|
book reviews
more books on brain diseasesreviewed by T. Nelson |
|
|
book reviews
more books on brain diseasesreviewed by T. Nelson |
by J. Dalmau and F. Graus
Cambridge, 2022, 662 pages
reviewed by T. Nelson
or the past two months, the press has been arguing about whether Vladimir
Putin has Parkinson's or terminal cancer. Some videos show him grimacing as
if in pain. Others show him with an unsteady gait and maybe a tremor. What
the heck, they ask, could be wrong with this guy?
I have no idea, but as this book shows, it is now well established that cancer is a major cause of neurological disorders. So it's quite possible that someone with cancer can exhibit dyskinesia, involuntary movements, postural tremor, gait instability, and psychiatric disturbances that may appear to a layman to be purely neurological.
How does that work? For reasons not fully understood, cancer breaks self-immune tolerance, which is supposed to prevent the body from making antibodies against itself. When that happens, the body makes antibodies against proteins on the surface or interior of cancer cells—which is not supposed to happen. These antibodies may be helpful at suppressing the cancer, but if they cross-react with proteins in the brain they will cause neurological problems such as psychosis, ataxia, seizures, memory loss, insomnia, and encephalopathy (irritability, confusion, and lethargy progressing to coma), depending on the antibody. This is called paraneoplastic encephalitis.
The first example, discovered in 2005, was anti-NMDA receptor encephalitis. It is an autoimmune reaction to a teratoma and occurs mainly in women. Patients or the people around them first notice psychiatric problems: they become combative, paranoid, agitated, and hyperemotional. They become insomniac. As the disease progresses, they experience severe psychosis along with seizures and rapid cognitive decline and make involuntary wiggling hand movements. Some have catatonia-like episodes in which their eyes are tightly shut and their jaw remains open. Eventually some become hypoventilated and must be placed on a ventilator. It is not a fun thing to have.
These aren't new diseases: the authors discuss a case from 1830 where a patient had psychiatric symptoms before vomiting up an abdominal teratoma, which cured her. We now know the cause is IgG1 antibodies that bind to the GluN1 subunit of the NMDA receptor in the brain, which is essential for neurotransmission.
At least 18 similar antibody diseases are known, including SOX1 antibody, which can cause paracerebellar degeneration or Lambert-Eaton myasthenic syndrome (LEMS), a form of partial paralysis. LEMS is often a sign of a serious cancer called SCLC or small cell lung cancer. Myasthenia gravis, a generalized weakness caused by antibodies against either the acetylcholine receptor or the esterase AChE, is typically a sign of a tumor in the thymus gland, called a thymoma. Antibodies to MOG, or myelin oligodendrocyte protein, cause seizures, encephalopathy, and a demyelinating syndrome similar to MS. In children it is now thought to be identical to ADEM (acute disseminated encephalomyelitis), a dangerous autoimmune response to measles infection, whereas in teens and adults it more often causes optic neuritis, where the patient experiences loss of visual function and feels pain when trying to move their eyes.
Many of these disorders are early signs of cancer, most often SCLC, testicular cancer, or thymoma. But they can also be produced by medical treatment. A new type of anti-cancer drug known as an immune checkpoint inhibitor turned out not to be as benevolent as once thought. Viruses can also cause them: the authors say that 27% of patients with herpes simplex encephalitis also get anti-NMDA receptor encephalitis. And levamisole, a drug formerly given to cancer patients as an immune-modulating agent and now found in 80% of the illegal cocaine in the US, is now known to cause leukoencephalopathy (a disorder of the white matter of the brain) and agranulocytosis (loss of granular leukocytes, a type of white blood cell).
Cancer patients may see CAR-T cells as a miracle cure, but 12–31% of those who receive them get severe neurotoxicity, which shows up as encephalopathy (a decreased level of consciousness, confusion, and seizures) due to CRS (cytokine release syndrome) or HLH (hemophagocytic lymphohistiocytosis, an often fatal disorder in which the red blood cells are destroyed).
We often also think the cerebellum is immune from neurodegeneration, but it's not so. In cerebellar ataxia, which can be caused by antibodies to gliadin, DNER, GAD, CASPR2, Yo, or carbonic anhydrase-related protein VII, patients have extensive loss of Purkinje cells, giving them an irreversible syndrome characterized by agitation, negativism, unintelligible speech, and unsteady gait. It often starts after cancer surgery.
Classical autoimmune and autoinflammatory disorders are not discussed much. The treatment is purely medical with almost no molecular biology. The authors include many case histories. Videos and an online copy of the book are available to owners of the hardcopy version. Sections 1 and 2 summarize the disorders. In Section 3 the disorders are presented again in individual chapters.
The treatment seems somewhat disorganized and repetitive. For example, on page 299, they repeat the same facts about MOG antibodies in ADEM several times. The diseases are presented in roughly decreasing order of the authors' confidence in their importance (and, in some cases, their existence). They emphasize over and over the importance of measuring antibodies in cerebrospinal fluid (CSF) instead of blood plasma and complain a lot about the quality of commercial antibodies and results derived from them.
Finally, in Section 4, we find out why. The authors are making a case that many cases previously diagnosed as schizophrenia are actually anti-NMDAR encephalitis:
[A]ll the symptoms of schizophrenia can also occur in autoimmune encephalitis, particularly anti-NMDAR encephalitis. The difference between these diseases does not reside in the psychiatric symptoms, but in the timing of the presentation, evidence of prodromal psychiatric features, accompanying neurological symptoms, abnormal diagnostic tests, . . . and detection of NMDAR IgG antibodies in the CSF, which are absent in schizophrenia. [p.505]
They say they re-analyzed CSF samples from some patients treated for psychiatric problems and found evidence that they were actually suffering from anti-NMDAR encephalitis.
There are a few kinks to work out on this theory, namely that the sex ratios don't match up and the fact that schizophrenia starts at the wrong age for cancer, so there must be something else that triggers it. But if they're right, we could be in for a minor revolution in the treatment of psychiatric patients.
jun 26 2022
by Matthew Williams, ed.
Springer, 2021, 241 pages
reviewed by T. Nelson
his multi-author book discusses changes in brain anatomy that occur
in schizophrenia (SZ). Each chapter focuses on a different brain region.
A big challenge in studying SZ arises from the fact that as soon as a patient is diagnosed, they're administered powerful antipsychotic drugs whose effects on brain physiology tend to overwhelm any physiological differences. That is, of course, their purpose, but it means that many findings described so far are artifacts of treatment. Even so, there are some consistent findings:
Overall brain symmetry looks more normal in schizophrenic brains than in controls. That is, the centerline of the brain from front to back is straight in schizophrenia brains but bent in normal brains. This is called brain torque.
At the same time, brains of schizophrenia patients have “occipital bending”, which is a developmental condition in which the occipital lobe in the back is distorted. This is only seen in 35% of patients and its significance, if any, is unknown.
There is a generalized loss of synapses and gray matter in many regions, particularly the temporal and frontal cortex, the amygdala, which is involved in emotional valence, and the nucleus accumbens, which is involved in addiction (though some studies on the latter two find no difference, and there are studies that find that gray matter volume is increased). Loss of gray matter automatically means ventricular enlargement, which is also found. Some regions, like the hippocampus, are hardly changed. There are many conflicting results, mostly because of differences in what is being measured, but also because of patient variability, drug treatment, and other factors.
Genome-wide association studies showed 8300 SNPs (single nucleotide polymorphisms, i.e. mutations) for schizophrenia, while proteomic studies found 84 proteins and 74 miRNAs. Thus, findings implicating one specific protein or neurotransmitter are automatically suspect due to the vast number of ways a protein can be affected by other proteins and by general loss of neurons and/or synapses.
Dopamine synthesis is hugely increased in the substantia nigra, apparently due to elevated tyrosine hydroxylase, which is the rate-limiting enzyme in its synthesis. You would think this would protect them from Parkinson's disease, but a new finding (not mentioned in this book) shows they have an elevated risk. Antipsychotic drugs affect the striatum (which is where the SN projects to) and cause tarditive dyskinesia, a different disorder also caused by L-DOPA, which is metabolized to dopamine in the brain.
The overall style is descriptive: in many cases authors simply say that something was ‘increased’ or ‘decreased’ without bothering to mention by how much; in almost no cases are error terms mentioned. Researchers seem mainly concerned with determining whether it's more productive to study SZ at the molecular, cellular, or anatomical level. The earlier hypothesis that SZ is caused by too much dopamine is still clinging to life, but other neurotransmitters like GABA and glutamate are catching up fast.
There are strong hints that SZ may be a neurodevelopmental disorder. One author mentions, just in passing, that 22q11.2 deletion syndrome, which is a partial loss of chromosome 22 that happens during gamete formation or in early development, produces a high risk of SZ. (Typical of this book, he doesn't say the amount of risk, but other sources say it's about 30%.) The lost section of DNA codes for several proteins including COMT, an enzyme that degrades dopamine and other catecholamines. Mice with an orthologous deletion (16qA13) get SZ-like abnormal behaviors.
Oddly enough, this syndrome, which is also called DiGeorge syndrome, can also induce autoimmune rheumatoid arthritis, which epidemiological studies show seems to protect against schizophrenia. This is what we in science call a Big Clue, but the book is too focused on reporting hard-to-reproduce neuroanatomical observations to mention it.
So, this book isn't the best way to learn about schizophrenia, but it's a pretty good way to learn neuroanatomy, as there are many color diagrams for each brain region. There is no index and no table of abbreviations.
An alternative text on neuroanatomy is John H. Martin's Neuroanatomy Text and Atlas, 5e, which has photos and 3D colored diagrams. If you just want to find things, a good one is the spiral-bound 1989 Structure of the Human Brain: A Photographic Atlas by DeArmond, Fusco, and Dewey. (It doesn't matter that this one is in grayscale; everything in the brain is some shade of beige.) If you're not too squeamish, get Nolte's The Human Brain in Photographs and Diagrams. All of 'em even have an index. Woo-hoo!
dec 29 2021
by Femi Oyebode
Cambridge, 2021, 264 pages
reviewed by T. Nelson
here are an almost unlimited number of ways people can be nutty.
By describing edge cases—not just rare and bizarre psychiatric
manifestations, but also unusual mental abilities—psychiatrist
Femi Oyebode hopes to gain insight into how the brain processes
information in ‘normal’ people. Here are some examples from
the book:
Musical Hallucinations
Totally distinct from earworms, musical hallucinations are melodies heard by the patient. These are unrelated to psychotic hallucinations, as the patient knows they're not real. Unlike earworms, they're hard to hum along with. They can be caused by benzodiazepines, anticholinergic drugs, hearing loss, or epilepsy. Hearing loss usually induces patriotic songs or hymns from childhood, while epilepsy tends to induce country or sometimes rock music. Anticholinesterase drugs stop them.
Charles Bonnet syndrome
A similar phenomenon is Charles Bonnet syndrome, except it's caused by visual impairment, often macular degeneration, but sometimes leprosy or epilepsy. The patient hallucinates wallpaper patterns, bushes, or sometimes complex musical scores. Patients have reported that these bits of music are complex and exceedingly difficult to play. It's believed that, just as with musical hallucinations, Bonnet syndrome is caused by deafferentation, as the brain tries to recreate visual stimuli that are no longer present. When vision is lost altogether, the hallucinations stop.
Ekbom syndrome
Ekbom syndrome, aka delusional infestation, is the belief that there are insects or other pathogens on or in the skin. Morgellons syndrome is a novel variant in which patients believe that fibers are growing in their skin. A classic symptom is the ‘matchbox sign’, where patients bring in a container of items they have found to convince their doctor. Most of these turn out to be carpet fibers or pieces of dirt. The median age of diagnosis is 57. It's often induced by drugs such as ciprofloxacin or stimulants such as cocaine, but it can also be a sign of B12 deficiency, diabetes, or chronic lymphatic leukemia.
Synesthesia
It's well known that the composer Scriabin put colors into his music based on his synesthesia. It's not so well known that there's not just pitch-color synesthesia, but also grapheme-color, time-shape, vision-touch, day-of-week-color, and taste-shape synesthesia as well. Synesthesia may have evolved as an aid to memory: people with this ability have enhanced memories due to richer encoding. One guy named Solomon Shereshevskii, who was highly skilled at memorizing nonsense words, reportedly experienced a 2000-hertz tone at 113 decibels as pink-red fireworks with a rough texture that tasted like a briny pickle.
Capgras, Frégoli, and intermetamorphosis
These three are just a few of the many misidentification syndromes. In Capgras, the patient believes an impostor has replaced a familiar person. Frégoli is when the patient is convinced a stranger is really a familiar person in disguise. Intermetamorphosis is when the patient thinks a familiar and an unfamiliar person are really the same person. These are all disorders of face processing, which involves the posterior fusiform gyrus, aka the occipitotemporal gyrus near the occipital lobe in the back of the brain, where visual processing occurs. As in prosopagnosia, where the patient is unable to recognize faces, there may be ‘covert’ face recognition, where the information bypasses the damaged brain area but is inaccessible to consciousness. In about 16% of cases, the syndrome can be a precursor to Lewy body dementia.
Couvade
Quite a timely disorder these days if you believe the press, couvade is the experience of false pregnancy in a male. In some societies couvade is a custom where the father ceremonially pretends to be pregnant like the mother in order to demonstrate sympathy or to magically protect the child. In other cases, it is a psychosomatic disorder induced by anxiety, which psychiatrists call compathy, the physical equivalent of empathy. When a woman gets false pregnancy, it is called pseudocyesis. Pseudocyesis can also result from GAHS, or galactorrhoea-amenorrhoea-hyperprolactinemia syndrome, which is a hormonal imbalance that could be a sign of something serious.
Body integrity identity disorder (Xenomelia)
Another one is xenomelia, formerly called body integrity identity disorder, where the patient experiences a mismatch between their ‘body schema’ (the mental image of one's body) and the physical body and demands surgery to fix it. The author says the first case was in 1785 when a man offered a surgeon 100 guineas to amputate his leg. When the surgeon refused, the man forced him at gunpoint to amputate it, then later paid him 250 guineas. Typically the patient will say “My soul feels as though it belongs to a body with only one leg.” One theory is that this disorder is caused by lesions in the left parietal lobe.
This disorder is obviously not confined to limbs. Given the strong overlap between xenomelia and paraphilias, many psychiatrists have argued that what we now call gender identity disorder has a similar etiology, which can be explained by what psychiatrists, in an amusing DoD-like term, call ‘erotic target location error.’
There are far too many unusual disorders, including multiple personality disorder (now called dissociative identity disorder), erotomania, and Cotard syndrome, where the patient is (falsely) convinced he or she is dead,* to cover in this short book, let alone this review. An example is Alice In Wonderland syndrome (AIWS), which has nothing to do with having blonde hair, a British accent, and an apron, but is a rare body-image illusion that involves distortions of shape or size of the patient's body along with feelings of depersonalization. It's been linked to Epstein-Barr virus, migraine, and febrile delirium, and there are a few reports in children given topiramate (an anti-seizure drug) or methylphenidate (an ADHD drug, aka Ritalin).
Fascinating book, highly recommended unless you're a hypochondriac.
* The patient insists, contrary to evidence, either that they are dead or non-existent. This distinguishes them from patients who are actually dead, who are generally more noncommittal.
dec 31 2021
by NJ Diederich, M Brüne, K Amunts, and CG Goetz, eds.
Oxford, 2024, 556 pages
reviewed by T. Nelson
hat do we know about differences in brain disease between humans and
other species? The impression one gets from this book is: not a hell
of a lot.
The only thing wrong with this book is the title. It's a beautifully printed book with clear color illustrations, and it's a good introduction to human neurodegenerative and neuropsychiatric diseases. Students might appreciate learning about the current challenges and limitations, and they'll pick up useful facts about neuroscience and brain anatomy. But the phrase ‘evolutionary roots’ makes it sound like a book on evolutionary biology, and it's not.
It's in three parts: brain anatomy, human brain diseases, and ‘perspectives.’ The first section is an elementary class on brain anatomy. You'll learn, for instance, that the human cerebellum, which controls movement, is only 20% of the total brain volume but contains 80% of the 86 billion cerebral neurons. Humans, monkeys, and apes have similar ratios of neocortex to total brain size, but the human brain is four times bigger than expected for a similar sized monkey or ape. Cells in human gray matter have 40% more synapses. Only humans have von Economo neurons, or VENs, that are altered in Alzheimer's disease, autistic spectrum disorders, and Parkinson's disease. And only human neurons have graded calcium-dependent action potentials that enable coding at the dendrite level. Also, as most people know, the human brain has more folds, known as gyri, on the surface than monkeys, chimps, and mice but fewer than elephants or killer whales.
The biggest difference is in glucose utilization. Rats and mice use 0.3–1.2 micromoles of glucose per minute; primates use 30–60; and humans use 450, nearly ten times more. MRI studies have shown that there are about 180–200 different brain areas in humans.
In the chapter on addiction, we learn that koala bears have evolved 27 new genes for the liver enzyme cytochrome P450 (CYP2C) that allow them to eat eucalyptus leaves, which are poisonous to other species. In the chapter on REM sleep behavior disorder, we learn that octopuses have REM sleep with “dynamic changes” in skin color as well as movements. The author says the Roman naturalist Pliny the Elder noticed that horses, dogs, cows, goat, and sheep all had movements while dreaming, but EEG recordings of the platypus show only slow waves typical of non-REM sleep, suggesting that sleep has evolved.
What does all this interesting comparative biology tell us about evolution of human brain diseases? All the authors seem to agree: not much.
Despite years of observation, there has not been compelling evidence of the presence of schizophrenia, ASD, or Alzheimer's disease (AD) in non-human primates. [p.105] . . .
No perfect or near-perfect replication model of the human PD [Parkinson's disease] phenotype has been developed in animals, and naturally occurring PD appears to be an exclusively human disease. [p.206] . . .
There has never been a report of a homologous condition [to schizophrenia] among the great apes, our closest relatives, in which there is (for example) an onset of disorganized or psychotic behavior in early adulthood. [p.320]
Well, okay, what about Huntington's disease, amyotrophic lateral sclerosis, ADHD, and major depressive disorder? These diseases all get separate chapters, but for the most part, non-humans aren't even mentioned. Evolutionary and molecular biology, which trace the evolution and function of DNA and proteins, aren't discussed.
Of course, there are many infectious and non-infectious brain diseases, like rabies, spinocerebellar ataxia, and mad cow disease (aka Creutzfeldt-Jacob disease), as well as a variety of inherited neurological disorders, that occur in both humans and animals. None of these receive consideration in the book, suggesting there's either not much evolutionary difference (which is surely not the case) or that their occurrence in animals is only of interest to mere veterinarians (a lower form of life, perhaps). The closest we get to ‘evolution’ is in Chapter 6, which discusses adaptive archaic introgression, which is when beneficial genes from Neanderthals, Denisovans, and other archaic humans get picked up by interbreeding. The authors say we picked up many genes for tobacco use, sleeping patterns, and duration of depression from the Neanderthals. Patients with more Neanderthal genes, for example, are less likely to have schizophrenia; if they do, their symptoms are milder. Unfortunately, that's as far as the authors can go, as we still have no clue what causes schizophrenia.
Part of what happened is that the editors aren't evolutionary biologists but specialists in Parkinson's disease and psychiatry, so the 22 short articles are mostly general reviews on human-specific brain diseases. Each ends with a bit of speculation on human lifestyle, greater lifespan, and diet as potential causal factors. For instance, in the chapter on Alzheimer's disease, the authors say
The cognitive advantages of enhanced parietal functions are more useful for reproductive success than the drawbacks of dementia, which usually occurs in late life stages, rarely achieved in hunter-gatherers and, anyway, less involved in the reproductive function.
This just-so approach, common in biology, can explain almost anything as having some hidden evolutionary benefit. For example, in the chapter on major depressive disorder (MDD), the authors speculate that the function of postpartum depression (a major depressive episode during pregnancy that is now said to happen in men as well as women) may be as a signal to other tribal members that more help is needed with the baby; if help is not provided, it turns into MDD, which makes it easier to desert the baby. Nature may be cruel, but that interpretation seems a little cold.
This topic is a wild west. Books range from undergraduate-level textbooks like Human Evolutionary Genetics to studies on bioinformatics and computational biology (which is sadly now being taken over by “AI”), to books clearly written by ChatGPT and books by creationists who don't believe a word of it.
So my advice is: cross out the title and write “Human-Specific Brain Disorders” on the cover and you'll never know the difference.
jul 01 2025. updated jul 06 2025