration in my own case. I have many ideas and I’ll hopefully write about them in the future. Of course, I also want to read all the new research papers I have missed in the last months. I will bring with me my handbook of anatomy for artists because I hope to be able to draw again, and I won’t miss this opportunity to leave some other handcrafted images behind me for posterity, that can’t care less, obviously! I would really like to finish the drawing below because I feel that in this draft I have found a truly elegant (and mechanically correct) solution for the hip joint of a female robot.QR-A_000026

Now I am useless, my mind doesn’t work and I am housebound. I can’t read, I can’t draw, I can’t do calculations, I can’t do coding, I can’t cook… This has been the quality of my life for most of the last 20 years. This is a huge waste: I would have used these years to perform beautiful and useful calculations and to pursue art. I would really make people understand how tragic this disease is in its cognitive symptoms, what we lose because of it. This is, in fact, the reason behind this blog post: I wanted to give an idea of what I can do when I feel better, and of what I would have done if there had been a cure.

I have lost most of my adult life, but I will never accept to waste a day without fighting back.

Lascaux

Lascaux

Nelle grotte francesi di una località chiamata Lascaux degli uomini dipinsero il mondo che li circondava, più di diecimila anni fa. E’ tutto ancora lì, come lo hanno lasciato.

 

 

Lo immagino su una roccia

seduto con il mento in un palmo

per cento e più dei secoli

della nostra storia

 

Immagino che si sia commosso

il Tempo per una volta

nelle stanze intime della terra

ha fermato i giorni a quel giorno

che l’ultimo dei pittori

lasciò un disegno

e portò via i suoi colori

 

Sono ancora lì i cervi megaceri

non si sono estinti i mammut

in quelle grotte

un fiume perduto si è conservato

ecco,  lo attraversa un gruppo di renne

per sempre

e l’altra sponda non arriva mai

 

Immaginate che mi sia commosso

seduto con il mento in un palmo

sulla riva di quel fiume

il mondo non si è perduto

 

La terra ha chiuso da tempo le gole

di quelle genti

ed è diventata pietra

eppure ho visto l’ultimo dei pittori

guardare il suo lavoro

seduto con il mento in un palmo

è ancora lì

e diecimila anni fa

non ha portato via i suoi colori

16/12/2010

 

Disturbi cognitivi nella ME/CFS

In questo frammento (vedi sotto) della sessione domande/risposte dopo la proiezione del documentario Unrest a Torino, si parla dei disturbi cognitivi nella ME/CFS. Come introduzione a questo argomento trovo pertinente una osservazione del neurologo Kristian Sommerfelt della università di Bergen (Norvegia):

“Questo [il distrubo cognitivo] è un sintomo tipico della ME e quello che secondo me causa le maggiori limitazioni. Io non credo che le limitazioni più importanti siano imputabili al fatto che i pazienti sperimentano fatica a seguito di attività fisiche o anche semplicemente quando devono stare seduti. Se fosse solo quella la difficoltà, credo che numerosi pazienti avrebbero avuto una vita molto migliore. No, il problema è che solo tentare di usare il proprio cervello, porta alla incapacità di utilizzarlo. La mente rallenta oppure – in alcuni casi – si blocca del tutto; dipende dal livello di gravità. (R)”

E’ utile ricordare che la diagnosi di ME/CFS non richiede necessariamente la presenza di deficit cognitivi per essere fatta. Tuttavia secondo gli ultimi criteri (in ordine cronologico) nel caso in cui il paziente non lamenti disturbi cognitivi, deve però soffrire di intolleranza ortostatica (ovvero di POTS o di ipotensione ortostatica) (IOM, 2015). E siccome nella intolleranza ortostatica sono descritti disturbi cognitivi, ne segue che implicitamente questi deficit sono necessari alla diagnosi. Tuttavia, anche se presenti, possono avere severità e caratteristiche molto diverse da paziente a paziente. Dal mio osservatorio di paziente curioso, ho notato che molti soggetti con diagnosi di ME/CFS non lamentano né disturbi cognitivi né intolleranza ortostatica. E la mia idea è che la patologia clinicamente definita dai criteri IOM 2015 sia in realtà un sottoinsieme relativamente raro in seno al gruppo definito dai criteri Fukuda del 1994.

Sono andato a Torino con lo scopo principale di riuscire a parlare di questo aspetto, prima che di ogni altra cosa. Quotidianamente vivo non solo la mia frustrazione dovuta a una mente non funzionante da quasi 20 anni, ma anche la sofferenza lancinante di alcuni pazienti giovanissimi con cui sono in contatto, che patiscono in silenzio l’esclusione dalle proprie vite a causa di questo problema. Trovo doloroso anche solo riguardare il video, perché nel quotidiano spesso cerco di sfuggire alla analisi lucida e impietosa che ho fatto in questa occasione. Ma spero che sia utile, che serva.

I disturbi cognitivi più frequentemente riportati in questa popolazione consistono in un rallentamento della velocità con cui la mente processa le informazioni. Mi sono reso conto qualche settimana fa che è possibile dimostrare con semplici passaggi (usando una rete che modellizzi nuclei di materia grigia collegati da materia bianca) che questo tipo di deficit si evidenzia soprattutto nelle attività mentali che richiedono la collaborazione di più aree cerebrali: cioè le attività più complesse. Per altro, se questo fosse vero, si spiegherebbe perché questi deficit non vengono rilevati nei test cognitivi usuali, i quali misurano l’efficienza delle singole funzioni mentali, e non la loro collaborazione in attività complesse che costituiscono però spesso il centro della nostra vita. Proverò a scrivere la dimostrazione quando starò meglio.

Di seguito due miei disegni che rappresentano – facendo ricorso all’allegoria dell’androide – proprio i disturbi cognitivi.

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loss