Kamis, 14 April 2011

John Langdon Down's Infectious Autism [PART 2]

John Langdon Down's Infectious Autism [PART 2]                                                                                  by Lawrence Broxmeyer, MD

 © 2011 All Rights Reserved                                                    

Registered: US Library of Congress           

 

 

Psychiatric Asylums on the European and American Continent, Late Nineteenth

Century

As far back as 1769, Scotsman Robert Whytt [20], reporting on approximately 20 cases, described the localization of tuberculosis in the meninges,  membranes which cover the brain and spinal cord. Realizing that the localization of tuberculosis there was often associated with mental disturbances, Whytt thus gave us the first description of tuberculous meningitis, at that time called morbus cerebralis Whyttii.  In describing the disease, Whytt noticed not only small masses called "tubercles" in the brain tissue, but hydrocephalus, an excess of ‘water in the brain'.

There is a circulating duct system of fluid in the brain and spinal cord. Just as the brain has a covering called the meninges, these membranes manufacturer and contain a cerebrospinal fluid which later circulates through channels of deep cisterns in the brain and then down the spinal cord. A block in this circulation, whether from a congenital condition or disease, can lead to an increase of cerebrospinal fluid around the brain. In the case of infants and young children, because the bones of their skulls are still unfused, this can result in an enlargement of the head. No matter the age, mental disturbances and even retardation can result as complications of such ‘hydrocephalus'. So intertwined was hydrocephalus with tuberculosis, that medical experts, by the end of the 19th Century, considered acute hydrocephalus as just another name for tuberculous meningitis.[21]

Since 1854, Wunderlich had recognized psychotic episodes, including schizophrenia, could be caused by small masses of tuberculosis ("tubercles") in the brain.[22] But as time passed, it became more obvious, just how commonly. The tubercles of tuberculosis, which often themselves formed masses called tuberculomas, were  launched through the bloodstream to the brain, and often found in infants and humans with no neurologic symptoms. But Marie documented symptomatic cases of tubercles as a cause of psychosis such as schizophrenia.[23]

TB meningitis was just the tip of the iceberg, and other investigators, as early as in 1908, uncovered  a more generalized inflammation of the brain matter, tuberculous encephalitis "as also being behind specific psychosis[24]  So the term tuberculous  "meningoencephalitis" was considered more accurate than just tuberculous meningitis. 

 

REFERENCES:

1.  Torrey EF Severe Psychiatric Disorders May be Increasing. Psychiatric Times 19:4  2002, April

2.  E. Fuller Torrey, M.D., and Judy Miller. The Invisible Plague: The Rise of Mental Illness from 1750 to the Present. Piscataway, New Jersey, Rutgers University Press, 2â€"2. xiii, 416 pp.

3.  Kessler, Ronald C, Archives Of General Psychiatry 1994

4.  Kessler RC McGonagle KA  Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994 Jan;51(1):8-19, p.12

5.  Hare, E. (1983) Was insanity on the increase? BMJ, 142, 439 â€"445.

6.  Wilkins R Hallucinations in Children and Teenagers Admitted to Bethlem Royal Hospital in the Nineteenth Century and Their Possible Relevance to the Incidence of Schizophrenia Journal of Child Psychology and Psychiatry 28:569-80 1987

7.  Clouston TS Phthisical insanity, in History of Psychiatry 2005Dec 64(4): 479-95

8.  Jacobi M Annalen der Irrenheilanstalt zu Siegburg. Köln, Dumont & Schauberg, 1837 pp.26, 63

9.  Greding J Sämmtliche medicinische Schriften C.W. Greding, Ed. Greiz, Henning, 1790  vI:277-350; II:145-162, 327-33

10. Kagan-Kushnir T Roberts W Snead C Screening Electroencephalograms in Autism Spectrum Disorders: Evidence-Based Guideline J Child Neurol March 2005 vol. 20 no. 3 197-206

11. Barr MW The relationship between tuberculosis and mental defect 6th Internat. Congr. Tuberc. Washington 1908. Philadelphia, Fell, 1908 (III, p. 88).

12. Barr MW The relation between tuberculosis and mental defect. 6th Internat. Congr. Tuberc. Washington 1908. Philadelphia, Fell, 1908 (III, p. 88

13. Anglade and Jacquin, Hérédo-tuberculose et idioties congénitales. Encéphale, 1907, 1, 136-57

14. Baruk H Psychiatric , Paris, Masson, 1938 (pgs. 202, 292, 865

15. Wing L, Shah A. Catatonia in autistic spectrum disorders. Br. J. Psychiatry. 2000;176:357-362

16. Löwenstein E Das Vorkommen der Tuberkelbazillämie bei verschiedenen Krankheiten. Münch. Med. Wschr., 1931,78, 261-263

17. Weeber R Ueber Blut- und Liquorbazillose. Wien. Med Wschr., 1937, 87, 285-6,

18. Melger R Tuberculosis y psicosis Rev. Asoc. Méd. Argent.,1943, 57, 1061-4

19. Lowenstein E Tubercle bacilli in spinal fluid. J.  Nerv. Ment. Dis., 1945, 101, 576-82

20. Whytt R Observation on the dropsy of the brain. Edinburgh, Balfour, 1768 pp.1-48

21. Chisholm H Encyclopedia Britannica Cambridge University Press 1911

22. Wunderlich C.A. Handbuch der Pathologie und Therapie Stuttgart, Ebner & Seubert, 1854 II, 2 p. 1638

23. Marie A Tuberculose et psychose. Bull. Soc. Méd. Paris, 1930, 2, 457-461

24. Lépine J. Tuberculose-encephalite. Psychoses. 6th Internat. Cong. Tuberc. Washington, 1908. Philadelphia, Fell, 1908, vol.1, pt.2 p.1076

 

Department of Pathology John's Hopkin's 1948

 

Arnold Rich was working on a problem which might have major implications towards Kanner's child psychiatry but he was having a problem with regards to the frequency of maternal to fetal transfer of tuberculosis.[1]    It was an issue with seminal significance in addressing Down's "developmental disorders", of which autism was a subset. It was also a matter which had been addressed by some of the greatest minds in medicine.

On the one hand Rich knew that: "It is now well established that tuberculous infection can be transmitted from mother to fetus through the placenta."  He references Warthin[2] in The Journal of Infectious Diseases, who said it was commonand then Siegel‘s study[3] in the American Review of Tuberculosis.  Siegel documented infants that had died from the disease one or two days after birth. Husted's study[4] even included tuberculous stillbirths.

But to further establish the importance of a link between maternal and perinatal tuberculosis, Arnold Rich would go into the numbers involved in the general population. Of all the infectious diseases TB was and always has been a disease of alarmingly large numbers.

For some time, it had been known that for some reason pregnancy, especially late pregnancy, and child bearing itself dangerously reanimated any form of tuberculosis in a woman's body. Thus in the first half of the twentieth century, the method of choice was early termination of pregnancy in the tuberculous mother.[5]   Menstruation itself had a similar deleterious effect, causing its own flare-up of tuberculosis in the body.

The numbers in front of Rich were incredible.

In a disease that according to the World Health Organization consistently kills more women of childbearing age than any other[Ibid], the age at which female tuberculosis mortality began to rise above male mortality coincided with the average age of  the onset of female menstruation. But the age at which it really surpassed that of males coincided with the period during which over two-thirds of all pregnancies occurred.

Rich conservatively estimated that a little over 2 million woman between 18-30 were pregnant in 1940. And since the total US population for woman of this age was approximately 17,700,000, it followed that 1 out of every 8 women in the United States was pregnant in this age range and 1 in 10 bore living children. This produced a pool of 200,000  opportunities to not only reanimate dormant and often undiagnosed maternal tuberculosis, with its drastically increased female mortality rate, but, with such reactivation, the possibility for the transmission of that disease to the fetus and new born.

In such a reanimation of latent tuberculosis, it was also striking that TB meningitis, infrequent  in adults, frequent in infants and toddlers, seemed to noticeably increase in child-bearing women from the reactivation of old deposits of cerebral tuberculosis.[6]

Rich already realized that regarding TB's fatality in the neonate, infant and early childhood  there was a definite pattern. Tuberculosis was definitely most fatal during the first year or two of life. After the second year, the death rate for infected toddlers fell markedly, probably through a decidedly greater ability to form protective antibodies between 2 and 5 then in infancy.[7]  Though the disease was still deadly for the remainder of the first 5 years, by far the safest period was that between 5 years and puberty where the death rate from TB drastically plummeted.  Often termed the ‘Golden Age of Resistance', for some reason children between 5 and 15 are more resistant to TB than adults, and, above all infants.  It was an interesting fact, creating a possible theoretical underpinning for Bender's assertion as to how autistic involvement in the very young, hardest hit in the first 30 months, could come back as a related schizophrenia with adolescence, towards the end of the ‘Golden age of Resistance".

There was a time when it was felt that newborns were completely devoid of resistance[8]to tuberculosis. But there  had since been sufficient studies to completely contradict this. In Braily's study[9] at Rich's own Johns Hopkins Hospital, of 65 infants who became tuberculin positive during the first year of life, two-thirds were alive and well at the end of five years. So the acquisition of tuberculosis by infants was not necessarily a death sentence. However its complications, including those involving the brain and nervous system,  could soon impact the individual for the rest of his or her life.

As to whether a tuberculous focus in the brain killed, Rich would soon find,  would be something that he could only refer accurately to as what card players call "the luck of the draw."

It is not generally appreciated that the development of small rounded nodules caused by tuberculosis, sometimes cheesy or "caseous" in the brain is a relatively common occurrence in children and childhood tuberculosis. It is usually symptomless. Such small nodules often then become arrested and encapsulated by the body's immune system. They are, to this day, called "Rich's Foci".  Many of us unknowingly have them.

But, stressed Rich, it was when small tubercle nodules happened to land in that part of the surface cerebral cortex near the meninges, or covering of the brain, no matter how small in size, that serious troubles began. Such infectious nodules often extended into this protective covering  through which fluid (cerebrospinal fluid) percolates on its journey through the brain and into the spine. Such a discharge of tuberculosis into the spinal fluid of the meninges (in its subarachnoid space), can lead and often does, to potentially fatal meningitis. The disease festers and is spread throughout the central nervous system. There need not be extensive infection, just one tiny nodule in the wrong place, near the meninges.

On the other hand, the development of small tubercles deeper in the brain substance, though relatively common, often gave rise to no symptoms whatsoever. Rich himself had seen one inch tuberculous masses, lodged in a silent area of the brain, yet entirely harmless.

A severe hypersensitivity reaction to tuberculoprotein could also occur in any tissue in the body, including the brain, in infants already hypersensitized to tuberculous protein while in their mother's womb. Burn and Finley[10] showed damage and death of cells as well as acute inflammation in the meninges in such instances. The inflammation that resulted required no TB bacilli, just the sustained diffusion of the protein of the tuberculosis bacilli  or its active split products through the placenta into a previously sensitized infant.

Through it all, one thing was certain. Tuberculosis did not always kill. That infants could survive even a massive dose of tuberculosis was amply demonstrated in the tragedy called the Lubeck episode[11]. At Lubeck, of 251 infants mistakenly injected with large numbers of virulent human tubercular bacilli, incorrectly thought to be the TB vaccination called BCG, 71.3% survived.

But the number of possible complications in those infants and children that survived TB's onslaught, including those to the brain and nervous system, Rich knew, would be enough to keep symptom-based psychiatry perturbed and under siege for some time to come.

 REFERENCES:

1.  Rich AR The Pathogenesis of Tuberculosis Chas C Thomas Publsh. Springfield Illinois, 1946

2.  Warthin AS Cowie DM A contribution in the casuistry of placental and congenital tuberculosis. Journ. Inf. Dis. 1:140 1904

3.  Siegel M Pathological findings and pathogenesis of congenital tuberculosis Am Rev Tuberc 29:297 1934

4.  Husted E Un cas de tuberculose millaire congenitale Acta Path et Microbiol Scand Supp 16:163. 1933)

5.  Kobrinsky S Preganancy and Tuberculosis Canad. M.A.J. Nov. 1948 vol. 59; 462-4

6.  Whitney JS Facts and Figures About Tuberculosis Natl. Tuberc. Assn 1931

7.  Halber W Hirszfeld H Untersuchungen uber die Antikorperentstehung bei Kindern im Zuzammenhang mit dem Alter Zeitschrift. F. Immunitatsf., 1927, 53, 391

8.  Cummins SL Tuberculosis in primitive tribes. Internat. Jour. Pub. Health 1920, 1, 137

9.  Brailey M Mortality in tuberculin positive infants. Bull. Johns Hopkins Hosp., 1936, 59,1

10. Burn CG Finley KH The role of hypersensitivity in the production of experimental meningitis Journ. Exp. Med. 1932, 56, 203

11. Die Sauglingstuberkulose in Lubeck. Arbeit. A. d. Reichsgesndhtsamte. 1935, 69

 

Penn State Department of Psychology, 1949

But Psychiatry was already under siege. In 1949, psychologist Philip Ash, in a University of Pennsylvania postdoctoral dissertation, proved that three psychiatrists faced with a single patient, and given identical information at the same moment in time, were able to reach the same diagnostic conclusion approximately twenty per cent of the time.[1] Subsequently, Aaron T. Beck, one of the founders of cognitive behavioral therapy, published a similar study in 1962 [2],which although it found psychiatric agreement a bit higher, at between 32% and 42%, still left its doubts regarding the reliability of a psychiatric diagnosis. 

Added to this came the The Rosenhan experiment[3],  a well known probe into the validity of psychiatric diagnosis conducted by Stanford psychologist David Rosenhan in 1972. Published in Science and entitled "On being sane in insane places", Rosenhan's study consisted of two parts. The first involved the use of mentally healthy associates or fake patients, who briefly pretended auditory hallucinations in an attempt to gain admission to 12 different psychiatric hospitals in 5 different US states. All of these mentally healthy persons were admitted and diagnosed with psychiatric disorders. All were also forced to admit they had mental illness and to take antipsychotic drugs as a condition for their release.

The second part of Rosenhan's experiment involved asking staff at a psychiatric hospital to actually detect  "fake" patients in a group that was all mentally ill. No fake patients were sent in this Phase II of the Rosenhan experiment, yet staffs at various institutions falsely identified large numbers of actual mental patients as pretenders.

The study was considered an important and influential criticism of psychiatric diagnosis. Rosenhan concluded "It is clear that we cannot distinguish the sane from the insane in psychiatric hospitals". It also illustrated the dangers of depersonalization and the mere slapping on of a label that goes on in these institutions. [Ibid]

As a result of such intrusions, the American Psychiatric Association (APA), in 1973, asked psychiatrist Robert Spitzer to chair a classification task force to try to thrash out more precise medically oriented parameters. The problem was that such a classification would still be symptom or syndrome focused. The end result was a  classification manual, along the lines of Emil Kraepelin's rejuvenated ideas, entitled the Diagnostic and Statistical Manual of Mental Disorders (3rd ed.) or DSM-III.[4] Though DSM-III was indeed more reliable [5] than its predecessors, it still offered no clear definition of the cause of the many different "mental illnesses" it defined.

Without causes, the mere categorizing of psychiatric diseases did not mean that they were valid to begin with, and not the result of direct physical illness. The APA admitted it had no idea of what caused its manual's supposed "mental" illnesses, while at the same time it felt completely confident in its ability to diagnose and "treat" them.

"The Diagnostic and Statistical Manual" (DSM), Paul McHugh, then Chair of Psychiatry at Johns Hopkins said, has "permitted groups of 'experts' with a bias to propose the existence of conditions without anything more than a definition and a checklist of symptoms. This is just how witches used to be identified." [6]

 REFERENCES:

1.  Spiegel A The Dictionary of Disorder New Yorker 56-63 2005 Jan

2.  Beck, A. T. (1962). Reliability of psychiatric diagnoses: A critique of systematic studies. American Journal of Psychiatry, 119, 210-216

3.  David L. Rosenhan, "On Being Sane in Insane Places," Science, Vol. 179 (Jan. 1973), 250-258.

4.  American Psychiatric Association (APA) Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: American Psychiatric Association 1980

5.  Hyler, S. E., Williams, J. B., & Spitzer, R. L. (1982). Reliability in the DSM-III field trials. Archives of General Psychiatry, 39, 1275â€"1278

6.  McHugh Psychiatry Research Reports The American Psychiatric Association. Division of Research. Summer 2001)

 

 Johns Hopkins Department of Pathology 1949

Rich knew of numerous cases where the human placenta was infected in tuberculous mothers and readily admitted that infection could easily pass from mother to fetus. But it was in the frequency that he could find the disease reaching  fetal tissue, limited by the diagnostic capabilities of his time, that Rich would have to speak of TB's transfer from the placenta to the fetus as "rare". William Henry Welch, who besides being a pathologist like Rich was also a bacteriologist, never would have agreed.

Welch was already on record[1] that the mere inability to pick up TB in the fetus or newborn wasn't an argument against frequent transmission to them. There were just too many factors involved, such as the hostile low oxygen of fetal blood which could tame even the most virulent TB bacilli for some time, making diagnosis difficult to impossible.

It wasn't only Welch that Rich thus put himself at odds with. German investigator Baumgarten who saw infection of the fetus by the spores of TB coming from the maternal placenta as a common occurrence.[2]  In fact, to Baumgarten , all tuberculosis, including neurotuberculosis, was most commonly acquired in the womb, in utero, in most cases, though there remained a  lesser possibility, that it could occur through infected sperm.

Ophuls mentioned that it was a well established fact that the semen of tuberculous individuals contains tubercle bacilli, even in the absence of genital TB.[3]  It was obvious then that the ovum from which the fetus will develop could also become infected. Kobrinsky cites Sitzenfrey as having "demonstrated the presence of bacilli in the interior of the ovum while still within the Graafian follicle".[4] Friedmann, carefully studying the possibility in rabbits, concluded: "It should be regarded as proved that tubercle bacilli can enter the fertilized egg cell, that the latter does not perish as a result of the invasion, but may develop into a well-formed animal. In addition, the bacilli transmitted in this way may still be present in certain organs of the newborn."[5] And among these organs were the brain and the central nervous system.

That tuberculosis is a sexually transmitted disease is a certainty. By 1972, Rolland[6]   wrote Genital Tuberculosis, a Forgotten Disease? And  in 1979, Gondzik[7] and Jasiewicz showed that even in the laboratory, genitally infected tubercular male guinea pigs could infect healthy females through their semen by a ratio of 1 in 6 or 17%. This prompted him to warn his patients that not only was tuberculosis a sexually transmitted disease, but also the necessity of the application of suitable contraceptives, such as condoms, to avoid it. Gondzik's statistics are chilling; his findings significant. Even in syphilis at its most infectious stage, successful transmission in humans was possible only in 30% of contacts.

Schmorl's work supported Baumgarten and Welch's contention of routine tubercular transmission to the fetus through the placenta. Schmorl's work again showed that indeed, tuberculous infection of the placenta in tuberculous mothers was much more common than formerly believed.[8]

But perhaps all of this work was upstaged by Leon Charles Albert Calmette at Pasteur.

 

REFERENCES:

1.  Welch WH  Papers and Addresses Vol. 2 Bacteriology, The Johns Hopkins Press, Baltimore, 1920 p.47

2.  Baumgarten P Ueber die Wege der tuberkulosen Infection. Zeitschrift. F. klin. Med., 6:61 1883

3.  Ophuls W Routes of Infection in Tuberculosis California State Journal of Medicine Vol XIV, No. 7 pp. 272-276 July, 1916

4.  Kobrinsky S Preganancy and Tuberculosis Canad. M.A.J. Nov. 1948 vol. 59; 462-4

5.  Friedmann: Experimentelle Beitrage zur Frage kongenitaler Tukerkelbazillenubertragung und kongenitaler Tuberkulose. Virch. Arch., 1905, clxxxi,150

6.  Rolland R., Schellekens L. Genital tuberculosis, a forgotten disease. Ned Tijdschr Geneeskd 1972; 116(52): 2377â€"2378.

7.  Gondzik M., Jasiewicz J. Experimental study on the possibility of tuberculosis transmission by coitus. Z Urol Nphrol 1979; 72(12): 911â€"914.

8.  Schmorl: Zur Frage der Genese de Lungentuberkulose. Munch. Med. Woch., 1902, il, 1379.1419

 

 

Institute Pasteur, Paris France, February, 1933

 

Calmette was on to something.

He had confirmed that TB's attack form going through the virtual filters of the placenta into fetal blood was viral, filter passing forms of tuberculosis. These were not being picked up by Rich's traditional TB stains or cultures. Nevertheless, they were responsible for wasting and death,[1] even while traversing a perfectly normal placenta.[2]

In going against the grain of a scientific research such as that done by Pasteur's Leon Charles Albert Calmette, Johns Hopkins Rich, for all his authority regarding the pathogenesis of tuberculosis, was skating on thin ice. 

Since its founding on June 4, 1887, the Pasteur Institute, for over a century, was a beacon for research.  HIV, tuberculosis, polio and the plague had all been probed. In addition, since 1908, eight Pasteur scientists had received the Nobel Prize for medicine. It was while working in Pasteur, that Calmette developed the world's first and to this day, only, recognized vaccine for tuberculosis, the BCG.

Calmette was fully aware of the void that Robert Koch, the discoverer of tuberculosis, had left for future scientists. Koch had done it on purpose. A confirmed monomorphist, Koch insisted that the TB bacilli had only one form which caused disease. Extremely influential, Koch moved to make certain that his operatives kept this view as the one most scientists, to this day, have adapted.

Koch knew better. Bacteria and mycobacteria certainly could have more than one form. With Almquist, he had observed different forms of typhoid in the blood of its victims. Nevertheless Koch would now began an intensive campaign to seize and rule the scientific and lay mind that "legitimate" tuberculosis only assumed, one form. Thus Brock[3] points out that despite the fact that Koch was a first-rate researcher, a keen observer and an ingenious technical innovator, he went from an "eager amateur" country doctor to "an imperious and authoritarian father figure whose influence on bacteriology and medicine was so strong as to be downright dangerous". And nowhere, according to Brock, was Koch a more dangerous and "opinionated tyrant" than in his rigid insistence on monomorphism, the idea that microbes could assume one truely infectious form and one form only. Yet Klebs[4], who actually examined Koch's own tubercular cultures, wrote otherwise. In addition to the traditional rods in Koch's culture plates, spherical forms were regularly found, as well as branching, slender filamentous, and granular forms. Many of these could actually pass a filter and therefore be interpreted as being "filterable viruses".

Koch's one-form rigidity wasn't making friends. There was widespread opposition from others who sensed his lack of evidence. They gravitated towards the more realistic, better documented theories of Nageli and Max von Pettenkoffer,  which showed that bacteria change forms as they evolve. Nageli and von Petterkoffer's view retained wide support almost to the turn of that century. Koch reflexively opposed Nageli's ideas as soon as he heard them. Much of Koch's clash with Pasteur was also based on Pasteur's discovery of variability among microbes. In that scuffle, mentions Brock, Koch could at times be so personally vicious as to be shocking.

Vicious or not, by 1939, bacteriologists Vera and Rettger[5] of Yale were contradicting him. Vera: "The single point on which all investigators have agreed is that the Koch bacillus does not always manifest itself in the classical rod shape. While at times and most commonly the organism appears as a granular rod, coccoid bodies, filaments and clubs are not rare."

To marginalize such thought, Koch and his followers, to this day, have banished all forms except one to the wastebasket hinterland of "involutional", or "degenerative" forms of the mycobacteria. They didn't count. No matter how many studies showed that all of these forms could regenerate to the classical TB rod.  Koch and his minions thus somehow prevailed. To Brock, Koch and his cohorts represent a prime instance of the excessive influence of a "cult of personality".  The problem was that someone somewhere down the line would have to pay for such cult generated ignorance.

Let it be said to their credit that, from the onset, the French saw right through Koch. Tuberculosis had many forms, including a filterable viral-like stage in its growth cycle. Although Fontes[6] was the first to document these, Macjunkin[7] and Calmette soon followed. Again and again, either cultures or extracts of organs from tuberculous victims, after thorough filtration through Chamberlain L2  Filters, produced tuberculosis when injected into experimental animals. And importantly, such forms passed right through the placenta from mother to fetus.

Some animals injected with viral, filter passing TB might appear normal during the time of observation, but when tested with tuberculin showed positive tuberculin skin tests beginning approximately 25 days after being injected with tubercular tissue or microbes. Other animals lost weight rapidly. And some died of a rapid progressive infection. It all depended upon the virulence of the filterable TB being used.[8]

In a series of 21 dead infants, born to tuberculous women, Calmette, along with Valtis and Lacomme concluded that their observations proved the frequent transmission of tuberculosis from the mother to the fetus by means of filterable forms of tuberculosis. At the same time Calmette established that such viral forms of tuberculosis were in the spinal fluid of perinatal meningitis.[9]

Even before Calmette, Von Behring felt that the seeds of tuberculosis, laid in infancy remained latent until resistance happened to become impaired. Then the disease became active. But Von Behring had no notion of the viral like forms that TB assumed as a survival strategy, the more so in low oxygen fetal blood.

It would take time until mainstream microbiology would  be forced to even acknowledge such viral forms. It would take a Nobel nominee by the name of Lida Holmes Mattman.

REFERENCES:

1.  Calmette A Valtis J Les éléments virulents filtrables du bacille tuberculeux.
Annales de médecine, 1926, 19: 553-560.

2.  Calmette A Valtis J Lacomme M Transmission Intra-Utérine Du Virus Tuberculeux de la Mère à L'enfant. Comptes rendus hebdomadaire des séances de l'Académie des Sciences, Paris, 1926 , 183: 835-837. Presse Médicale, 1926,90:1409

3.  Brock Thomas D Robert Koch â€" A Life in Medicine and Bacteriology ASM Press pp. 392,  January,1999 p.4

4.  Klebs E Weitere Beitrage sur Geechichte der Tuberkulose. In: Arch F. Exper. Pathol u. Pharmacie, v 17, No. ½, pp.1-52 m. 3 Taf. 1883

5.  Vera HD Rettger LF Morphological Variation of the Tubercle Bacillus and Certain Recently Isolated Soil Acid Fasts, With Emphasis on Filterability J. Bacteriology 1940 June; 39 (6) 659-687

6.  Fontes ann. De l'inst. Oswaldo Cruz, 1910

7.  MacJunkin, F. J. Exper. Med., 33:751, 1921) Arloing and Dufourt (Arloing F, Dufourt. Press med., Jan. 5, 1927 p. 17

8.  Arloing F  Dufourt  Presse med. January 5, 1927, p. 17

9.  Calmette A Tubercle Bacillus Infection and tubercujlosis in Man and Animals, Williams & Wilkins Baltimore 1923) (Calmette A Valtis J. Virulent filterable elements of the tubercle bacillus Ann. Med. 19:553 1926 

 

 

Pathology Lab of Arnold Rich, Johns Hopkins 1950

 

There was a struggle going inside the mind of Arnold Rich, and its implications would affect Western medicine for decades to come. Under variations in the forms TB can assume, Rich's words don't always  match his conclusions. He concedes that depending upon the type of culture plate that tuberculosis is incubated on the shape of the organism changes, partly because of culture medium, partly because of the age of the culture itself. Even the conditions under which this growth occurs, such as temperature and amount of oxygen figured in. He emphasizes that non-acid fast stainingrods may be present, especially in young cultures, whereas in older cultures and  infected tissues, "beaded forms" were common.

Koch had noticed these beaded forms.  Somewhat granular and protruding from stalks, Koch felt them to be potential "spores" through which infection could be propagated.  But Koch was unable to observe the granules break off into separate segments.

Much[1], on the other hand, for decades, not only watched the granules break off ("Much's granules"), but regenerate into classical TB bacilli. Much was also able to document that they weren't always acid-fast, and that this could be why they had not been recognized as the spores of what would, with time, again become the acid-fast staining TB bacilli microbiologists looked for.

Then there was  M.C. Kahn's work. Kahn, using ideal technique[2], described, in the most precise manner, his direct observations of the actual growth of minute filter-passing granular forms of TB into fully developed and virulent bacilli, capable of independent proliferation and producing progressive tuberculosis.

Whether granular or otherwise, such viral-like or cell-wall-deficient (CWD) forms of tuberculosis, often mistaken for mycoplasma,  are today widely known as "L-forms", named after the Lister Institute by  one of its scientists, Emmy Klieneberger[3],   L-forms are cell-wall-deficient by virtue of a breech in their cell wall which allows them the plasticity to assume other forms including granular forms.

Little recognized in Rich's time, L-forms of tuberculosis have since even been found in mother's milk.[4]

Rich, working in the 1940's wanted to believe very much in these viral forms of tuberculosis. They explained the many times that he knew he was dealing with tuberculosis but could not, even as a pathologist see the germ. Nevertheless, this knowledge, relatively new at the time, was not substantiated enough. After all, Kahn had observed the transformation of granular forms to mature bacilli in vitro, in a culture plate. This did not mean to Rich that every TB bacilli once in humans had to go through this same cycle in its reproduction.  So, despite Kahn directly assuring him by personal communiqué that he had solidified his findings in vivo, in laboratory animals, Rich was not ready to acknowledge granular "viral" cell-deficient forms of tuberculosis, which were key to the mystery of how certain forms of TB sieved through the placenta's chorionic villi into the fetus, escaping detection.  

Rich's statement that in certain cases, even when the maternal placenta was laced with TB bacilli  "acid-fast stains of a large number of sections of the fetal tissues failed to disclose  a single bacillus" was correct. Welch had predicted it. The viral cell-wall-deficient forms could only be picked up by special stains, cultures and techniques which Rich had no access to.

In the meantime Rich's hypothetical statement of "rare" transmission was having difficulty. Many infants were reacting to the TB skin test weeks to months after birth, even without known exposure after birth.

 REFERENCES:

1.  Much H Uber die granulare, nach Zieh nicht farbbare. Form des Tuberkulosevirus.    Beit. Z. Klin. D. Tuberk., 1907, 8, 85, 357

2.  Kahn, MC The developmental cycle of the tubercle bacillus as revealed by single cell cultures. Am. Rev. Tuberc., 1929, 20, 150

3.  Klieneberger- Nobel E.   Origin, development and signifincance of L-forms in bacterial cultures. J Gen Microbiol 1949; 3: 434â€"442

4.  Garvin DF L forms isolated from infection in Microbial Protoplass, Spheroplasts and L Forms Guze LB, Ed Williams & Wilkins Baltimore pp.472-483 1968)

 

 

The Department of Biological Sciences at Wayne State University Detroit, Michigan, 1982

 

The answer to the mystery of the mechanism behind autism and a host of other diseases of unknown cause lay in a doctor called Lida Holmes Mattman.

Microbiologist and virologist Mattman , a Ph.D., an immunologist, and a 1997 nominee for the Nobel Prize in Medicine, knew something that few scientists on the planet still truly understand. Bacteria had a life cycle and could assume many forms. She also knew which special stains, cultures and techniques would have to be used to detect them.

Mattman, of course, had access to modern techniques that her predecessors didn't, including electron microscopy, immunofluorescence, PCR and other molecular assessment techniques.

Her book, "Cell Wall Deficient Forms," first written[1] in 1974, was regarded as an invaluable education tool among researchers, students and physicians in the field of microbiology. The problem was that at that point not all of them were accepting it.

By 2001Mattman concluded , regarding the human placenta, that: "There is little doubt that the minute filterable form of bacteria move from the mother's capillaries to those of the fetus."

She was referring to those tiny filterable bacteria either without a cell wall or having a breach in that cell wall. Mattman  was an expert on such forms, and her bookabout them which went into its 3rd Edition[2] in 2001.  When Mattman's "Cell wall deficient Forms" of bacteria, which she also referred to as "stealth pathogens", lose or have their cell wall disrupted, they become plastic, having the ability to assume many forms. Some are so tiny that they pass a 22μm filter, the so-called viral stage of a bacteria.  Cell wall disruption also changed the way these microbes stained. Cell Wall Deficient tuberculosis did not stain with the same "acid-fast" stain that the classical TB bacillus did.

Tuberculosis was one of the first placental infections to be accurately described. Since Lehmann's first description, the subject had came under intense scrutiny. Mattman spent considerable time talking about the transplacental passage of cell wall deficient forms (CWD forms) of TB and the mycobacteria to the fetus.

She knew that of all the pathogens, tuberculosis and its fellow mycobacteria relied on their stealth, cell-wall-deficient forms for their singular survival record inside humans. Thus she was drawn, early on, to the subject.  Her 1970 paper remains a classic on such forms.[3]

Calmette, said Mattman, knew that TB must traverse the placenta in its viral stage since the placenta, in most cases, remained intact with no obvious damage.  Calmette noted that after such infection with cell wall deficient tuberculosis quick fetal death might occur. But if the child is born alive it could result in death through emaciation by one month. And there were those cases in which the infant suffered no ill effects.[4]These were the infants that were infected but nevertheless vigorous.

But what really troubled Mattman where those cases, only established in the early 1970's in which seemingly healthy mothers, with no symptoms, where also able to pass to their infants cell wall deficient forms of TB which nevertheless killed their offspring.[5] So "stealth" were the cell wall deficient tuberculosis in the menstrual blood from one mother who's offspring became ill a few days after birth, that it took eight animal passages to finally yield the pathogen.

Mattman warned that tuberculosis mainly grew as pleomorphic (many formed) stealth pathogens[Ibid p. 189]  In one long series, American labs were only picking up 50% of tubercular sputum samples by not looking for its cell wall deficient (CWD) forms.[6]

Brieger[7] at Cambridge demonstrated such mainly pleomorphic stealth growth when he inoculated tuberculosis directly into the amniotic sac, the outer layer of which is part of the placenta. Rapidly, cell-wall-deficient granules formed that did not stain with traditional acid-fast stain. Within 3 days, other cell-wall-deficient forms, the long branching fungal filaments of TB, appeared. TB is a mycobacteria with both bacterial and fungal  ("myco" means fungal) forms.  Brieger then did the same with fowl tuberculosis in chicken embryos with similar results.[8] Cell-wall deficient forms again formed, again not identifiable by traditional stains.

While American traditionalists remained skeptical of the clinical significance of Mattman's  stealth, cell-wall-deficient forms, the Russians never doubted them.[9][10][11]  Instead they churned out study after study, proving the destructiveness of cell wall deficient tuberculosis to the central nervous system . By 1996 Insanov[12] warned that an infection with cell wall deficient forms in children not only made standard treatment less effective, but created a disease with a gradual, insidious onset, and a slow accumulation of cerebral damage in children. This made the disease more difficult to diagnose, because its slow burn into young nervous systems allowed months to year before its full spectrum of damage was obvious.  Insanov showed that cell wall deficient forms in tuberculosis meningitis accounted for an incredible 87.6% of the tuberculosis found in children with TB meningitis and 87.3% of those in adults. How could such statistics be ignored?

It's not that Americans hesitated to acknowledge the importance of "latent" tuberculosis[13] and how it could persist within a child or adult for years without causing disease. They just couldn't seem to correlate the phenomena with Mattman's stealth pathogens.

To Lida Holmes Mattman, it was bad enough that most 21st century bacteriologists still ignored those cell wall deficient bacterial forms responsible for much adult illness of ‘unknown' cause. But with such stubbornness, perhaps, there was a just retribution involved in that, the same researchers that ignored her findings were suffering along with the general population.  But when it came to innocent children and newborns not being able to be diagnosed or treated properly for diseases because of such recalcitrance, that is where she drew the line.

 REFERENCES:

1.  Mattman LH Cell Wall Deficient Forms CRC Press, Cleveland  pp. 411 1974

2.  Mattman, LH Cell Wall Deficient Forms â€" Stealth Pathogens 3rd Edition. CRC Press Boca Raton 2001

3.  Mattman, L. H. (1970), Cell Wall Deficient Forms of Mycobacteria. Annals of the New York Academy of Sciences, 174: 852â€"861

4.  Calmette A Valtis J  Lacomme A Nouvelles recherches expérimentales sur l'ultravirus tuberculeux, C.R. Acad. Sci., 186, 1778-1781, 1928

5.  Dorozhkova IR Deshkekina MF Ereneeva AS Zemskova ZS Ilyiash NI and Zhukova EK  On the question of inborn tuberculosis, Tuberk Probl. 10, 80-83, 1972

6.  Pollock HM  Wieman EF  Smear Results in the Diagnosis of Mycobacterioses Using Blue Light Fluorescence Microscopy, J. Clin. Microbiol., 5:329-331, 1977.

7.  Brieger EM The Host Parasite Relationship in Tuberculous Infection, Tubercle, 30:242-253, 1949

8.  Brieger EM Glauert AM  A Phase-Contrast Study of Reproduction In Mycelial Strains of Avian Tubercle Bacilli, J. Gen. Microbiol., 7:287-294, 1952

9.  Gadzhiev GS Characteristics of the mycobacteria in children with tuberculous meningitis Probl Tuberk. (11):8-10 1990

10. Golanov VS Andreev LP Characteristics of bacterial discharge in patients with different forms of pulmonary tuberculosis Probl Tuberk 5:43-5 1994

11. Gadzhiev GS Characteristics of the mycobacteria in children with tuberculous meningitis Probl Tuberk. (11):8-10 1990

12. Insanov AB Gadzhiev FS Comparative analysis of the results of spinal fluid microbiological study in children and adults who suffered from tuberculous meningitis. Probl tuberk. 1996; (5):25-8

13. Parrish NM Dick JD Mechanisms of latency in Mycobacterium tuberculosis. Trends Microbial 6(3):107-12 1998)

 

CONCLUSION:

Most of us agree with Ploeger that "developmental diseases" like autism and Down Syndrome occur in the fetus before birth. We also know that the changes that occur and the symptoms that result are likely from an infectious process. Actually the evidence for mental illness, including autism and schizophrenia, as being the result of an infectious disease is quite extensive.

Medical residents are often told "Don't look for zebras". Don't look for the exotic or the esoteric cause of a disease. And the best diagnosticians among them never forget this. For the purposes of this paper, part of not looking for zebras would have to include asking what infectious process statistically most affects not only women of childbearing age, but their children….and at the same time is nerve-seeking (neurotropic) by its very nature. According to statistics such as can be obtained from WHO (World Health Organization) and a host of other sources, that disease, hands down, is tuberculosis and the mycobacteria.

Just as appropriate, were this the case, might be the admonishment of a resident who brings up the issue of vaccines or their ingredients as a direct as opposed to an indirect influence on autism. One must distinguish primary cause from aggravating circumstance. First of all, most of the vaccines in today's infant/maternal schedules have a direct contraindication to such potential chronic, even dormant tubercular infection.  And physician/researcher Hartz, after extensive human trials, appeared in a older issue of The Journal of the American Medical Association (JAMA), insisting that mercury compounds were "positively injurious and detrimental to one afflicted with tuberculosis".[1] In addition some of the oil adjuvants used to increase a vaccines potency are lipids or oils that are cholesterol precursors, becoming cholesterol in the body[2] This cholesterol surge is a big boost for any dormant systemic tuberculosis already in the body, who's very ability to maintain infection is linked to its ability to acquire cholesterol. So crucial is this unique ability of TB to use cholesterol in the body for both carbon and energy sources, that if it were not for its ability to grow off of cholesterol, tuberculosis, like other pathogens, would be unable to resist eradication through cytokine attack and the attempts of certain activated white blood cells called macrophages to starve it of essential nutrients. It is a true survival mechanism acquired after eons and eons which has made TB, from a historic sense, probably the most successful pathogen on the planet.[3] 

So in comparative and simpler terms, one might look at an injection of certain vaccine adjuvants, squalene among them, whether inside or outside of a vaccination, as lighting up chronic foci of tuberculosis like a Christmas tree.

J. Langdon Down, who really was the first to deal with autism in a subset of his children thought that Down's children, "for the most part", originated from TB in their parents. He was also the first to use "developmentally disabled" for such cases, a euphemism which the public liked and could much more readily absorb than the developmentally disabled from tuberculosis. Was John Landon Down just pulling from an imaginary shortlist when he focused on the fact that, in most cases, his developmentally disabled children, a subset of who were autistic, resulted from parental tuberculosis? Not at all.  Down was a high-end product of English science, and what the British lacked in the well-organized and well-financed state run laboratories of the Germans, they more than made up for in their astute powers of observation. Down also could, even then, draw on an extensive library of research on the subject which pointed towards the same direction as his thoughts. It was only then, and after compiling compelling statistical evidence, that he came to the conclusion he came to and published his thoughts.

Time went by, and evidence accrued. Antidepressants, hailed as "new breakthrough drugs" in mental illness, were really discovered as a by-product of the tuberculosis research in the 1950's. Having proven  anti-tuberculous activity, they weren't used clinically as antidepressants until the 1960's. The first being  imipramine, now called a tricyclic antidepressant (TCA). Almost concomitantly came antidepressants known as monoamine oxidase inhibitors (MAO's), also with anti-tubercular activity.  This was only after It was noted that TB patients given MAO inhibitors experienced a state of elation and euphoria where only depression had existed before.

Yet from their onset, results and studies, no matter how much they confirmed TB's role in mental illness, were tainted by a public that would hear none of them. After all, to be diagnosed insane or tubercular were two of the greatest stigmas that could be thrust not only upon a patient but his or her immediate family. So insanity or mental illness was either given medical labels that few understood, or reduced to a "nervous disorder" and TB was always that "not me" illness, often referred to as a "chest ailment", during which "nervous disorders" often occurred.

In 1997Adhikari and Pillay[4] were quite straightforward on a subject traditionalists never have admitted to as other than "a rarity". Pillay wrote in Tuberculosis in the Newborn: An Emerging Problem: "Congenital TB can result from hematogenous (blood) dissemination of M. tuberculosis after maternal mycobacteremia, rupture of a placental tubercle into the fetal circulation, or ingestion of infected amniotic fluid or maternal blood at delivery. The mother might not have symptoms of TB disease, and subclinical maternal genital TB also can result in an infected neonate". This seems straightforward enough. The fetus can be infected by the mother with TB while still in her womb. The mother might not have symptoms of TB. And that it was an "emerging problem". But there was another emerging problem happening at the same time. Autism had already begun to skyrocket.

By 1999, Pillet, in the Archives of Pediatrics, went over the difficulties in early diagnosis of neonatal tuberculosis. His conclusion as so many others before him was that its frequency was being underestimated and its diagnosis often difficult because its initial manifestations were often delayed. [5] By stating this, Pillet was saying what Insanov and Welch had already brought up in the distinct delay of disease process as a result of the cell-wall-deficient (CWD) forms of tuberculosis in the newborn which would take time to revert to classical disease.  This is also what Calmette and Mattman brought attention to. Calmette was warning pathologists CWD forms caused few tissue changes to the placenta and Mattman was warning even healthy, otherwise asymptomatic pregnant woman that a focus of tuberculosis somewhere in their body could generate stealth, cell-wall-deficient forms of tuberculosis into the blood to infect their fetuses. Rich had already  pointed out the extreme activation of even silent TB that occurs during pregnancy.

In October of 2003 Gourion[6] and others appeared in the Journal of Autism and Developmental Disorders  reporting on how neonatal cerebral tuberculosis had evolved into a member of the autistic spectrum of disorders, namely Asperger's syndrome (AS).

More importantly, a cross comparison between neuropathology and imaging studies done on TB meningoencephalitis (Hosoglu, 1998) (Ozates 2000) and those from the autistic spectrum, including Asperger's (McAlonan 2002) (Gilberg 1993) (Happe & Frith 1996), seemed to match, including a study of the decreased metabolism in the brain's cingulate gyri. (McAlonan 2002) (Gilberg 1993) (Happe & Frith 1996) (Haznedar 2000) This was important.

In linking Asperger's syndrome (AS), a known disease in the autistic spectrum to neonatal TB meningitis Gourion, Pelissolo, and Lepine joined Schoeman's previous implication[7] that tuberculosis and its neonatal brain lesions were behind the neurodevelopmental disorders, including the autistic spectrum of infancy, childhood and beyond.

No one who has ever witnessed the pathetic "head banging" of an autistic child can truly come away unswayed. Many explanations have been offered  by workers in the field, some of them unconvincing. That pain relief is a possibility has occurred to a few.  They mention a child is more likely, for example to bang his head when he has an ear infection or is suffering from some other physical discomfort in the head. This makes sense, but some of the other explanations do not.  

For the sake of the "developmentally disabled" children in our midst today alone, no less those that grow to adolescence and adulthood , it is both our obligation and responsibility to carefully review the historic debate of tuberculosis's stealth role in the psychiatrically impaired and developmentally disabled.

Perhaps the current Government sponsored trials using anti-tuberculous medicine for autism will bring us more in that direction. 

 

REFERENCES:

1.  Hartz HJ  Ultimate Results in the Treatment of Pulmonary Tuberculosis With Mercury Succinimid  Journal of the American Medical Association 55(11):915-918 p. 917)

2.  Carlson BC Jansson AM, Anders Larsson The Endogenous Adjuvant Squalene Can Induce a Chronic T-Cell-Mediated Arthritis in Rats. American Journal of Pathology, Vol. 156, No. 6, June 2000 pp 2057-2065.

3.  Pandey AK Sassetti Mycobacterial persistence requires the utilization of host cholesterol. PNAS March 18, 2008 vol. 105 no. 11 pp. 4376-4380

4.  Adhikari M, Pillay T, Pillay DG. Tuberculosis in the newborn: an emerging problem. Pediatr Infect Dis 1997;16:1108-12

5.  Pillet P, Grill J  Congenital Tuberculosis: Difficulties in Early Diagnosis Arch Pediatr 6(6):635-9 1999 Jun

6.  Gourion D Pelissolo A Neonatal Tuberculous Meningitis in a Patient with Asperger‘s Syndrome Journal of Autism and Developmental Disorders, Vol 33(5):559-60 October, 2003

7.  Schoeman CJ Herbst I The effect of tuberculous meningitis on the me and motor development of children South African Medical Journal 87(1):70-72 1997

 

Lawrence Broxmeyer, MD

Copyright 2011 All Rights Reserved                               

Registered:   US Library of Congress

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Jack Kelly is a freelance writer.

Lawrence Broxmeyer, MD, is currently a licensed internist and medical researcher. He was on staff at New York affiliate hospitals of SUNY Downstate, Cornell and New York University for approximately 14 years. He pursued as lead author and originator, a novel technique to kill TB and the mycobacteria with outstanding results. [The Journal of Infectious Diseases 2002 Oct 15;186[8]:1155-60]. Recently he wrote a chapter in Sleator & Hill's textbook Patho-biotechnology, published by Landes Bioscience.

 


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