Some close up observations regarding the 2017 Hawaii rat lungworm problem.

Courtesy Wikipedia photo

Blogger grand rounds, and the rest of a story.

Early this April, last month, a youngish adult male, of Tongan birth, presented to the local emergency room with diffuse head, extremity, and body pain, fever, and poor appetite. He denied nausea. He had fever, cough, and diffuse myalgias, with temperature 38 C (minimal fever) and blood WBC elevated at 21.7/nL with 83% neutrophils, 5% bands,3% eosinophils. Chest X-ray was clear. He was discharged with doxycycline and hydrocodone prescriptions.

He returned a day later, with cough and dyspnea. WBC was down to 15.9/nL, with 1% bands and 6.7% eosinophils; he was discharged with an inhaler for bronchitis.

He returned to ER again 5 days later, with resolution of the body aches, cough and dyspnea but a 3 1/2 day history of bilateral dull headache and constant, sharp pain in the left chest, leg and lateral foot. He was afebrile. WBC was 28.4/nL with 18% bands and 4% eosinophils. LP showed 160 WBC/microL with 92% lymphocytes, 3% monos, 3% neutrophils, 2% eosinophils, protein elevated at 105 mg/dL, glucose normal. He was given antibiotics, antivirals, and hydration. The current writer was consulted, and it was felt the patient either had HSV-2 or early angiostrongylus meningitis with radiculitis. When questioned about exposures, the patient denied consumption of unwashed produce. He depends on catchment of rain for wash water, but drinks only bottled water. DNA PCR for HSV-2 had been negative, and an addtional request done at that time for angiostrongylus cantonesis DNA was also negative. Dexamethasone and albednazole was added, and patient felt well enough to be discharged the next day, after having received 400 mg of albednazole and 8 mg of dexamethasone total since the day before.

However, the global headache and left leg and foot pain remained, and the patient was unable to pay for the remaining doses of albednazole as an outpatient. He returned to the hospital four days later and was given analgesics and additional dexamethsone. Eleven days after that, he returned to the ER with continued headache and left leg and foot pain, and a second LP showed 650 WBC/microL with 80 lymphs, 11% eosinophils, 5% neutrophils, and 4% monos. CSF protein was 120 with normal glucose.

Additional history was obtained. Spoiler alert! :-) Note that anyone who can figure out a particular identity from the above lab values has already got the medical records. No HIPAA issues here.


In late March, about a week prior to onset of symptoms, the patient had consumed kava with 5 other men. The kava had been stored outdoors in an open container, and was later found to have been contaminated, with a slug found at the bottom of the kava bowl after the kava beverage had already been consumed.

Two of those men found out about the patient's diagnosis and presented to the Hilo Medical Center's emergency department just one day following the patient's hospital discharge (the day after I had first spoken to him). These men were friends and confidants of the patient who were aware of the patient's illness. They were evaluated in the ER with LP and had were diagnosed with eosinophilic meningitis, with CSF samples showing typical high WBC with eosinophlia and high protein with normal glucose. History given by two of these men, interviewed the day after the initial index patient's subsequent second LP, indicated that in the weeks following the contaminated kava ingestion all 6 of the men had become ill with symptoms including headache. Yet, only those later two were initially diagnosed with typical CSF findings on initial LP, and our patient, who was actually the first of the six to have a spinal tap, had negative CSF PCR testing for Angiostrongylus DNA on his first LP, and was only considered a probable case until the second LP. The other three contaminated kava partakers have not to my knowledge yet been confirmed to have had eosinophilic meningitis, even though they were symptomatic from their exposure to the organism.

Dateblood WBC (per nanoliter)blood % eosCSF WBC (per microliter)CSF % EOS
Initial presentation (pre-meningoradiculitis)29.42
One week later, 4 days post meningitis onset24.810 1602
3 weeks later24.40 650 11

Consider the type of parasitic infection that is due to Angiostrongylus cantonesis. This tiny nematode roundworm spends its adult stage in the pulmonary arteries of the rat, within the rat's lungs, whence the common name "rat lungworm." The adult worm drops its eggs, which hatch into first stage larvae (about 0.27 to 0.30 mm length) which travel downstream in the lungs, rupture the alveoli, and travel with associated lung fluids up to the trachea and rat throat, where they are swallowed and pass out with feces to the ground. There, the first stage larvae may be ingested by molluscs such as snails and slugs. Once in the snail or slug, the first stage larvae live in the body of the mollusc for at least 45 days during which they mature through their first and second (0.42 to 0.47 mm length) molts to reach the third larval stage (0.42 - 0.49 mm length), where they are capable of infecting vetebrates, such as rats, which might eat the slugs. In addition, if the slug dies, the larvae may move out of the slug's body and live up to several days. Potentially infective larvae have been detected in slime trails of infected Australian snails, suggesting that contacts other than actual slug ingestion may allow infection to occur.

Once the vertebrate host ingests the third stage larvae, they enter the gut, then exit the intestine via tunneling into the veins. Entering the circulation, they are carried throughout the body, with large numbers lodging in the terminal circulation of the brain and spinal cord. From there, the third stage larvae move to the meninges, where they produce eosinophilic meningitis while maturing to the fourth and final larval stage (0.85-1.0 mm length) within about a week. The fourth stage larvae migrate within the central nervous system for about 12 days in rats and then molt into the adult worms which, in the rat, re-enter the venous circulation and are carried to the pulmonary arteries, where they fully mature (15.5-23.0 mm length and 0.25-0.35 mm diameter) and the life cycle then repeats.

Rats seem required for the nematode to reach its adult form and complete its life cycle. When the parasite is accidentally ingested by humans or monkeys, the fourth stage larvae do not generally reach adulthood or leave the central nervous system, instead dying in place while causing meningitis, often with radiculitis and occasionally also encephalitis, in the brain and spinal cord regions where they have migrated.

Comments from the front lines:

  • 1. Eosinophilic meningitis is a rare illness in this country and state, even on the Big Island. I have seen only a couple dozen cases in the past 7 years, and yet I think that has given me more experience with the acute presentation of the illness than any other neurologist whose practice has been confined to US soil. Neurologists in certain other countries, like Thailand, have far more experience with this disease.
  • 2. Secondary contamination of food and drink, consumed by a group, provides us with a natural experiment in the complex relationships between exposure to an infectious agent and disease and between disease and public health statistics.
    It seems to us who count hospitalizations for eosinophilic meningitis that there are two to three times as many cases of rat lungworm disease as the state health department is willing to release as numbers to the media, because the State's current criteria for diagnosis requires CSF to be positive for DNA by PCR, which seems, from my perspective, to not be a completely sensitive test, missing perhaps 50% of early cases.
    I am certain that milder cases are commonly not diagnosed, because an LP is generally not done in milder cases. Consider the six symptomatic men who drank the slug-contaminated kava, all of whom, I was told, became ill. How many officially documented cases has the health department counted of the 6? Perhaps 3? I am understanding of the need to not overdiagnose this rare condition, but I wonder if the fact that the two biggest economic drivers of the Big Island economy -- tourism and agriculture -- may be at risk if the problem increases might influence the State to minimize its morbidity count?
  • 3. Albednazole-dexamethasone combination therapy is probably better than the CDC recommendation of prednisolone therapy alone. Personal experience here: when I first started seeing acute cases of the illness, in early 2011, I used prednisone alone, as per the official federal government CDC in Atlanta's recommendation, and I saw a couple cases get worse over weeks. I since have given albednazole, currently for 1 week with dexamathasone for 1 week, and have not seen any more of that subacute worsening. I believe that albednazole prevents maturation and further migration of the parasites if given early.
  • 4. The current United States pricing on albednazole is obscenely high. How high is that? Online, getting imported mail-order 90 tabs of generic albednazole 400 mg is about $80. The US pharmacy price is for the same amount is over $40000.
    This huge price discrepancy is due both to US restrictions on drug imports and regulations making it harder for generic chemical factories to make FDA approved generics. The Obamacare Act failed to fix this known problem with affordability, despite the name of the Act. Thanks Obama. I don't really fault the drug companies for being predators. They are what they are. I fault the US for failing to allow free markets, thus allowing those monopolies protected access to their continued sucking of US health consumer money.
  • 5.Published accounts of Angiostrongylus cantonesis meningitis infections suggest a prodrome of abdominal pain or nausea prior to the meningitis, but in this and many other cases the prodrome suggests a systemic immune response with a type I hypersensitivity component.
    The flulike symptoms and a cough treated with bronchodilators in the case above (and many others in my experience) might be that of the body reacting systemically to the presence of the parasite in the circulation before the meningitis itself begins. This is where a screening blood test, perhaps for some kind of antigen, might be possible and allow early diagnosis. At present there is no such test.
  • 6. There is a category of chronic pain and fatigue patient who tends to decide that their symptoms are evidence that they suffer from an undiagnosed case of the chronic infection dejour, be it yeast, Lyme, or, here in Hawaii, rat lungworm.
    For further perspective here, just ask any infectious disease specialist in the Northeast about chronic Lyme. When I say above that in my experience that eosinophilic meningitis on the Big Island is under-diagnosed, I should emphasize I mean acute cases are under-diagnosed, not any chronic illness.

Centrist

I am a political centrist. In today's polarized political climate, this means that almost all the politically opinionated people I speak with are opposed to centrism. We seem unpopular everywhere.

Chronic traumatic encephalopathy as backstory?

So the deceased's lawyer wants the brain autopsy results. Why? So that the NFL might be held liable for the brevity of a life characterized by violence?

Here.

Weekend bioRxiv Preprint Review: Sex Differences in the Brain

The preprint of a summary of measures of brains in 5,216 donors to the UK's Biobank program was released on bioRxiv this past week. As a summary, they found that male brains were slightly larger in most structures, on the average, than female brains. This should not be surprising given that human males are on average slightly larger than human females. After controlling for average brain volume, though, there was still frequently a 0.7 to 0.8 Cohen's D value effect size of biological gender on many brain measures, with male brains usually larger on such measures, except, as has been noted before, female brains had a slightly thicker cortex and a larger corpus callosum.

The chart above is to show the degree of overlap for such differences in an ideal normal distribution case. The charts below reflect the actual current study under review's data. It's important to note that such size differences do not generally influence social aspects of gender. For example, persons who identify themselves more with their opposite biological sex (the trans-gendered) have scans that reflect on average measures that reflect their biological sex, not their psycho-social preference for gender. A further point: variances between individuals were larger than variance between men and women, reinforcing that we need to understand a mutiplicity of each individual's own personal qualities in order to better understand them and their abilities, much more than we need to rely on a single fact such as gender. As the paper says, "Overall, for every brain measure that showed even large sex differences, there was always overlap between males and females (p. 8)."

============================================

ABSTRACT

Sex differences in the adult human brain: Evidence from 5,216 UK Biobank participants

Stuart J. Ritchie1,2*, Simon R. Cox1,2, Xueyi Shen3, Michael V. Lombardo4,5, Lianne M. Reus6, Clara Alloza3, Matthew A. Harris2,3, Helen L. Alderson7, Stuart Hunter8, Emma Neilson3, David C. M. Liewald1,2, Bonnie Auyeung1, Heather C. Whalley3, Stephen M. Lawrie3, Catharine R. Gale2,9, Mark E. Bastin2,10,11, Andrew M. McIntosh2,3, Ian J. Deary1,2

bioRxiv preprint first posted online Apr. 4, 2017; doi: http://dx.doi.org/10.1101/123729.

SEX DIFFERENCES IN THE HUMAN BRAIN

Summary

Sex differences in human brain structure and function are of substantial scientific interest because of sex-differential susceptibility to psychiatric disorders [1,2,3] and because of the potential to explain sex differences in psychological traits [4]. Males are known to have larger brain volumes, though the patterns of differences across brain subregions have typically only been examined in small, inconsistent studies [5]. In addition, despite common findings of greater male variability in traits like intelligence [6], personality [7], and physical performance [8], variance differences in the brain have received little attention. Here we report the largest single-sample study of structural and functional sex differences in the human brain to date (2,750 female and 2,466 male participants aged 44-77 years). Males had higher cortical and sub-cortical volumes, cortical surface areas, and white matter diffusion directionality; females had thicker cortices and higher white matter tract complexity. Considerable overlap between the distributions for males and females was common, and subregional differences were smaller after accounting for global differences. There was generally greater male variance across structural measures. The modestly higher male score on two cognitive tests was partly mediated via structural differences. Functional connectome organization showed stronger connectivity for males in unimodal sensorimotor cortices, and stronger connectivity for females in the default mode network. This large-scale characterisation of neurobiological sex differences provides a foundation for attempts to understand the causes of sex differences in brain structure and function, and their associated psychological and psychiatric consequences.

New Evidence for Early Formation of Long-Term Memory

In the study abstract below, Kitamura and others show that long-term memory traces in the outer cerebral cortex of the mouse are laid down early in the experience to be remembered. Prior to this study the prevailing opinion was that neuronal traces for short-term memories are initially created only in the hippocampus and transferred later to long term cortex. The study below shows that initial weak traces of long term memory are created simultaneously with the strong short term memory traces in the hippocampal short term memory region, and that, over a couple weeks, the cortical area traces become stronger and more active and the corresponding hippocampal areas fade in their activity.

This suggests that prior theories were too simplistic, perhaps because they tended to model memory after human information storage, such as writing or memory disk, where information is generally laid down once and remains the same strength thereafter unless erased. Modeling the brain after our technology metaphors can be misleading.

==============================================================

ABSTRACT

Engrams and circuits crucial for systems consolidation of a memory

Takashi Kitamura1,*, Sachie K. Ogawa1,*, Dheeraj S. Roy1,*, Teruhiro Okuyama1, Mark D. Morrissey1, Lillian M. Smith1, Roger L. Redondo1,2,†, Susumu Tonegawa1,2,‡

Science 07 Apr 2017

Vol. 356, Issue 6333, pp. 73-78

DOI: 10.1126/science.aam6808


The network of memory consolidation

Memories are thought to be formed in the hippocampus and later moved to the neocortex for long-term storage. However, little is known about the mechanisms that underlie the formation and maturation of neocortical memories and their interaction with the hippocampal network. Kitamura et al. discovered that at the onset of learning, neurons for contextual fear memory are quickly produced in the prefrontal cortex. This process depends on the activity of afferents from both the hippocampus and the amygdala. Over time, the prefrontal neurons consolidate their role in memory expression. In contrast, the hippocampal neurons slowly lose this function.

Episodic memories initially require rapid synaptic plasticity within the hippocampus for their formation and are gradually consolidated in neocortical networks for permanent storage. However, the engrams and circuits that support neocortical memory consolidation have thus far been unknown. We found that neocortical prefrontal memory engram cells, which are critical for remote contextual fear memory, were rapidly generated during initial learning through inputs from both the hippocampal–entorhinal cortex network and the basolateral amygdala. After their generation, the prefrontal engram cells, with support from hippocampal memory engram cells, became functionally mature with time. Whereas hippocampal engram cells gradually became silent with time, engram cells in the basolateral amygdala, which were necessary for fear memory, were maintained. Our data provide new insights into the functional reorganization of engrams and circuits underlying systems consolidation of memory.

An amazingly shallow review of travels in Hawaii in the NYT this month.

The NYT March 2017 travel writer's perspective picture:

What we photographed during a similary awesome (to us) hike in 2016. Note the focus on the lava and the scenery, not the tourists themselves:

Yet another travel writer fails to surpass Mark Twain's Letters from Hawaii. This new travelogue could be seen as a sad reminder of how we cannot easily escape our issues if we bring the problematic attitudes with us. I can but quote others on this kind of attitude:

I just want people to take a step back, take a deep breath and actually look at something with a different perspective. But most people will never do that.
--Brian McKnight

"Though we travel the world over to find the beautiful, we must carry it within us or we will find it not."
--Ralph Waldo Emerson

The NYT travel review reviewed above can be found

Here.

On Probabilities and Confirmation Holism

According to a theory of knowledge called confirmation holism, we believe facts on the basis of their being part of a larger body of knowledge that we believe in total. For example, my belief in Sweden is a part of my knowledge of geography and history as a whole. I would have to doubt much of what I know of the nations and history of the world to disbelieve in Sweden.

One problem that's been advanced against such confirmation holism is the idea that we must have to assign each fact we know a probability, and then, by the laws of probability, don't we calculate the odds of our entirety of holistic conjunction of facts just as the product of the individual probabilities? For example, if we believe each fact of a 500-fact conjunction with p = 0.95, does this make our degree of belief in the 500-conjunct equal to (0.95)^500, or just 0.0000000000073?

But, of course, we DON'T calculate the probabilities of the whole this way! The multiplication rule for the conjunct of two probabilities assumes that those probabilities are independent! . And, in the case of confirmation holism, that is exactly what we would deny.

Some close up observations regarding the 2017 Hawaii rat lungworm problem.

Blogger grand rounds, and the rest of a story. Early this April, last month, a youngish adult male, of Tongan birth, presented to the lo...