{17754} Parkinson's vs. normal (midbrain sections)

The crew at K.U. writes about the long latent period of common parkinsonism: Neurology 42(4S4): 27, 1992.

The result of the neuronal loss is a movement disorder, with "pill-rolling" resting tremor, festinating gait, bradykinesia, cogwheel rigidity, and mask-like face. Many patients become demented (if the nucleus of Maynert is also full of Lewy bodies: Neurology 43: 986, 1993; co-existing Alzheimer changes are even more common and the relationship to Parkinsonism is unknown), though you may have trouble separating this from depression.

Known causes include Von Economo's encephalitis ("post-encephalitic parkinsonism", with neurofibrillary tangles in the substantia nigra neurons instead of Lewy bodies), boxing (South. Med. J. 82: 543, 1989), and the "designer drug" (MPTP, "Ecstasy") fiasco of a few years ago. Dopaminergic neurons are the only ones that take the drug up, and it produces mitochondrial damage and a permanent Parkinson-like sydnrome ("The case of the frozen addicts!")

* Vascular disease causing Parkinsonism is rare but occurs: K.U. case Neurology 40: 1218, 1990.

Most cases do not seem to be familial, but some are (Arch. Neuro. 49: 1205, 1992; Neurology 41(5S): 82, 1991.) The known Parkinsonism genes:

• alpha-synuclein, a presynaptic protein involved in synaptic plasticity; in the disease, it twists and accumulates (autosomal dominant PARK1=SNCA; Neurology 43: 69, 1993; Geriatrics 46(S1): 52, 1991; Neurology 45: 502, 1995; Science 256: 2045, 1997 Nat. Genet. 18: 168, 1998; Nat. Med. 8: 564 & 600, 2002); one extra copy gives parkinsonism without dementia, while two extra copies give parkinsonism plus Lewy body dementia: Lancet 364: 1167, 2004.
• tyrosine hydroxylase (autosomal recesssive; Neurology 41: 719, 1991).

• Parkin, autosomal recessive (PARK2) early-onset Parkinsonism: NEJM 342: 1560, 2000; it's the protein that ubiquinates synphilin-1 which in turn interacts with synuclein (Nat. Med. 7: 1108, 2001; update Science 304: 1328, 2004).
• tau (a variant, Picks-plus-Parkinsonism: Neurology 54: 1787, 2000; Am. J. Path. 153: 1359, 1999)

The epidemiologic link between insecticide and/or herbicide exposure and Parkinsonism continues to be discussed, especially since MPTP produces permanent Parkinsonism and works like many insecticides on the mitochondrial complex 1 system. Nobody's been looking hard at the epidemiology in recent years; living your life in farmland seems to be a risk, and there was a study where Dieldrin was found in 6 of 20 Parkinson's brains, and none of 14 controls (Ann. Neuro. 36: 100, 1994), and two pretty-good-looking epidemiologic studies (Neurology 43: 1150, 1993; Neurology 42: 1328, 1992). Rotenone, which like other insecticides resembles MPTP chemically and pharmacologically, produces Lewy body parkinsonism in mice (Science 290: 1068, 2000). So far there's no model of the chronic disease using herbicides, though some of these produce acute effects on the dopaminergic system as do many other substances (Science 290: 1068, 2000).

The claim that cigaret smoking is protective against Parkinsonism is by now clearly true (Neurology 45: 1041, 1995; Epidemiology 10: 327, 1999). So is caffeine (Drugs & Aging 18: 797, 2001). Nobody knows why; animal research is in its early stages.

Most cases are "idiopathic", and begin in later middle age. Look for the distinctive (but not pathognomonic) "Lewy bodies", round pink masses of neurofilament material, in dopaminergic (and other) neurons. Big autopsy series: Arch. Neuro. 50: 140, 1993.

* Acupuncture and every other "complementary / alternative remedy" studied for Parkinsonism have been flops (Neurology 57: 790, 2001).

The adrenal medulla autotransplantation experiment resulted in non-viable grafts. An animal model of Parkinson's responds dramatically to embryonic stem cell therapy: Proc. Nat. Acad. Sci. 99: 2344, 2002. The proposal to try stem cells in people has turned into a symbolic political battle which I think most people who have devoted their lives to the battle against disease find disheartening. We await more publications, but it's a hopeful area (Nat. Med. 7: 381, 2001).

Remember the parkinsonism mimics, which include manganse toxicity, Lyme disease (Arch. Path. Lab. Med. 127: 1204, 2003), and now West Nile.

Corticobasal degeneration ("Pick's Type B") is a dementing disease with ballooning neurons, inclusions resembling Pick bodies, and motor problems (notably alien limb, "My hand escaped and is doing its own thing.")

Astrocytic plaques are the histological hallmark of corticobasal degeneration.

* These people may have neurofibrillary tangles, with straight rather than twisted filaments, as in progressive supranuclear palsy.

The disease is notoriously unresponsive to therapy. Reviews: J. Neuro. Neurosurg. Psych. 68: 304, 2000; Arch. Neuro. 55: 957, 1998, pathology J. Neuro. 246 S-2: II 6-15, 1999.

Multiple systems atrophy is now considered a single disease, because of its distinctive inclusions in the oligodendroglia.

Striatonigral degeneration (* multiple system atrophy C) is a degenerative disease in which the caudate and putamen atrophy along with the substantia nigra. Patients have a similar clinical syndrome to Parkinson's, but do not respond to L-Dopa therapy and do not have Lewy bodies.

Shy-Drager (see Ann. Int. Med. 125: 194, 1996) is striatonigral degeneration with the loss, in addition, of the intermediolateral neurons of the spinal cord and resulting autonomic disturbances. I've never seen a case, though it's in the differential diagnosis of every patient with orthostatic hypotension, and is perennially discussed.

Progressive supranuclear palsy ("PSP", Steele-Richardson) is an underdiagnosed, fairly-common (Neurology 44: 1015, 1994; Med. Clin. NA 83: 369, 1999) dementing disorder of older adults with eye movement disorders (initially, they just can't look upwards), other movement disorders, and often dementia. Neuronal loss is most prominent in the deeper brain structures, and the key to diagnosis is neurofibrillary tangles found mostly in the basal ganglia and brainstem. Abnormal fiber tufts as the distinctive histologic sign: Acta. Neuropath. 96: 401, 1998. NIH workshop, with criteria for diagnosis: Neurology 44: 2015, 1993 (* they want us to call it Steele-Richardson-Olszewski syndrome, nobody's going to...), also Brain 118(3): 759, 1995.

* A claim that the sufficient cause was the A0 allele of the tau protein gene (neurofibrillary tangles), with tandem repeats, did not hold up; however homozygotes seem more severely affected (J. Neurol. 247: 206, 2000) and the allele does seem to put one at risk for several other neurodegenerative diseases: Neurology 53: 1219, 1999.

* Neurofibrillary tangles in PSP have straight, rather than twisted, filaments. PSP as a taupathy; Lancet 356: 170, 2000.

Lewy body dementia features neurons packed with Lewy bodies throughout much of the brain. These patients have a rapid Alzheimer-like illness with some extrapyramidal symptoms (stiff and slow but usually no tremor), visual hallucinations, and (often) exquisite sensitivity to neuroleptic drugs (chlorpromazine, etc.) It's not rare, but almost never diagnosed in life. See Br. Med. J. 305: 673, 1992; Neurology 42: 2131, 1992; clinico-pathologic correlation including tips on how to tell this from Alzheimer's in life Arch. Neuro. 59: 43, 2002.

* Most of these patients also have tangles; the more tanlges, the harder it is to tell it from Alzheimer's clinically (Neurology 60: 1586, 2003).

Dystonia musculorum deformans is a disease of children in which the muscle tone increases around the body, twisting it into curious positions. The one known gene is Torsin A (TOR1a / DYT1) which does not always express completely (Neurology 59: 445, 2002; Arch. Neuro. 57: 333, 2000.) Neurosurgical procedures on the deep brain structures has resulted in spectacular recoveries (review Ped. Neuro. 14: 145, 1996).

* Hereditary spastic paraplegia is a family of thankfully-rare progressive genetic disorders (dominant and recessive) of varying expressivity; at least eight loci are already known (J. Neuro. Neurosurg. Psych. 72: 43, 2002).

WORTH MENTIONING HERE: Essential tremor ("benign familial tremor") is a very common (1-2% of humankind), banal intention tremor. It is inherited as an autosomal dominant, first manifests around age 20, and typically vanishes as soon as the "patient" drinks one beer (i.e., here's the three questions you need to ask to pretty-much clinch the diagnosis). If the patient really wants to be treated, try low-dose propranolol or gabapentin (Arch. Neuro. 56: 807, 1999). More important, explain the nature of the process, and that it is not Parkinsonism or mental illness. (* These people do seem to be at maybe double the risk for Parkinsonism later in life, but stay tuned. Neurology 45: 645, 1995.)

THE SPINOCEREBELLAR ATAXIAS (update Mayo Clin. Proc. 75: 475, 2000)

This array of autosomal degenerative diseases has recently been sorted out thanks to the Human Genome Project. Except Friedreich's and ataxia with vitamin E deficiency, all are autosomal dominant. The pathologist sees only neuronal loss and maybe gliosis.

Type I spinocerebellar atrophy feature damage to the gene for "ataxin 1", and this also exhibits long tandem repeats and Sherman's paradox (see below; Nat. Neurosci. 3: 157, 2000). So do Type II (ataxin 2; Eur. J. Hum. Genet. 7: 841, 1999) and Type III (Joseph's, a Portuguese ethnic disease and probably the commonest in this group, ataxin 3). All these do their harm by producing a product whose long repeats gum up the nucleus.

* Olivopontocerebellar degeneration (* multiple system atrophy P) is the old name for SCAI and SCAII; in 1990 in these notes, I predicted it would prove to be a Sherman's paradox disease and this has come true (J. Neuropath. 57: 531, 1998).

Friedreich's ataxia is an autosomal recessive disease with somewhat variable expressivity. Onset is in late childhood, when pes cavus (high-arched feet), clumsiness and speech problems develop. Patients become wheelchair-bound after a few years, and may have a cardiomyopathy. There is gliosis of the posterior columns, dorsal corticospinal tract, and spinocerebellar tracts; the cerebellar cortex and other motor areas may also be involved. The cause is trinucleotide repeats in frataxin, a gene responsible for keeping iron from accumulating in mitochondria; Gene and review: Science 271: 1423, 1996.

Unlike other long-repeat diseases, this is a loss-of-function gene, hence the recessive inheritance. Because of Sherman's paradox, Friedreich's used to be considered "often dominant". Any idea how this could have been?

Ataxia with vitamin E deficiency mimics Friedreich's, but is caused by lack of vitamin-E transfer protein. Of course this is also autosomal recessive. Giving the vitamin in big doses is effective treatment. See NEJM 333: 1313, 1995. Though very rare, it's the only really treatable entity in this group, so be sure to think of it!

* Smith's dentatorubral atrophy is yet another Sherman's-paradox disease ("atrophin"; J. Biol. Chem. 274: 8730, 1999).

* The episodic ataxia family includes a mutation in the voltage-gated potassium channel gene; ataxic / dysarthric episodes especially follow a startle.

We've already mentioned ataxia-telangiectasia (gene ATM).

* I have never seen or read about the "amphicytes" mentioned in "Big Robbins".

* Men carrying mild alleles of fragile X (i.e., not enough tandem repeats yet) are prone to develop cerebellar ataxias and dementia (Brain 125: 1760, 2002.)

AMYOTROPHIC LATERAL SCLEROSIS ("Lou Gehrig's disease"; "creeping paralysis"; motor neuron disease complex; Am. Fam. Phys. 59: 1489, 1999; NEJM 344: 1688, 2001)

This is actually four diseases, featuring loss of the motor neurons

1. Amyotrophic lateral sclerosis (loss of upper and lower motor neurons); this is the common one

2. Progressive bulbar palsy (cranial nerves are most severely affected)

3. Progressive muscular atrophy (lower motor neurons only)

4. Primary lateral sclerosis (upper motor neurons only)

ALS is a disease of older middle age, progressing to profound disability (usually without mental impairment) in a few years. Most ALS cases are sporadic (but see below). There is a slight male predominance

Current thinking has involved destruction of motor neurons by excitotoxicity (Mayo Clin. Proc. 66: 54, 1991; J. Neurol. 247-S1: I-7, 2000). This is supported by the finding that the anti-glutamate agent riluzole causes a modest slowing of the progression of ALS (NEJM 330: 585, 1994).

* The sick neurons contain ubiquitin-positive inclusions of various sorts, thought to be altered or abnormal proteins that resist degradation (Brain 114: 775, 1991). Most distinctive is the Bunina body, a Lewy-like body composed of cystatin.

One ALS-like motor neuron disease (* "konzo") results from poor people eating semi-poisonous cassava root during food shortages (Lancet 339: 208, 1992; chilling reading).

* Medical history and "natural healing" buffs: This is the same plant that the right-wing Laetrile proponents of the 1970's fraudulently claimed would prevent and cure cancer.

The link between cycad (false sago palm) flour and ALS-dementia-parkinsonism complex of the indiginous people of Guam remains speculative. There is now an animal model using the toxin cycasin (Exp. Neurol. 155: 11, 1999). Thankfully the disease is becoming less common, but has not vanished.

* The most recent work has failed to support the old claim of a relationship with old polio (Acta Neuropath. 97: 317, 1999).

Hereditary ALS (about 10% of cases are hereditary) is often caused by a defective superoxide dismutase gene: Science 261: 986 & 1087, 1993; Nature 362: 59, 1993; transgenic mice with the mutant form get sick too Proc. Nat. Acad. Sci. 93: 3155, 1996. The mechanism remains totally obscure; in one model, the protein is misfolded: Brain 127: 73, 2004. Therapy with creatine: Nat. Med. 5: 347, 1999.

* Motor neuron disease from mutant dynactin: Nat. Genet. 33: 455, 2003.

* Another locus (alsin, ALS2): Nat. Genet. 298: 160, 2001; Arch. Neuro. 60: 1768, 2003.

* Inhibiting production of interleukin 1-beta also seems to slow the loss of cells in the ALS knockout mouse: Nature 388: 31, 1997

ALS complex is very common in Japan, where it causes perhaps 1 death in a few hundred; there is a terrible stigma attached, and Japanese deny and conceal it.

Amyotrophic lateral sclerosis is the classic disease cited in considerations of physician-assisted suicide. (Why?) About one Dutch patient in five now chooses this route (NEJM 346: 1638, 2002). And a majority will consider assisted suicide, but most will choose hospice instead (NEJM 339: 967, 1998).

* Kennedy's disease is a bulbospinal atrophy and lack of masculinization of male patients, caused by lack of an androgen receptor. This is yet another trinucleotide repeat disease.

The other illness to rule out in apparent ALS is "multifocal motor neuropathy", caused by autoantibodoes against GM₁ ganglioside. This responds to treatment as other autoantibody diseases (cyclophosphamide, gamma globulin).

Amyotrphic lateral sclerosis WebPath Photo

Amyotrophic lateral sclerosis WebPath Photo

Amyotrphic lateral sclerosis WebPath Photo

Muscle in ALS Wash. U., St. Louis Illustrated notes

Werdnig-Hoffman disease (spinal muscular atrophy type I) is an autosomal recessive disease causing loss, in the few months before and after birth, of most of the lower motor neurons. It is the most severe of the spinal muscular atrophies, caused by various mutations at the SMN locus (Nat. Genet. 16: 265, 1997).

SCHIZOPHRENIA, ET CETERA

Schizophrenia (Lancet 353: 1425, 1999; Mayo Clin. Proc. 77: 1068, 2002) is the most important of the "functional psychoses", supposedly affecting about 1% of humankind in every culture, every bit as devastating as Alzheimer's disease, but under-investigated (i.e., patients don't lobby, there's an awful stigma, and the rich are seldom affected). Schizophrenics consume 2.5% of health care expenditures, constitute 10% of the totally and permanently disabled, and represent around 14% of the homeless (Psych. Clin. N.A. 16: 413, 1993). Schizophrenia reviews: Lancet 346: 477, 1995; NEJM 330: 681, 1994.

* There are rumors that schizophrenia is becoming less common among young people in the U.S. Perhaps this is because of 'flu shots, and/or perhaps this is due to fetal monitoring and more frequent cesarean sections (and perhaps this will prove to be the great benefit of fetal monitoring; stay tuned here.)

Even in the DSM-IV era, I find Bleuler's "Four A's" helpful: Autism (apparent absorption in self and fantasy), Ambivalence (maintaining contradictory attitudes in logic-tight compartments, with striking lack of insight), loose Associations, and flat Affect. In schizophrenia, these are much more striking even than in us "normal folk".

Don't confuse schizophrenia ("fragmentation of the mind") with "multiple personality", a dissociative state that rarely occurs spontaneously but that is easy to produce iatrogenically using hypnosis. (The fad is over -- induce multiple personalities today, or even talk to one, and you'll end up in court.)

Sensitive physicians know that the negativism, coldness, and lack of motivation of the schizophrenic can be as upsetting to family members as the delusions and hallucinations. Tell them it's nobody's fault and that it isn't that they are not loved.

Reasonably good models for schizophrenia (i.e., both being very crazy and being oriented in the three spheres) include acute intermittent porphyria, lupus, chronic mercury poisoning, ergotism, pellagra, neurosyphilis, frontal lobe meningioma, and some of the psychedelic experiences.

Until recently, all public discussion of schizophrenia was dominated by ideology. In the 1960's ("B.F. Skinner says, 'Give me a child until it is seven and I'll make it into anything'"; "All people are born equal and if you aren't getting what you want, it is society's fault"; etc.), behaviorists wrote dogmatically about "the schizophrenogenic mother" ("She said to the child, 'I love you', but her body language said otherwise, and this prevented the child from distinguishing fantasy from reality"; "the double bind", etc., etc.) In the early 1970's, it was all the fault of "the schizophrenogenic father" instead; as with the "S-mother", evidence was "anecdotal" (i.e., the biological parents of crazy people act screwy themselves; stress sometimes precipitates symptoms) and "based on sound theory" (i.e., "all people are born the same", the left-wing/Skinnerian ideology of the day). Some 'sixties revolutionaries discussed schizophrenia as "a disease caused, more than any other, by our reactionary society", or denied its existence altogether (a Dr. Thomas Szasz, author of The Myth of Mental Illness, described witch-hunts and incarcerating people just for being different). 'Sixties rhetoric emphasizing that traditional society was unreasonable and thus the people in the mental hospitals must be the sane ones. "The King of Hearts" put this on the silver screen. Ken Kesey (One Flew Over the Cuckoo's Nest) and Dr. R.D. Laing (The Politics of Experience) wrote their best-sellers. (Dr. Laing's own life-story was not nice.) The ACLU defended the rights of crazy people to refuse treatment (one 1970's study showed 99% were totally grateful after being brought back to earth). And some psychologists inveighed against the use of the obviously-effective phenothiazine drugs, which began cutting through hallucinations and delusions as soon as they were introduced in the 1950's. Confusing fantasy with reality always causes problems, and the beautiful 'sixties rhetoric resulted in disaster for the mentally-ill and their families. Today, only a few psychoanalysts still talk about curing schizophrenia through psychotherapy, and the rest of the world (even the other psychiatrists) just laughs at them (Nature 354: 693, 1991). There are still occasional complaints from non-phsyicians about psychiatry being wicked because it is "authoritarian", or obsolete because it is "culture-bound" or "institutionalized" or "modernist rather than postmodernist" (Br. Med. J. 322: 724, 2001). These people ignore the fact that for the past fifty years, free-world psychiatrists have only used coercion when a person cannot take care of himself/herself or a danger to others, and an examination of any psychiatry textbook will show that the discipline is characterized by a variety of perspectives and ways of understanding a particular person's problems.

The end result of all this of course, was de-institutionalization ("out of the back wards, into the back alleys"). This pleased the Left ("We're for every individual's freedom to be different"; "Even though the inmates got free food, clothing, shelter, medical care, and protection, and were otherwise unemployable, it violated their civil rights to have them work in the laundry and not get minimum wage and benefits"), the Right ("We're against able-bodied people living at public expense"), optimistic physicians ("The grateful patients will come regularly to their community mental health centers to get their medicines refilled"), and real humanitarians (there were, after all, serious abuses in the old "asylum" system). Well, everybody was pleased at first.... Today, the non-compliant mentally-ill whose families can no longer stand them are homeless, and this gets described as a "human rights problem" by the same people who got the asylums closed in the 1970's. Do you think Dr. Szasz ("Mental illness is a myth") has ever talked to his local "bag person"? By the way, schizophrenics are more likely to commit crimes, including violent crimes, including murder (Psych. Clin. N.A. 15: 575, 1994; a schizophrenic is 8 times as likely to commit murder as a non-psychotic counterpart: Arch. Gen. Psych. 53: 497, 1996), and only a fool believes that psychiatry can protect the public in today's political-economic "mental-health" environment. The truth is that schizophrenics are more likely than non-schizophrenics to commit all categories of crime except sex crimes (Lancet 355: 614, 2000). In fact, people who stalk strangers (rather than previous sex partners) are usually psychotic (Lancet 355: 199, 2000). Even writers who seem to be advocates for "community mental health" and who emphasize that a majority of stranger-murders result from fights in bars or among druggies cannot hide the reality of senseless violence from schizophrenics (especially against family members and friends: Br. Med. J. 328: 754, 2004). As part of the illness, many schizophrenics do not believe they are sick, and do not want to take their medicine. Thanks mostly to "laws that protect the rights of the specially-challenged", it remains extremely difficult to keep a schizophrenic confined even after multiple episodes of dangerous behavior. The shooting of two guards in the US capitol by a chronically belligerent, chronically threatening, non-compliant schizophrenic named Russell Eugene Weston who had just been given "Greyhound therapy" (a one-way bus ticket out of the state) by the Montana mental-health system should have had an impact, but it didn't. Michael B. Laudor, a schizophrenic who successsfully completed the curriculum at Yale Law School and who sold book and movie rights to his success story for $2 million, stopped taking his medicine and a few days later stabbed his pregnant girlfriend to death. In both of these high-profile cases, the families knew there was going to be trouble, but couldn't do anything. The much-hyped recent "study" (Arch. Gen. Psych. 55: 393, 1998) finding that mentally-ill people in the community were no more likely to be violent than their underclass neighbors suffered from serious flaws, including omitting anybody who had been in jail, and not counting threats of violence, swinging-and-missing, fire-setting, or trashing rooms as being violent. More recently, several studies have made it clear that schizophrenics are much more likely to commit violent crimes, especially violent sex crimes (Crim. Behav. Ment. Health 14: 108, 2004 -- note the conflict with some previous studies). A schizophrenic (compared with a non-schizophrenic) is over four times more likely to have been convicted of a crime (21.6% vs. 7.8%), and a violent crime (8.2% vs. 1.8%); the rate of substance abuse among schizophrenics is tremendously high but this doesn't explain all of this (Am. J. Psych. 161: 716, 2004). At present, there are around tens of thousands of chronically mentally ill Americans confined in jails for vagrancy. The truth is that this represents a conscious decision by society to turn care of these people over to law enforcement personnel (who are, for the most part, reality-oriented and respectful of the legitimate rights of all people) rather than non-physician (and non-scientifically-oriented) "mental health experts". But the damage has been done. One of the major moral failures in my life was not speaking up when a group of mental health professionals called a nun a "self-righteous bitch" for no other reason than saying that she preferred -- just for herself -- a celibate lifestyle devoted to caring for the sick and needy. (My course evaluation would probably have been affected adversely, but I'm still ashamed I said nothing. This happened in 1974 or 1975.) On my "psych" rotation, the physicians talked to me again and again about how frustrating it was to have to work with such screwy "fellow-professionals" who wielded so much power. Perhaps things have changed since the mid-1970's. Among my favorite articles from the 1990's was "The Government-Sponsored Revolving Door" in NEJM 333: 777 & 794, 1995. Schizophrenics on welfare learn to act crazy and get admitted while they're broke and waiting for their checks, and recover when the check arrives; and in the study sample, the typical welfare-schizophrenic's largest single expenditure was for cocaine.

It is now perfctly clear that schizophrenia is a major organic nervous system disease. Before the disease fully manifests itself, brain cells die off and brain atrophy occurs (Am. J. Psych. 155: 1661, 1998); this is already well-underway during the first episode (Am. J. Psych. 157: 1829, 2000). Certain association areas in the cortex and thalamus are hit especially hard (Am. J. Psych. 159: 59, 2002); the more cortex lost, the worse the outcome (Am. J. Psych. 158: 1140, 2001). For a review of various studies at the light microscopic level, see Brain 122(4): 593, 1999; findings differ in different studies but generally agree that there is neuronal loss and cellular disarray in the cortex, without gliosis. The loss is selective, with the dorolateral prefrontal cortex severely involved and nearby Broca's area completely spared (Arch. Gen. Psych. 60: 69, 2003; Am. J. Psych. 159: 1983, 2002); the more that's gone, the worse the outcome (Am. J. Psych. 158: 1140, 2001). Counting dendrite intersections: Am. J. Psych. 161: 742, 2004. In some families, it has been reported to be monogenetic (Nature 336: 164, 1988, locus on chromosome 5; but this has not been reproducible; molecular genetics Br. Med. J. 305: 664, 1992; Scottish kindred has chromosome defect at 11q21: Am. J. Hum. Genet. 52: 551, 1993); familial schizophrenia locus Science 288: 678, 2000. Neuregulin 1: Am. J. Hum. Genet. 71: 877, 2002; Am. J. Hum. Genet. 72: 83, 2003. More on the genetics: Lancet 361: 417, 2003. Even in cases without simple inheritance, the genes obviously dominate family environment (old work on schizophrenia genetics: Lancet 1: 79, 1989; Nature 339: 305, 1989; Nature 340: 391, 1989; non-schizophrenic relatives tend to be a little-bit screwy and fill DSM criteria for schizophrenia-like illnesses Arch. Gen. Psych. 50: 527, 1993, J. Nerv. Ment. Dis. 182: 443, 1994; the adoption studies from Scandinavia, where they keep good records: Arch. Gen. Psych. 51: 442, 1994). The best known locus (and it clearly is real) that confers susceptibility to schizophrenia is dysbindin, on the glutamine neurons (J. Clin. Invest. 113: 1353, 2004.) In twins discordant for the disease, magnetic imaging detects distinctive differences in the brains of the schizophrenic twin (NEJM 322: 789 & 842, 1990) which have been confirmed by neuropathologists (Schiz. Res. 3: 295, 1990; Br. Med. J. 305: 327, 1992; South. Med. J. 85: 907, 1992; more on twins J. Nerv. Ment. Dis. 181: 290, 1993). In monozygotic twins who are clearly discordant for schizophrenia, being the crazy twin correlates very strongly with obstetrical complications and/or problems during pregnancy or shortly after birth (Am. J. Psych. 151: 1194, 1994; there was no relation to trauma or to substance abuse; also Am. J. Psych. 157: 196, 2000; pre-eclampsia as a major risk Arch. Gen. Psych. 56: 234, 1999). In the poor nations, where obstetrical catastrophes and infantile brain trauma are more common, the rate of schizophrenia is supposedly no higher, but there's a strong link to these insults (Am. J. Psych. 151: 368, 1994). And prenatal exposure to famine and malnutrition is a strong risk factor: Am. J. Psych. 157: 1170, 2000. Nowadays, there are a host of anatomic studies, all pointing to abnormal anatomy in schizophrenia (MRI: Psych. Clin. N.A. 16: 281, 1993; Am. J. Psych. 151: 752, 1944; Am. J. Psych. 151: 343, 1994; the latter links symptom types and abnormal anatomy; autopsy J. Neur. Neuros. Psych. 57: 474, 1994; circuits on imaging Nature 378: 120, 1995). Currently, there's a lot of interest in obstetrical complications and/or a catastrophe during the second trimester of gestation as the added insult that makes the hereditary trait manifest itself: Br. Med. J. 305: 1256, 1992; Am. J. Psych. 149: 1355, 1992. And so forth. Schizophrenia's gotta be "multifactorial", with etiologies differing from patient to patient, and the psychiatrists are now recognizing this (Psych. Clin. N.A. 16: 269, 1993; Schiz. Bull. 19: 355, 1993).

Today's neuroleptic-antipsychotic drugs are potent dopamine antagonists, and dopamine-like drugs (notably amphetamine) can make a person act crazy and paranoid (but without the distinctive thought disorder of the schizophrenic). However, the old story about "high dopamine causes schizophrenia, low dopamine causes Parkinsonism, they are two ends of a continuum" just doesn't hold up to today's neuroscience; there are places in the schizophrenic's brain where dopamine is high, and other places where it is low (Am. J. Psych. 148: 1301 & 1474, 1991; striking decrease in D1 receptors in the prefrontal working-memory-processors that in turn correlates with the negative symptoms: Nature 385: 634, 1997). And the newer anti-schizophrenic drugs (clozapine, etc.) are "atypical neuroleptics" that selectively block the subset of dopamine receptors (D4) not involved in the extrapyramidal side effects of the more familiar anti-schizophrenic drugs, as well as 5HT2a receptors. Watch for more about D4 protein, which varies from person to person, and the origins of psychiatric illness: Nature 358: 109 & 149, 1992. D4 allele correlates with novelty-seeking / thrill-seeking (Nat. Genet. 12: 78, 1996). D2 claims flop: Science 264: 1696, 1994. No one has been able to link schizophrenia to any dopamine receptor gene yet: Am. J. Hum. Genet. 52: 327, 1993; Arch. Gen. Psych. 51: 288, 1994.

More plausible is the phencyclidine model for schizophrenia (ever see someone go crazy on "angel dust?"), and there's some new evidence that the N-methyl-D-aspartate receptor (blocked by phencyclidine and ketamine) is defective in schizophrenia (Am. J. Psych. 148: 1474, 1991; the ketamine model Arch. Gen. Psych. 51: 199, 1994). Another exciting focus is on under-expression of glutamate receptors, especially in the middle of the temporal lobe (Lancet 337: 450, 1991). Yet another is the finding of a striking increase in sporadic (not familial) schizophrenia following influenza A infection in the fifth month of pregnancy (Lancet 337: 1248, 1991; Arch. Gen. Psych. 47: 869, 1990; Am. J. Med. Genet. 48: 40, 1993). There is a huge excess of schizophrenics born in February and March, and in the city rather than in the country (NEJM 340: 603, 1999). An arcane statistical study of mental and behavioral illnesses that affect primarily the poor (Science 255: 946, 1992) concludes that (in contrast to depression, criminality, and illegal drug abuse), the tendency to schizophrenia causes downward social mobility, and is not the result of bad living conditions.

De-stigmatize and de-mystify this dread illness -- and explain the hallucinations not as "evidence of being crazy", but as exaggerations of perceptual errors that happen to anyone under stress (J. Nerv. Ment. Dis. 179: 207, 1991). The more the family misunderstands (and therefore criticizes) the patient, the worse the prognosis (Lancet 340: 1007, 1992); your role as educator is extremely important here. Tip: To control "the voices", try one ear plug, or a Walkman, or singing softly to oneself (Br. Med. J. 302: 327, 1991). There was a flap in the early 1990's about neuroleptic treatment causing earlier onset of Alzheimer's in schizophrenics. It's evidently not so (Am. J. Psych. 154: 861, 1997 autopsy studies.)

Childhood autism (formerly "childhood schizophrenia", semi-glamorized in the film "Rain Man"; reviews Ped. Clin. N.A. 40: 567, 1993; NEJM 347: 302, 2002)

This is an inborn (usually), organic, sometimes-familial, usually sporadic disease of the brain that impacts dramatically on children's ability to imagine, socialize and communicate. The kids show intensive interest in one or two subjects, exhibit a narrow and repetitive lifestyle, lack intonation and body language, and show poor muscular coordination. You'll learn about the way these children think and behave on "Pediatrics".

There's a consensus now that the disease arises from neuronal problems that begin before birth. By now, the morphometric differences between autistic and non-autistic populations are robust and consistent from nation to nation (Brain 128: 268, 2005; Arch. Gen. Psych. 61: 291, 2004; Brain 124: 1317, 2001). There is less gray matter in the fronto-striatal and parietal areas, smaller hippocampus, and less white matter in the cerebellum and fornices. Autistic children's brains actually average larger than those of typically-developing children (Neurology 59: 184, 2002). The neuropathology findings are also being clarified (small cells in places in the limbic system, abnormal microcolumn architecture in the frontal cortex, others: Brain 127: 2572, 2004; Neurology 58: 428, 2002), but this will be much more difficult.

Autism often seems to have an onset sometime during the first three years of life, and this may be fairly sudden. This makes sorting out "possible causes of autism" much more difficult, and makes evaluating anecdotal evidence all the more frustrating. What's more, occasionally there is a primary cause. Autism developing secondary to a brain tumor: Dev. Med. Child. Neuro. 34: 252, 1992.

* One group looked at head circumferences before the onset of symtoms; they found they were unusually small at birth, and unusually large at one year (JAMA 290: 337, 2003). If this turns out to be correct, then autism is one more programmed disease of nervous tissue.

Autism is a continuum, with the totally uncommunicative person at one end, and the odd, disliked, clumsy, loner kid who grows up to be a high-functioning, academically-inclined single adult after learning (by trial and error rather than instinct) how to relate to people (Lancet 350: 1761, 1997). In the next few years, watch for a fad for diagnosing nerds (young and old) as "suffering from Asperger's disease" and applying for disability privileges.

* Pseudoscientists have been particularly cruel to those who care about autistic children. Bruno ("I'm on the child's side!") Bettelheim, of U. of Chicago, assumed a priori that autism was the result of abuse and neglect, scapegoated the parents, and treated these children in an intensive, lucrative "orthogenic" milieu therapy. Of course, he never published his statistics, and he's now remembered as a charlatan (Pr. Kind. Kind. 41: 316, 1992, abstract 93109943; Skep. Inq. 24(6):12, 2000). More recently, a technique called "facilitated communication" was developed, in which the operator uses the child's hand as the planchette of a Ouija board. Even if the child has never communicated or seemed to understand language, the hand will spell out elaborate stories. If the child is shown one picture and the (unknowing) operator is shown a different picture, and the child is then asked what the picture showed, the "child" will describe only what the operator saw (Ment. Retard. 31: 49, 1993 and many, many more). Gee whiz! The first commentators (1987, also J. Aut. & D.D. 21: 561, 1991) in the refereed literature knew that "facilitated communication" was bunk, but supported it because it would make the public believe that autistic kids, kids with cerebral palsy, and so forth were more like ordinary folks. In other words, politics and propaganda are more important than truth. As you might expect, the "children" often produced stories of elaborate secret sexual abuse, using the vocabulary of sleaze-pornography. Even after the above-referenced article was published, at least one parent in Kansas was sent to prison entirely on this evidence. The literature contains some accounts (notably by a group at SUNY) in which "the child's story was proven to be true" by the confession of the accused (no good physical evidence though); however, nowadays it is commonplace for a person accused of a sex crime, often on no real evidence, to be offered leniency in exchange for a confession ("admit you did it and accept counselling, or we'll send you to prison for life"). In 1994, "facilitated communication" (the subject of a media "miracles of healing" hype in the early 1990's) got massive negative TV coverage, which finished particular folly off. Freeing several dozen imprisoned people, all convicted of child molesting solely on this evidence, will take longer. I am not making this up. How this crock happened: Child Abuse & Neglect 22: 1027, 1998 ("Its proponents' resistance to allowing the technique's validation relying on the paradigm of normal science has resulted in its broad dissemination without support", i.e., all this talk about "Thomas Kuhn", "postmodernism", and so forth ruins the lives of innocent people).

* The whole MMR-vaccine-and-autism scare resulted from a study in Lancet with obvious selection bias; the kids had been brought forward by parents who believed the MMR vaccine had caused their autism. Lancet 351:637, 1998 also includes some stuff on supposed intestinal pathology; the only "consistent" lesions are normal findings (the authors think that groups of eosinophils in the ileum are abnormal even though everybody's got them) and big lymph nodes with big germinal centers (incredibly, they made a deal out of tingible body macrophages here, everybody's got them too; no controls of course). Were they right to fast-report a possible health hazard? Wrong to rush to publication with no proper controls? Reasonable people will differ. In Feb. 2004, the Lancet apologized for publishing it and revealed that Dr. Wakefield, the principal author, was actually in the pay of a legal-aid service hoping to sue over immunizations. More about how this particular strangeness happened: West. J. Med. 174: 87, 2001. Dr. Wakefield, who still holds out that he was right, admits that he's most impressed with anecdotal evidence, and perhaps he's actually seeing an ultra-rare phenomenon hidden in statistics (I think he could be right): Br. Med. J. 324: 386, 2002. But the fact that he apparently withheld information about a major conflict of interest will probably ruin him as a scientist. One of my cyberbuddies, a Ph.D. bioscientist who had a child with autism, is confident of Wakefield's essential integrity, and it's clear that Wakefield shows none of the signs of charlatanism that you see in most other independent thinkers.

Ileal Lymphoid Hyperplasia
How the Wakefield
MMR business got going


Anyway, in children reported to have autism following MMR or other immunization, there's no dose-response relationship, and no relationship to whether a batch of vaccine actually contained thimerosal (ethylmercury, the supposed toxin): JAMA 290: 1763, 2003. A huge case-controlled in Britain shows no link: Lancet 364: 963, 2004.

Claims that there is a GI lesion in autism (including a great deal from the "leaky gut" independent thinkers) collapsed in the early 2000's but remain popular: Am. J. Gastro. 98: 1777, 2003; BMJ 325: 419, 2002.

Asperger's ("high functioning autism") is a new "disease", supposedly affecting boys, running in families. Asperger's boys tend to be of normal or high intelligence, strongly focused on single topics (for example, math, chess, computers, a musical instrument, train schedules, pathology, skydiving, flattop haircuts, etc., etc.), are physically clumsy, find other people bafflng, but don't commit crimes (well usually, the ones that do are refractory to treatment: Med. Sci. Law. 42: 237, 2002). They have to work hard to learn to read body language and to relate to others. I suspect Asperger's will turn out to be a fad diagnosis but that its study will show something about the wiring of personality. See N.Z. Med. J. 112: 60, 1999; J. Aut. Dev. Dis. 28: 457, 1998; Acta Psych. Scand. 97; 99, 1998; Br. J. Psych. 172: 200, 1998; Br. J. Hosp. Med. 55: 80, 1996.

Of all the patient-care specialties, I am most intrigued by psychiatry. Many other pathologists share my fascination with the life of the mind.

Biological psychiatry is only now coming of age. Remember that different kinds of synapses may use the same neurotransmitter.

Right now, the study of the very-common obsessive-compulsive disorders is a major topic in psychiatry; watch this elucidate different types of serotoninergic synapses (Mayo Clin. Proc. 67: 266, 1992; Postgrad. Med. 91: 171, 1992; Arch. Gen. Psych. 49: 21, 1992; subtle cues to basal ganglia dysfunction Brain 114: 2191 & 2203, 1991; Arch. Gen. Psych. 47: 27, 1990, notably such stuff as visuospatial coordination; this is no surprise because Sydenham chorea produces obsessions and compulsions: Am. J. Psych. 146: 246, 1989; caudate on PET scan display before and after therapy: Arch. Gen. Psych. 49: 681, 1992). For unwanted intrusive thoughts about a past or present problem, set the business down in a cohesive form on paper. Moderate catechol O-methyl transferase deficiency and obsessive-compulsive: Proc. Nat. Acad. Sci. 94: 4572, 1997. Not totally unrelated: Serum from Tourette's patients causes a similar illness in rats if and only if there are antinuclear or antineuronal antibodies (Am. J. Psych. 159: 657, 2002).

Bipolar disorder is obviously genetic with several distinct syndromes and likely loci (Am. J. Psych. 160: 999, 2003; Arch. Gen. Psych. 60: 497, 2003). The genes remain elusive; Sherman's paradox seems to operate Am. J. Hum. Genet. 53: 385, 1993; the "usual suspects" include tryptophan hydroxylase, and catechol o-methyltransferase (Am. J. Psych. 159: 23, 2002). Unipolar depression links nicely to the serotonin transport gene (Lancet 347: 731, 1996).

Attention-deficit disorder, with difficulty focusing (even on play), is wired in the caudate and its connections to the frontal lobe (Am. J. Psych. 151: 1791, 1994; update from neuroimaging is impressive: Lancet 362: 1699, 2003). The mouse model is the knockout mouse lacking dopamine transporter: Science 283: 397, 1999.

The big news in dyslexia in 1996 was the discovery that if you help these kids distinguish different phonemes early, they do much better (Br. Med. J. 313: 1096, 1996, Child. Dev. 65: 41, 1994). As I predicted in the 1980's, the US fad to forbid the teaching of phonics resulted in a lot more cases of dyslexia (Psych. Sci. 2(2S): 31, 2001, big review); sadly, it took neuroscientists rather than people possessed of simple common sense to end this fiasco. Some people are not verbal (speaking, reading) despite otherwise normal intellectual function; there's now a known gene that causes its recipients to be unable to use suffixes or complex grammar, and have a lot of trouble not only being understood, but moving their faces (Nat. Genet. 18: 168, 1998). As a college student in the late 1960's when B.F.Skinner was dogma ("Environment is everything"), I say I'm getting the last laugh.

We await effective therapy for borderline personality ("I hate you, don't leave me!" and more), and I wonder whether it's hard-wired or simply a lack of living skills (which are hard to teach).

You will hear plenty of glossalalia (i.e., people who believe they are speaking a language they themselves do not understand) among people who are clearly mentally ill, the majority being psychotic; review J. For. Sci. 47: 305, 2002. Whether it is ever really of supernatural/paranormal origin is something you'll need to decide for yourself.

Interpersonal therapy, a common-sense "innovation", is the psychotherapy for the managed care era, where things have to be cheap and have to work. It's effective for depression (you'll probably also want to medicate): (1) deal with any grief and loss issues, emphasizing what's still intact; (2) solve interpersonal role disparities (i.e., conflicts over who is supposed to do what); (3) deal with role transitions (that was then, this is now); (4) teach them interpersonal skills and make them practice between sessions. They also (5) learn to watch for goofy "I can't because..." thinking that prevents them from doing the things they need or want to do, and having them report each week. It turns out that simply letting your patients learn and practice these skills from an internet site is more effective than talking to them in a nurturing and supportive way: Br. Med. J. 328: 265, 2004. The sites were Blue Pages and Mood Gym. Here is another site I've found helpful (follow the links).

Somatization disorder ("somatoform disorder" JAMA 278: 673, 1997) is still considered "all in your mind" -- I believe this is wrong. The typical patient is a low-achieving young adult with anxiety, depression, and personality problems ("borderline", etc.) However, these folks also have lots of aches, pains, and symptoms that cause substantial disability. This is a patient type well-known across cultures (Am. J. Psych. 154: 989, 1997). I predict (2001) that it will be found to have a strong organic basis and eventually an effective organic therapy. (Uh, doc, you did rule out porphyria, right?)

Also watch Kleine-Levin syndrome (spells of hypersomnia and polyphagia with bizarre behavior), or "sleep-related eating disorder". This in turn may or may not be related to compulsive nighttime icebox-raiding.

Seasonal affective disorder: Arch. Gen. Psych. 41: 72, 1984 (said it all; wavelength Am. J. Psych. 148: 509, 1992; watch for melatonin to help these folks).

Narcolepsy is real (Mayo Clin. Proc. 65: 991, 1990); patients must have HLA-DR2 / DQ1 (Lancet 341: 406, 1993) and drop over suddenly like a rag doll from time to time. The brain lacks the neurotransmitter hypocretin, though this is usually not the locus (Nat. Med. 6: 991, 2000; update and additional complexity Lancet 363: 1199, 2004).

The transsexual brain: Ordinary men have huge, and ordinary women have tiny, central divisions of the bed nuclei of the stria terminalis in the hypothalamus (BSTc). Among several male transsexuals (gender-dysphorics, "I'm a woman trapped in a man's body!!"), gay or straight, every one had a tiny BSTc nucleus (Nature 378: 68, 1995). More recent work confirms this even more impressively: J. Clin. End. Metab. 85: 2034, 2000. Despite the politics, some patients find their being unhappy with their sex organs disappears on low doses of medication (Aus. NZ. J. Psych. 30: 422, 1996). Hypersexuality seems to be in the wiring (Can. J. Psych. 46: 26, 2001), so it's not surprising that the 1990's push to define "sexual addiction" as an entity was a total failure (Clin. Psych. Rev. 18: 367, 1998). By contrast, the common paraphilias seem to be acting-out, either a way of dealing with your hatreds or simply avoiding the problems of being "normal". Despite the greater tolerance of (and even promotion of) "minority sexual practices" among consenting adults, these people tend to have overall poor interpersonal skills. If they find real friendship in the "alternative" community, it seems to me it's a good thing, but not the best life could offer.

Post-traumatic stress disorder is nothing new ("Skipper Ireson's Ride", shell-shocked WWI veterans), and is serious and real, but is now highly politicized. It is most severe in torture survivors, but any brush with death or bad mistreatment (rape, child abuse) can leave a person jumpy, sleeping poorly, and suffering from flashbacks. Two accounts from physicians appear in BMJ Dec. 2, 2000. One found a deeper appreciation for how delicate and uncertain life is, and spirituality became far more important in his life. The volume of the hippocampus is lower in PTSD patients whose trauma took place in adult life (J. Clin. Psych. 62(S-17): 47, 2001, others), but not when the abuse happened in childhood (Biol. Psych. 50:305, 2001). We don't know whether this identifies people more at risk for PTSD after trauma, or whether this is due to beatings sustained to the head, or whether it is an effect of torture. A prospective study that might have helped didn't get results (Am. J. Psych. 158: 1248, 2001). There are glucocorticoid receptors in the hippocampus, and in some models, glucocorticoid excess itself (Cushing's in humans, mice given high doses) causes atrophy of the hippocampus via glutamate excitotoxicity (Arch. Gen. Psych. 57: 925, 2000; Biol. Psych. 45: 797, 1999). People who have long-term severe depression also have marked atrophy of the hippocampus (Proc. Nat. Acad. Sci. 100: 1387, 2003); interestingly, the volume of the hippocampus is apparently normal at the beginning of these patients' illnesses; another report finds normal volumes but altered shape (Am. J. Psych. 160: 83, 2003). You'll have to decide for yourself about just how prevalent post-traumatic stress disorder is in people whose "stress" seems only part of normal life; lawyers are now alleging PTSD after fender-benders, hearing off-color jokes, etc. (Science 301: 465, 2003).

Must reading (when you have time!): A chilling article entitled "Violence: The Neurological Contribution"; Arch. Neurol. 49: 595, 1992 (it is simplistic to ignore either neurology or sociology). Mice without nitric oxide synthetase are hypersexual and hyperaggressive (Nature 378: 336, 1995).

One current big fad in psychiatry is "debriefing", i.e., they bring a psychiatrist to talk to you after any really bad experience, loads of "counsellors" after a natural or man-made disaster, in the belief that this expensive intervention prevents long term psychopathology; I can't see why it should, and now it's pretty clear that it doesn't work (Br. Med. J. 310: 1479, 1995). Curious exceptions, at least in Britain, home of the stiff-upper-lip: Br. J. Psych. 169: 405, 1996 notes the contrast between the way the system totally ignores kids who've seen their loved ones killed in car wrecks with the flood of "counsellors" who descended on Dunblane in 1996.

* NOT TESTABLE, BUT WORTH YOUR ATTENTION: The current health-and-disease crazes are within the proper scope of any introductory study of pathology. Thankfully, the "repressed memories" business is now history.

Probably the worst feature of this fiasco was that it tended to discredit stories of child abuse that are really true, and to transform concern over child abuse into a preoccupation of the right-wing and left-wing lunatic fringes. As usual, the real losers are the children. (For a more sympathetic account of "enhanced memories", by a close friend of a leading advocate, see U.S. News Nov. 29, 1993; nothing in this or any other article makes me think the "memories" are true.) Now ("Ramona vs. Ramona" redefined a therapist's duty to third parties) that the goofy "therapists" are being sued like they should be, we can hope this fiasco is nearly over. Medilegal articles: Med. Sci. Law. 39: 112, 1999, Am. J. Psych. 156: 749, 1999; NZ Med. J. 111: 225, 1998; Comp. Psych. 39: 338, 1998. Even Geraldo reversed himself on "enhanced memories" in 1995, declaring it to be "cr_p". In 1999 I was pleased to meet an attorney who told me that he "makes a good living" in a practice devoted almost entirely to suing these therapists, who he tells me in his part of the country are mostly "social conservatives."

For me, science is not the interpretation of dreams of Sigmund Freud, but the realization of dreams.

-- Joseph, one of "The Three Christs of Ypsilanti"

I love America! No one is responsible for what they do!

-- Karel Roden, pleading insanity in "Fifteen Minutes"

Confusing fantasy and reality always leads to disaster.

-- Goethe

Sane psychiatry for the primary-care physician: A lot of the general practice of medicine is psychiatry. Here's how to be a good part-time psychiatrist most of the time. You get more information by asking open-ended questions and inviting the person to talk, but sooner or later you'll need to have things that are worthwhile to say, yourself. If you actually want to help people with emotional and behavioral problems, focus on reminding them of what they can do, what's still intact (bad for any secondary gains, but good medicine), living in the present, and so forth. Today's psychiatrists give them "behavioral homework", which is simply common sense. Depression etc., both result from negative life events, and causes negative life events (J. Nerv. Ment. Dis. 185: 145, 1997). Cognative-behavior therapy actually changes the PET scan, but in complementary ways to what prozac does (Arch. Gen. Psych. 61: 34, 2003). Keep reminding people of how their screwy behavior and unrealistic attitudes hurt them and those around them. Help them learn living and coping skills (i.e., explain to them how to do stuff that the rest of us may take for granted) rather than jabbering on about ("working through") their past traumas and present follies. Spending too much time figuring out exactly caused the problem can enable ongoing, harmful behaviors. Get them to confront their fears as boldly as they can. And don't call this "empowerment", the 1990's grandiose-trendy word; troubled people already have the power to do plenty. To alter your feelings, alter your behavior first -- "fake it 'till you make it." Be strong. Don't do that any more. Don't run back to things that are childish. If you keep doing that, all you'll get is _____. Find pleasure and meaning in some other way. People growing up in crazy environments acquire behaviors and attitudes that enable their emotional (and even physical) survival there, but that serve them badly in the larger world. Whatever the circumstances, one's emotional ties to one's origins are strong and these people resist change. You can help people realize why this is and that they don't need to be locked into it forever. You may disagree with what a crazy person says, but don't argue; people who are not psychotic will come around as they realize that their thinking is no longer helpful and that they can change their behavior to deal with a world that's saner than their own childhood homes. Don't expect most people ever to understand all that may be obvious to you. But most people can learn new skills. Learn how to use a modest selection of the psychopharmaceutical agents, and use them sensibly; if a medication isn't working in two months, change it or just drop it. Remember the basics: Neurotics are troubled (lots of things upset them), personality-disorder folks are troublesome (they will upset you), and schizophrenia and most of the bad-affect states respond to medication but not to talking. Non-psychotic people with ideas that they recognize as not making sense can usually figure out, with your help, what the obsession stands for, and try to get what they really want by some more realistic route. Marriage counselling is largely the delicate art of getting the two people to listen to one another on a daily basis, and to extend basic human kindness across gender-differences (i.e., a man and a woman can learn to be nice to each other even though they cannot possibly understand each other; the other person isn't acting that way just to be hateful; "the relationship is more important than being right", and so forth). When a relationship fails, remind the person of the ways in which the former beloved / the rival are doing the person a favor. There is no physician-patient confidentiality when a human life is in danger. Physicians respect the religious beliefs of each patient, as long as nobody's getting hurt in a big way; these beliefs are a good topic for discussion. Totally sane people often report experiences with the paranormal (whatever that is, when I was an intern, a group of 15 housestaffers at lunch got into a discussion of out-of-body experience, who among us had experienced it personally, and what you told the patients who came in all worried after experiencing it; we decided it was "normal but something we don't understand"). And crazy people often report experiences with the paranormal (whatever that is; the crazies' experiences are much more diverse and atypical than the "normals"). In my lifetime as a student of medicine, I've never seen a disease that was considered "organic" in the 1950's prove to be "psychosomatic", but I've seen the opposite many times (hypertension, asthma, stomach ulcer, inflammatory bowel disease, atopic eczema, blepharospasm, and torticollis are only the beginning; there are even genetic animal models for folks like your instructor who strongly prefer to keep our fingernails super-short). And a good psychiatrist, seeing mental illness as arising from brain, appreciates both the cognitive-insight and the pharmacological therapies (Science 275: 1586, 1997).

CNS TUMORS

Brain Tumors Radiology-Pathology Uniformed Services

Brain Tumors I From Chile In Spanish

Brain Tumors II From Chile In Spanish

Brain Tumors III From Chile In Spanish

INTRODUCTION

You are familiar with the old expression "malignant by location". This is especially applicable to brain tumors, which may be histologically benign but difficult to remove surgically without damaging important things.

Risk factors for brain tumors are, for the most part, obscure. Trauma (including having been a boxer) and lymphangiomyomatosis (the lung disease) seems to be risk factors for meningiomas. You know Turcot's anti-oncogene deletion syndrome as a risk factor for gliomas, and of course, previous radiation (i.e., for acute lymphoblastic leukemia or solid cancers of the brain or its coverings) is implicated, too (Cancer 67: 392, 1991).

Just as brain cells may be difficult to distinguish, the histogenesis of most of these tumors is seldom obvious from morphology.

All gliomas are best considered malignant, though some are more malignant than others.

Malignant primary brain tumors are locally invasive, and may spread via the spinal fluid ("neuraxis dissemination", J. Neurosurg. 83: 67, 1995), but very seldom metastasize to the rest of the body.

"Psychiatric" changes are common as the first signs of a brain tumor. Frontal lobe tumors seem to produce personality changes and/or depression and/or loss of interest, while temporal lobe tumors seem to produce hallucinations and/or mania and/or amnesia and/or "panic attacks" (West. J. Med. 163: 19, 1995). Charles Whitman, the University of Texas sniper, had a glioma involving his frontal and hypothalamic areas.

Numbers to remember: Around 1% of random autopsies includes a primary brain tumor. In adults, 70% of primary brain tumors are supratentorial. In children, 70% of brain tumors are infra-tentorial.

* Junk science! You're heard the pop claim that cellular telephones cause brain tumors. The idea is that "radiation causes cancer"... or perhaps somebody realized that juries in junk lawsuits won't understand the difference between microwave radiation that makes cell phones work and ionizing radiation that damages the genes. In the most recent study, people who use cell phones have only 9/10 of the risk of getting an acoustic neuroma than do non-users, there is no correlation with duration or total use, and the neuroma is somewhat more likely to be on the opposite side. Neurology 58: 1304, 2002. I have already drawn the obvious conclusion.

GLIOMAS

The common tumors arising within the brain itself.

Service pathologists are pretty good at telling them apart. One recent study of inter- and intra-observer variabilty drew the incidental conclusion that oligodendrogliomas are more common than the books say -- making up about 25% of gliomas (Cancer 79: 1381, 1997).

*The molecular biology was worked out in the 1990's. p53, as you'd expect, probably heralds the transition to high grade, and not surprisingly, loss of p53 induces greater sensitivity to procarbazine (i.e., the cells do not try to repair their DNA). Surprisingly, most of the more aggressive gliomas have amplification of the EGRF gene (Am. J. Path. 148: 1047, 1996; J. Neurosurg. 82: 841 & 847, 1995). p53 mutation is a grave prognostic indicator in pediatric gliomas, independent of everything else: NEJM 346: 420, 2002. Astrocytomas grow faster if they have trisomy 7 and/or monosomy 10 (Am. J. Clin. Path. 108: 166, 1997). Prognosticating low-grade gliomas using PCNA (proliferating cell nuclear antigen), MIB-1, and Ki-67 positivity: Cancer 76: 1809, 1995; Cancer 77: 373, 1996; Cancer 79: 849, 1996; for MIB-1 see below. Much more will be discovered.

*The great white-knuckle call in neuropathology today is "recurrent glioma vs. radiation necrosis" (J. Neurosurg. 82: 436, 1995). Nowadays we are doing molecular typing to solve this toughest of calls: Am. J. Clin. Path. 121: 671, 2004.

Astrocytoma / Anaplastic Astrocytoma / Glioblastoma multiforme

These are the most common primary brain tumors in adults (about 80%), and are a continuum of malignancy. There is a slight male predominance.

Astrocytomas tend to become more malignant with time, and ultimately most will probably become glioblastomas. And there is likely to be a mix when you examine the tumor.

Astrocytomas are poorly circumscribed, whitish brain tumors. Microscopically, they may recall protoplasmic, fibrillary, fibrous, or gemistocytic astrocytes, or grow as spindle cells or xanthoma-like cells, or (most often) present a mix.

Protoplasmic astrocytomas are perhaps the most familiar, with the tumor cells each bearing only a few processes, and a background of little holes ("microcystic"); these tumors cells actually look like stars ("astro", Am. J. Clin. Path. 103: 705, 1995).

*In "diffuse astrocytoma" every astrocyte in a region seems to turn neoplastic at once. In "gliomatosis cerebri" (which may be the same thing), the entire brain, especially the white matter, is invaded. I used to wonder about a virus infection; however, it's now quite clear that most of these are aneuploid, like true malignant tumors (Neurology 56: 1224, 2001; Ann. Neuro. 52: 390, 2002). Staining and possible molecular mechanisms: J. Clin. Path. 58: 166, 2005.

*Astroblastomas (odd name) exhibit perivascular pseudorosettes (J. Neurosurg. 83: 550, 1995).

New Daumas-Duport grading system: Count one for each of these criteria:

• nuclear abnormalities


• mitotic figures


• necrosis


• vascular endothelial proliferation ("glomeruloid tufts").

Grade I: Zero criteria
Grade II: One criterion
Grade III: Two criteria
Grade IV: Three or four criteria

* Today, the new World Health Organization system, a slight variation, seems to be gaining favor.

• Astrocytoma (grade II): Minimal analasia, rare or no mitotic figures
• Anaplastic astrocytoma (grade III): More disturbing anaplasia and/or more mitotic figures
• Glioblastoma (grade IV): Glomeruloid tufts and/or any coagulation necrosis and/or very ugly

{01497} astrocytoma
{01501} astrocytoma
{01503} astrocytoma
{01518} astrocytoma
{01531} astrocytoma
{15706} astrocytoma
{01504} astrocytoma
{01506} astrocytoma
{01507} astrocytoma

Astrocytoma Pittsburgh Pathology Cases

Astrocytoma "Cystic" / "Juvenile" WebPath Photo

Glioma Don't worry about what kind. WebPath Photo

Brainstem glioma Don't worry about what kind. WebPath Photo

Brainstem glioma Don't worry about what kind. WebPath Photo

Glioma Don't worry about what kind. WebPath Photo

Well-differentiated astrocytoma WebPath Photo

Astrocytoma WebPath Photo

Astrocytoma Hungary

Anaplastic astrocytomas ("grade 3"), unlike regular astrocytomas, have some anaplastic features.

Newer research on prognosticating astrocytoma behavior has focused on counting cells in growth phase -- typically by staining with MIB-1 antibody. These counts correlate strongly with aggressiveness (Cancer 79: 849, 1997; 82: 2459, 1998).

Simply counting the mitotic figures (rather than noting their presence or absence) has also proved a powerful prognosticator: Camncer 82: 1749, 1998.

Glioblastoma multiforme is a floridly malignant, variegated (many colors, many kinds of histology) tumor.

{01575} glioblastoma multiforme
{01576} glioblastoma multiforme, butterfly

Butterfly glioma KU Collection

Glioblastoma Multiforme Australian Pathology Museum High-tech gross photos

Glioblastoma Hungary

Cerebellar glioblastoma Hungary

Endothelial proliferation ("glomeruli", etc.; you can do a reticulin stain and it will make these areas stand out) and "palisading" of cancer cells around necrotic areas are typical.

Despite massive efforts, five-year survival rate is still near-zero, but even after careful examination, it occasionally happens: Cancer 98: 1645, 2003.

{01582} glioblastoma multiforme
{01584} glioblastoma multiforme, dead stuff
{01585} glioblastoma multiforme
{01587} glioblastoma multiforme, gemistocytes
{01596} glioblastoma multiforme, monster cells
{17721} glioblastoma multiforme

Glioblastoma Pittsburgh Pathology Cases

Glioblastoma WebPath Photo

Glioblastoma WebPath Photo

Glioblastoma WebPath Photo

Gliosarcoma Hungary

Gliosarcoma Pittsburgh Pathology Cases

Gliosarcomas exhibit both glial and mesenchymal differentiation; they often follow radiation (Cancer 75: 2910, 1995).

*The old canard about their mesenchymal component "arising from the proliferating endothelial cells of a glioblastoma" was recently refuted by some simple staining studies: Arch. Path. Lab. Med. 121: 129, 1997.

Adult astrocytomas always infiltrate the surrounding tissue, and extend far beyond the obvious tumor mass.

Growing astrocytoma cells from the "histologically normal" tissue far away from the mass is easy: J. Neurosurg. 86: 525, 1997.

Brainstem gliomas

These are pediatric, malignant astrocytomas, which tend to involve the brainstem and turn into glioblastomas. Many cures are obtainable with radiation.

Juvenile pilocytic astrocytomas (J. Neurosurg. 82: 536, 1995; Cancer 72: 1335, 1993)

These are indolent tumors that typically involve the cerebellums of children. Even if the histology looks nasty, they are likely to grow only very slowly.

"Pilocytic" (hair-like) astrocytes are long and thin, and "Rosenthal fibers" are typical.

* Although these are often cured, patients grow up to be substantially less happy then their counterparts. The teenaged years, during which the young person realizes that he/she will never be able to keep up with peers in many different aspects of life, are especially stormy (J. Neurosurg. 96: 229, 2002).

{01542} juvenile pilocytic astrocytoma

Pilocytic astrocytoma Pittsburgh Pathology Cases

Pilocytic astrocytoma Pittsburgh Pathology Cases

Pilocytic astrocytoma Lacking Rosenthal fibers Pittsburgh Pathology Cases

Juvenile Pilocytic Astrocytoma Pittsburgh Illustrated Case

Oligodendrogliomas

These are uncommon gliomas of adults that typically occur in the centrum semiovale.

Grossly, they are gray and soft, often with little calcifications (ask a radiologist). Microscopically, the tumor is sheets of fried-egg cells, with round central nuclei and clear cytoplasm. Often there is a admixture of astrocytoma.

{01618} oligodendroglioma
{01620} oligodendroglioma
{01624} oligodendroglioma with calcifications (shown reddish-purple here)
{01626} oligodendroglioma with calcifications

Their behavior is unpredictable.

Ependymomas

These arise from the single layer of glia that lines the ventricles.

Pediatric ependymomas generally arise in the fourth ventricle. As you'd expect, they can cause hydrocephalus and are tough to excise.

{01642} ependymoma (trust me)
{15699} ependymoma (trust me)

Adult ependymomas are the common spinal cord glioma (astrocytomas less common -- J. Neurosurg. 83: 590, 1995.)

Pathologists talk about rosettes (little attempts to make neural tubes, but without a whole lot of scuzz in the middle as in a Homer-Wright rosette of medulloblastoma-neuroblastoma), pseudo-rosettes (around vessels), and blepharoplasts (the basal bodies of cilia, visible by * PTAH stain).

The histologic grade is evidently the major prognostic indicator: Cancer 100: 1230, 2004).

{01650} ependymoma
{1654} ependymoma
{01656} ependymoma, blepharoplasts

Anaplastic ependymoma Pittsburgh Pathology Cases

Ependymoma WebPath Photo

Ependymoma WebPath Photo

Ependymoma WebPath Photo

Ependymoma Hungary

*Childhood ependymomas and choroid plexus papillomas and SV40 virus (or its kin): NEJM 326: 988, 1992. This is holding up for other gliomas as well (Cancer 94: 1037, 2002; J. Neurosurg. 95: 96, 2001; Am. J. Med. 114: 675, 2003), but there's considerable doubt that this is actually a pathogen; more likely it's reactivation. You already know that SV40 contaminated some of the early polio vaccines.

* Ependymomas and choroid plexus papillomas expressing genes from the JC virus: J. Neurosurg. 102(S3): 294, 2005.

* Myxopapillary ependymomas arise from the filum terminale and are histologically distinctive.

{01665} * myxopapillary ependymoma
{01666} * myxopapillary ependymoma

Myxopapillary ependymoma

WebPath Photo

Sub-ependymomas are the most indolent of gliomas, arising from the ventricular walls. The classic case is an asymptomatic mass found at autopsy in the fourth ventricles of an older man. These tumors can occasionally be symptomatic (rays: AJR 165: 1245, 1995).

Choroid plexus papillomas may occur at any site in the ventricles, and are most common in children. They are generally benign, but cause problems by overproducing spinal fluid or blocking its flow.

* Future pathologists: Distinguish these from metastatic carcinoma by their being GFAP positive! The rare choroid plexus carcinomas have anaplasia and local invasion.

* You will be bewildered by the current experiments using herpes simplex virus, its thymidine kinase, and gancyclovir to infect and then selectively kill glioma cells. Suicide gene therapy. J. Neurosurg. 79: 729, 1993; J. Neurosurg. 81: 256, 1994, Proc. Nat. Acad. Sci. 93: 3525, 1996. There is now talk of occasional cures (Neurology 58: 1109, 2002).

Melanotic choroid plexus papilloma Pittsburgh Pathology Cases

Choroid plexus carcinoma Pittsburgh Pathology Cases

NEURONAL TUMORS

Neuroblastomas can arise in the cerebral hemispheres of children, and ganglioneuromas and gangliogliomas (i.e., a mix of neoplastic neurons and glia from a common clone: Am. J. Path. 151: 565, 1997) can be found in the CNS, too.

Ganglioglioma
Pittsburg Illustrated Case

Primitive neuroectodermal tumors ("PNET's") in the CNS itself are generally medulloblastomas.

These typically arise in the cerebellum of younger people ("the commonest posterior fossa tumor in children"), and tend to spread up and down the neuraxis by way of the spinal fluid.

These tumors strike at random. Turcot's (familial polyposis plus brain tumors) and the basal cell nevus syndrome (PTCH antioncogene deletion) are the two known risk factors.

{31933} medulloblastoma, cord
{01677} medulloblastoma
{01686} medulloblastoma
{01687} medulloblastoma (cord and dura)
{18761} medulloblastoma

Medulloblastoma KU Collection

PNET of brain Pittsburgh Pathology Cases

Medulloblastoma WebPath Photo

Medulloblastoma WebPath Photo

Medulloblastoma Hungary

Dysembryoplastic neuroepithelial tumor Pittsburgh Pathology Cases

Medulloblastoma
Electron micrographs
VCU Pathology

The new systems for grading correlate quite well with outcome (Cancer 94: 552, 2002).

Neuropathologists point out that these cells show both neuronal (Homer-Wright rosettes, pseudo-rosettes) and glial (GFAP-positive) differentiation. The various histologic types of medulloblastomas: Am. J. Surg. Path. 16: 687, 1992.

Medulloblastomas may excite a desmoplastic, fibrous response ("fibrous medulloblastomas", the old * "cerebellar sarcoma").

The tumor is radiosensitive, or may be found early enough to enable a surgical cure. There is about a 50% 5-year survival.

There is considerable interest right now in healthy diet / supplementation for mother while the child is unborn as protective against PNET's of the brain. An alleged strong link to nitrosamines fizzled, but folate-vitamins-iron were found to significantly reduce the risk. Definitely stay tuned (NEJM 329: 536, 1993).

*Somebody FINALLY said it: "The time has come to discard the archaic concept of 'cell of origin'" (Am. J. Path. 144: 444, 1994). Medulloblastoma (nobody's ever identified a "medulloblast") is one good example.

Polar spongioblastoma Cordouroy tumor Pittsburgh Pathology Cases

Neurocytoma Pittsburgh Pathology Cases

MENINGIOMAS (Lancet 363: 1535, 2004)

These are tumors of the arachnoid cap cells, and make up about 20% of primary brain tumors and around 25% of spinal canal tumors. Most occur where there are arachnoid granulations (i.e., next to the falx, or on the lesser wing of the sphenoid bone. However, they can occur on any surface in the head.

Patients are usually middle-aged, and there is a slight female predominance.

The basic biology of these lesions is obscure. There is a link to head trauma (Science 254: 1131, 1991) and many meningiomas exhibit monosomy 22 (Science 254: 1153, 1991; Cancer 77: 2567, 1996). They express the progesterone receptor, and RU-486 (mifepristone, "the abortion pill") is now in use for nonresectable meningiomas (the weird politics: JNCI 89: 912, 1997).

* The old-fashioned high-dose dental x-rays probably did cause meningiomas: Cancer 100: 1026, 2004.

Grossly, the tumors are usually firm, and solid, perhaps with a whorly pattern on cross section.

Future radiologists: Look for thickening of the bone over the meningioma.

Microscopically, there may be primarily whorls and nodules (as in healthy arachnoid; this is the syncytial meningioma), or spindle cells (fibroblastic meningioma), or intermediate forms (transitional meningiomas; look for psammoma bodies).

You can find mixtures of the above, various degenerative changes, or occasionally, evidence of malignancy.

All about the histopathology of meningioma and its applicability to prognosis: J. Neurosurg. 77: 616, 1992; Cancer 85: 2046, 1999.

*Occasionally, a hemangiopericytoma will look grossly like a meningioma. These tend to be more aggressive.

Meningiomas can generally be removed for cure; recurrences may be more and more abnormal cytologically.

* In this era of CT scans, we are discovering lots of "incidental asymptomatic" meningiomas. Whether to operate: J. Neurosurg. 92: 766, 2000 -- tough call.

Multiple meningiomas: Think of neurofibromatosis; not surprisingly, the NF2 gene on chromosome 22 is often mutated in its conserved region in any meningiomas (Am. J. Path. 146: 827, 1995).

*Meningiomatosis: Lots of little meningiomas around proliferating blood vessels, forming a mass that needs to be removed, since it causes seizures (Arch. Path. Lab. Med. 119: 1061, 1995; Arch. Path. Lab. Med. 120: 587, 1996).

{00221} meningioma, gross
{31996} meningioma
{00224} meningioma, micro
{09459} meningioma, with psammoma bodies
{09460} meningioma
{09462} meningioma

Meningioma Pittsburgh Pathology Cases

Meningioma WebPath Photo

Meningioma WebPath Photo

Meningioma WebPath Photo

Meningioma WebPath Photo

Resected meningioma WebPath Photo

Meningioma Pittsburg Illustrated Case

Meningioma WebPath Photo

Meningioma WebPath Photo

Meningioma WebPath Photo

Meningioma Hungary

Meningioangiomatosis Pittsburgh Pathology Cases

Fibrous tumor of the meninges Pittsburgh Pathology Cases

OTHER BRAIN TUMORS

Primary non-Hodgkin's lymphomas of the brain ("microgliomas" is an archaic misnomer): reviews Cancer 74: 1383, 1994; J. Neurosurg. 82: 558, 1995 (HIV negative cases); Am. J. Clin. Path. 121: 246, 2004 (post-transplant CNS lymphomas)

Transplantation and AIDS have rendered this an important topic. Epstein-Barr virus is usually present (and strongly suspect as a cause) in transplant and AIDS lymphomas, though not in sporadic brain lymphomas (Neurology 43: 1591, 1993).

You already know that EBV and herpes 8 (Kaposi's sarcoma virus), together or separately, are infamous causes of non-CNS lymphomas in the immune-compromised. Herpes 8 seems to be exonerated, however, as a cause of CNS lymphomas, being present only in the bystander cells (J. Clin. Path. 54: 617, 2001).

* Not surprisingly, the rate of primary CNS lymphoma is way down over the past few years (Cancer 95: 193, 2002), except among very old folks. Why?

* The concern that polyomavirus may cause CNS lymphomas has been dismissed by molecular biology: Neurology 63: 1299, 2004.

A host of diffferenttypes of lymphoma histologies have been reported, with a tendency nowadays toward bigger, meaner-looking cells (Blood 96: 4084, 2000). These tumors tend to follow vessels (check the reticulin pattern; reticulin is likely to be rather dense in these tumors, which helps us tell they are not just inflammation). Death usually results in a few weeks to a year two.

*We used to think that these tumors mostly stayed local in the CNS, and that systemic lymphomas can't present as apparently-localized CNS lesions. Some authors now urge staging for all "primary CNS lymphomas" (Cancer 77: 827, 1996).

Hemangioblastomas are distinctive tumors of the cerebellum that mimic very low-grade renal cell carcinoma (!).

Like renal cell carcinomas, these tumors even produce erythropoietin and cause polycythemia. Patients generally have Von Hippel-Lindau anti-oncogene deletion syndrome. Look for impressive blood vessels, and * foam cells.

* The VHL locus in health has to do with producing erythropoietin in response to hypoxia, so probably this makes sense (Blood 92: 3388, 1998).

* Futre pathologists: These tumors even resemble renal cell carcinoma by their positivity for ezrin, an epithelial cell marker responsible for anchoring actin to the cell membrane (Am. J. Path. 148: 367, 1996). Every once in a great while, a hemangioblastoma occurs outside the cerebellum (Arch. Path. Lab. Med. 127: e382, 2003).

{01878} hemangioblastoma
{01882} hemangioblastoma
{01884} hemangioblastoma

Chordomas are uncommon tumors of the vestigial notochord (ask a comparative anatomist) that occur at the sacrum or clivus. Some are to bland histologically as to be considered "malignant only by location", but even these are deadly, taking out the cranial nerves progressively until death ensues.

* Don't worry about the histology, which features "bubble cells". Pathology update Cancer 93: 40, 2001. Once uniformly lethal, new radiation technicques are giving apparent cures for a few patienst: J. Neurosurg. 91: 432, 1999, others.

{01897} chordoma (note the resemblance to primitive cartilage)
{01899} chordoma
{01906} chordoma ("bubble cells")

Coccygeal chordoma Pittsburgh Pathology Cases

We have already mentioned colloid cyst of the third ventricle as a cause of hydrocephalus.

Craniopharyngiomas: Rathke's pouch tumors in the pituitary-hypothalamic region. As before, look for machine-oil cysts grossly and the recapitulation of embryonic teeth (ameloblasts, calcium, squames) microscopically.

{01855} craniopharyngioma
{01858} craniopharyngioma
{01860} craniopharyngioma
{01861} craniopharyngioma
{10962} craniopharyngioma
{1857} craniopharyngioma cyst fluid

Hypothalamic hamartoma Pittsburgh Pathology Cases

Craniopharyngioma KU Collection

Craniopharyngioma Notice the benign squamous pearl KU Collection

Teratomas (Am. J. Ob. Gyn. 173: 226, 1995), dermoids (Arch. Path. Lab. Med. 119: 371, 1995), lipomas, epidermal cysts, and so forth may be seen, especially within congenital (?) defects in the corpus callosum.

Germinomas of the pineal, hypothalamus, and elsewhere ("midline!") usually mimic seminoma, less often embryonal cell carcinoma, choriocarcinoma, and/or other testicular cancers; the more primitive-looking the cancer (i.e., not seminoma), the worse they behave (J. Neurosurg. 86: 446, 1997).

Hypothalamic germinoma
Electron micrographs
VCU Pathology


Metastatic cancer (contrary to "Big Robbins") is by far the most common brain tumor.

The most common primary sites are lung (by far; seeking the primary ARJ 168: 1339, 1997), breast, melanoma, kidney, and gut.

Around 50% of smokers dying of lung cancer have "brain mets", and these are not uncommonly the actual cause of death.

The best place to find them is at the corticomedullary junction (perhaps the cancer cells get trapped as the vessels narrow at their entry to the white matter -- once your instructor's pet theory, now confirmed Cancer 77: 1551, 1996). There is generally much edema around a "met", and treatment just to reduce the edema helps.

{09442} melanoma
{29393} breast cancer metastasis

Metastatic Malignant Melanoma Virginia Pathology Cases

Metastatic lung cancer WebPath Photo

Metastatic melanoma Hungary

Metastatic melanoma in brain WebPath Case of the Week

Paraganglioma of the filum terminale Pittsburgh Pathology Cases

Metastatic cancer in the spinal canal often encases the spinal dura and impinges on nerve rootlets. The meninges (cord and brain) may also be packed with a thin layer of cancer ("meningeal carcinomatosis", a diagnosis typically made only at autopsy.)

*Surgical excision of a solitary metastasis with hope for a long-term survival: J. Neurosurg. 83: 605, 1995, Chest 109: 271, 1996; Cancer 78: 711, 1996. Happens, rare; usually colon primary.

Don't forget the paraneoplastic autoimmune CNS syndromes:
• Sudden blindness? Oat cell carcinoma. (* Antibodies against recoverin in the retina).
• Stiff-person syndrome? (* a paraneoplastic syndrome in breast cancer features antibodies against amphiphysin Neurology 50: 94, 1998). You recall that the ordinary form features antibodies against glutamic acid decarboxylase instead)
• Opsoclonus-myoclonus (various antibodies)
• Limbic encephalopathy (various antibodies)
• Cerebellar ataxias (various antibodies)

OTHER NERVOUS SYSTEM DISEASES

DEMYELINATING DISEASES

Multiple sclerosis is a common, dread neurologic disease in which myelin is lost successively in many ("multiple") plaques throughout the white matter.

Although "MS" is clearly autoimmune, the exact etiology remains unclear. Review Arch. Neuro. 58: 1975, 2001.

Patients are typically young adults. "Big Robbins" points out a strong Caucasian predominance and weak familial tendency and links to certain HLA antigens (Neurology 43: 548, 1993; Arch. Neurol. 50: 256, 1993). More interestingly, adults who spent their first 15 years entirely in the tropics are almost never affected.

Some familial MS links to the gene for myelin basic protein (Lancet 340: 987, 1992 Finland, Neurology 61: 520, 2003 other caucasians), an antigen that seems to be a principal target for immunity in MS. T-cells rearranged to attack myelin basic protein are abundant in MS lesions in humans, and rat T-cells bearing the same rearrangement cause experimental allergic encephalomyelitis in rats (both Nature 362: 68, 1993). Other familial MS is not linked to the myelin basic protein gene (Lancet 341: 1179, 1993, more since).

*Glial cells in MS express inappropriate HLA antigens on their surfaces. Astrocytes at the edges of lesions express MCH class II (HLA-DR), which is bizarre. They also express MCH class I antigens in and around the lesions (Arch. Neuro. 48: 1244, 1991).

Biopsy material from fresh MS plaques shows the oligodendroglial injury (not death) is the early injury in multiple sclerosis. They die at the center of plaques, and proliferate at the edges, and they can re-myelinate if they recover (Mayo Clin. Proc. 68: 627, 1993).

Ask a virologist about links to viruses. The usual suspects of past years have been Epstein-Barr virus (the most persuasive, I've thought for many years: Epidemiology 11: 220, 2000; now JAMA 289: 1533, 2003; molecular mimicry NEJM 349: 185, 2003; high EBNA-1 IgG titer as a teen, an aberrant response, predicts future MS risk JAMA 293: 2496, 2005 and Neurology 62: 2277, 2004), human measles virus, herpes 6, herpes 7, and canine distemper virus.

* Support for the idea that Epstein-Barr virus is the culprit comes from the finding that 100% of MS patients are seropositive for this virus, usually at relatively high titer, and that the mechanism of molecular mimicry between myelin and EBV antigen now seems understood (NEJM above).

HHV6 is now being identified as replicating in active MS plaques of many (but not all) MS patients, but not in control brains. This is another bug that it's reasonable to think is ubiquitous in the tropics and less common in chilly regions. Since the main article (Science 278: 710, 1997), the work has been widely replicated, but many MS patients have no sign of HHV6.

The mouse model uses (* Theiler's) virus, and mice that go on to get mouse-MS are those in which infection induces lasting expression of MHC-I antigens on brain cells: Mayo Clin. Proc. 67: 829, 1992.

* A claim from anti-immunization activists and tort layers about hepatitis B vaccine and other immunizations causing MS flopped: NEJM 344: 319 & 327, 2001.

*Nitric oxide is produced in bulk in the acute lesions (confirmed Am. J. Path. 158: 2057, 2001), and nitric oxide scavengers almost totally prevent / treat one of the mouse models (Proc. Nat. Acad. Sci. 94: 2528, 1997). Further... the active species may be peroxinitrile, which is scavenged by uric acid (!), and large registries show no patient with both MS and gout (Proc. Nat. Acad. Sci. 95: 675, 1998). Follow-up with an animal model: Proc. Nat. Acad. Sci. 99: 16303, 2002. Definitely stay tuned.

Lesions form episodically in MS, contributing to its picture of exacerbations and remissions.

"Sclerosis" in this context means loss of myelin and oligodendroglia, with preservation of axons and massive proliferation of astrocytes. The lesions are sharply-circumscribed, yellowish or grayish (pink if very active), firm areas. The can occur anyplace in the CNS; the favorite site is adjacent to the ventricles, often symmetrically.

Actually, axons tend to be lost specifically in the long tracts: Brain 127: 1009, 2004.

Microscopically, demyelination begins around the blood vessels. During the active phase, the plaques are packed with T-helper and T-suppressor cells, and presumably there is some autoimmune component to the pathogenesis (providing the rationale for immunosuppression using ACTH).

In the burned-out, chronic lesions, there are still oligodendroglia with processes wrapped around the axons, but they do not remyelinate the axons; the axons themselves appear abnormal, with thin and thick areas (NEJM 346: 165 & 199, 2002).

{01428} multiple sclerosis, myelin stain of white matter (note areas where the blue-staining myelin is lost)

{31776} multiple sclerosis
{31779} multiple sclerosis
{31797} multiple sclerosis
{31994} multiple sclerosis
{00527} demyelination in the spinal cord

Multiple sclerosis Autopsy brain KU Collection

Multiple sclerosis Pittsburgh Pathology Cases

Multiple Sclerosis Tom Demark's Site

Demyelination in multiple sclerosis WebPath Photo	Demyelination in multiple sclerosis WebPath Photo
Multiple sclerosis Hungary	Multiple Sclerosis Pittsburgh Illustrated Case

*Very bad MS simulates brain tumors, grossly and microscopically (Am. J. Surg. Path. 17: 537, 1993 for the distinction).

Most (not all) cases of MS present as varying neurologic deficits that come (and go) unpredictably.

Key symptoms of this protean disease include optic nerve involvement ("retrobulbar neuritis"; "the patient sees nothing and the doctor sees nothing"), problems with coordination, paresthesias, weakness in a limb, and problems with conjugate eye movement. Usually intellect is preserved, especially early in the disease.

Many (not all) patients progress to severe disability as sites of injury accumulate. The spectrum of disability (1/3 little, 1/3 moderate, 1/3 severe): QJM 83(300): 325, 1992. * MS costs $35,000 per year (Arch. Phys. Med. Rehab. 74: 26, 1993).

Treating MS mostly involves immunosuppression.

Interferon-beta (Br. Med. J. 310: 345, 1995) has become standard.

* Cladribine (2-chloro-deoxyadenosine), a not-very-toxic lympyhocyte suppressor: Proc. Nat. Acad. Sci. 93: 1716, 1996. This is finding some use but remains "unproven", with conflicting results.

Glatiromer, a mix of short peptides made of alkaline amino acids (J. Clin. Immuno. 109: 641, 2002; Neurology 57: 731, 2001), helps in the treatment of MS, probably by simulating myelin basic protein. This and/or interferon-beta Lancet 359: 1453, 2002) and/or high-dose intravenous immunoglobulin (Arch. Neuro. 56: 661, 1999; mechanism unknown) is now the mainstay of therapy.

In fact, it seems as if interferon often keeps very-early MS from fully declaring itself: Lancet 357: 1576, 2001.

Natalizumab, the α₄ integrin inhibitor ("Antegren", "Tysabri"), seems to be a breakthrough for multiple sclerosis therapy: NEJM 348: 15, 2003. It was withdrawn in February 2005 after two reports of progressive multifocal leukoencephalopathy.

* A regimen of vitamins and carotenoids completely fails to affect the course of multiple sclerosis: Neurology 57: 75, 2001.

MS variants mentioned in your texts:

Marburg MS: Rapidly progressive

Devic's disease: Aggressive form with retrobulbar neuritis and large lesions in the spinal cord (i.e., blindness and paralysis)

* Uh... before you diagnose multiple sclerosis, it's good to be sure that you're not really dealing with Sjogren's encephalopathy, Hashimoto's encephalopathy (draw an anti-microsomal antibody, they may be euthyroid), Beçet's, or Lyme disease.

* A lone activist ("Nancy Markle", an internet alias; she has never come forward) is behind the flood of (fabricated) reports of aspartame causing multiple sclerosis (also lupus, brain tumors, and so forth). Anybody who's completed a college biochemistry course will recognize the bunko artistry ("Methanol causes metabolic acidosis", "Methanol, phenylalanine and aspartic acid are all neurotoxins", etc., etc.) In 1999, when "Ms. Markle" published a made-up story about the Multiple Sclerosis Foundation suing the FDA and the makers of aspartame, the MSF had to denounce her as a shameless liar; since her true identity is unknown, they could not take any further legal action. Is this a clever trick by a sugar-industry partisan? We'll probably never know. Update on the disinformation campaign: Br. Med. J. 329: 755, 2004.

Acute disseminated encephalomyelitis ("post-infectious encephalomyelitis"; "post-vaccinial encephalomyelitis") is a rare disease that tends to follow (by a few days to 2 weeks) one of the "childhood diseases" or one of the old-fashioned immunizations with lots of impurities (especially rabies). Coma rapidly develops; many patients die, but most recover with little or no residual difficulty. In fatal cases, there is striking demyelinization around the blood vessels. See Ann. Neurol. 33: 18, 1993 (by Dr. Kepes at K.U.) There really are not strict criteria for the diagnosis yet: Neurology 56: 1313, 2001.

Acute necrotizing hemorrhagic leukoencephalitis is a (fortunately rare) disease that tends to follow a minor viral illness. There is both perivenous loss of myelin, and hemorrhage and necrosis throughout the white matter. There is a heavy, mixed inflammatory infiltrate.

Acute Hemorrhagic Leukoencephalopathy
Pittsburgh Illustrated Case

*The disease strikes down a young doctor: South. Med. J. 87: 851, 1994 (scary reading).

Both of the above diseases are considered perivenous encephalomyelitis, autoimmune havoc against myelin (with type III immune injury in the severe variant). The animal model is experimental allergic encephalomyelitis, induced by injections of myelin basic protein; the disease can also be transmitted by T-cells specifically reactive for myelin basic protein Neurology 43: 1028, 1993.

Leukoencephalopathy following cancer therapy is coming to be more widely recognized. Chemotherapy and radiation are both capable of doing serious or even fatal damage (Neurology 62: 451, 2004). The problem appears weeks to months after the therapy.

Central pontine myelinolysis represents demyelinization (with axon preservation) in the central pons. The histology resembles multiple sclerosis.

Central pontine myelinolysis can be quite extensive and render a person "locked in".

Once mysterious (or attributed to alcohol abuse), we now believe this usually represents an unfortunate result of too-rapid correction of severe hyponatremia (uh oh, Doc....) Puzzle that one out! The new name is osmotic myelinolysis. I have seen this lesion three times in my autopsies; in each case, it was unexpected. (* This isn't the only possible cause: see J. Clin. Path. 44: 909, 1991). Review Mayo Clin. Proc. 76: 559, 2001 (replacing sodium "within recommended limits" doesn't guarantee safety). Picture NEJM 333: 1259, 1995.

Central pontine myelinolysis
Hungary

{31988} central pontine myelinolysis

OTHER METABOLIC DISEASES OF THE CNS

Subacute combined degeneration of the cord is a curious term for a curious lesion: destruction of the myelin and axons of the posterior columns of the spinal cord caused by vitamin B₁₂ deficiency.

Later, the brain and descending pathways are affected. This is a tragic disease to miss, since it's easy to administer the vitamin.

The brain damage can be permanent.

Now that food is supplemented with folic acid, we'll be seeing more of this. (Why?) A 14-year-old vegan gives herself spinal cord disease that thankfully is caught in time: Clin. Ped. 40: 413, 2001.

Hashimoto's encephalopathy, seen in about 1% of patients with Hashimoto's thyroiditis, involves the white matter underneath the cortex. It is now clear that the pathology includes an immune-based lymphocytic vasculitis You treat it with thyroid replacement and glucocorticoids. Reviews: Neurology 49: 623, 1997. Neurology 61: 1124, 2003.

Alcoholism probably isn't good for the brain all by itself. But the most famous sequelae (Wernicke-Korsakoff) are the result of thiamine deficiencies (Wernicke's from a prolonged fast: For. Sci. Int. 47: 17, 1990).

One-night drunkenness and chronic alcoholism have no known morphologic counterparts.

*You'll learn in your "Psych" unit about brain-waves that are markers for not-learning-from-bad-experiences, etc., etc. Your lecturer, like possibly even some of you, had a few semi-bad experiences with alcohol as a college frosh. Your lecturer then said "To heck with this", and now rarely drinks. By contrast, the future problem drinker doesn't learn.

Cerebellar vermal degeneration (better than "atrophy"; * superior aspect is most heavily involved) is typical of chronic alcoholism, but is nonspecific.

* "Bergmann gliosis" merely refers to astrocytes replacing the lost Purkinje cells, in alcoholism or whenever they are lost in large numbers.

Does the "moderate drinker" really get more cortical atrophy in old age? Yes! -- Stroke 32: 1939, 2001. No! -- J. Neur. N. Psy. 71: 104, 2001. Definite maybe! -- Alc. Clin. Exp. Res. 22: 998, 1998.

{17659} superior vermal atrophy

Superior (anterior) vermal atrophy

WebPath Photo

* Marchiafava-Bignami disease is a mysterious ailment, mostly affecting alcoholics and (less often) anorectics and the badly-neglected.

The deep white matter of the cerebral hemispheres (centrum semiovale, and especially the corpus callosum) demyelinates and may even undergo necrosis.

Nobody knows the cause. It's reported mostly from Europe, and used to be linked epidemiologically to Italian red wine. Perhaps an adulterant (arsenic?) was the cause.

Contrary to classic teaching, the disease is often reversible with good nutrition and cessation of drinking. Great photo NEUM 351: e10, 2004.

{31986} Marchiafava-Bignami

Marchiafava-Bignami
Hungary

In suspected Wernicke-Korsakoff, look in the mammillary bodies and periventricular gray of the diencephalon for bleeds and/or gliosis.

{31763} Wernicke's
{31985} Wernicke's
{31985} Wernicke's

Wernicke's From Chile In Spanish

Wernicke's WebPath Photo

Blood alcohol levels (gm/dL).... 0.05-0.1... happy 0.1-0.2... drunk 0.2-0.35... kisses mother-in-law, shoots best friend 0.35 & up... books say "coma & death"; many are still driving

Methyl alcohol causes necrosis of the retinal cells (ganglion cells, rods, cones). In acute fatal cases, there is cytotoxic edema and necrosis of the entire brain.

{31984} methyl alcohol poisoning. Not a pretty sight.

Reye's syndrome brains show only cytotoxic edema and perhaps Alzheimer II glia.

Carbon monoxide encephalopathy is often followed (in severe cases that survive for some months) by necrosis of the globus pallidus (less often, the hippocampus, Purkinje cells, and white matter).

{31751} carbon monoxide after-effects
{18751} carbon monoxide after-effects
{31742} carbon monoxide after-effects

*One of your lecturer's friends in medical school suffered this catastrophe after saving five people from a burning building. After recovering from coma, he had major motor problems.

Methotrexate encephalopathy causes necrosis of the white matter. Look for mineralization of the axons.

Arsenic poisoning produces petechiae throughout the deep brain substance.

{00206} fatal arsenic poisoning
{00209} fatal arsenic poisoning

Manganese toxicity selectively affects the motor system, and produces parkinsonism-plus-dystonia ("strut like a rooster"). However, it does not work on the substantia nigra, but at some site farther down, probably the globus pallidus (Neurology 45: 1199, 1998).

* The folks at KU actually have six welders sick with this, so it's not something to overlook (Neurol. 62: 730, 2004.



* Manganese is actually an essential nutrient. In 1999, the Environmental Protection Agency started a flap about possible toxicity from manganese and/or its organic derivative (used in gasoline) in drinking water (Neurotoxicology 20: 379, 1999). Among other things, the article describes asterixis as "Parkinson-like symptoms". I'd put this in a class with the EPA's "agent orange" and "radon in the homes" pronouncements -- shouting "Fire!" where there is none. Nowadays, mainstream science dismisses the EPA as a mere mouthpiece for politicians with no ability to do, or interest in doing, real science (Nature 412: 677, 2001, more).

Wilson's disease features copper deposition, especially in the basal ganglia.

Wilson's is probably several diseases, and some patients have primarily neurologic disease while others have primarily hepatic disease.

Bad Gaucher's disease, Hunter's disease, Hurler's disease, Sanfilippo's disease, Tay-Sach's disease, and Niemann-Pick's disease feature intra-neuronal storage of their respective products, and eventually loss of mentation.

Also worth remembering are Lesch-Nyhan and phenylketonuria. Neither is a storage disease, but both are inborn errors of metabolism with serious effects on the nervous system.

Leigh's subacute necrotizing encephalomyelopathy (as bad as it sounds) is the result of any of at least 14 different deficiencies in cytochrome C oxidase.

Familial myoclonus epilepsy is several illnesses.

"Lafora disease" features Lafora bodies in the neurons and (convenient for pathologists) sweat glands (Neurology 61: 1611, 2003). * Genes EPM2A/Laforin or EPM2B (Nat. Genet. 35: 125, 2003)

* Another form (not the Lafora body kind) is caused by mutant cystatin (cystine protease inhibitor): Nature 381: 26, 1996.

The leukodystrophies feature bad myelin, rather than demyelinization; typically, the diseases are autosomal recessives and there is problem breaking down myelin.

Metachromatic leukodystrophy ("sulfatide lipidosis") is a deficiency in aryl-sulfatase A. The metachromasia is due to sulfatide accumulation.

* Marrow transplantation is being tried for these people with some success (J. Ped. 133: 129, 1998.

{31803} metachromatic leukodystrophy patient
{31807} metachromatic leukodystrophy, gross
{31981} metachromatic leukodystrophy, micro. The blue dye stains the metachromatic stuff pink.

* Zellweger's is caused by a lack of functioning peroxisomes in liver, brain, and kidney.

Krabbe's globoid cell leukodystrophy is a deficiency in galactocerebrosidase. There's bad myelin, with eventual loss of oligodendroglia, plus lipid-laden macrophages clustering around vessels.

* This is yet another disease for which marrow transplantation is currently being used.

{32004} Krabbe's globoid histiocytes

* Pelizaeus-Merzbacher disease, mutated protolipid protein of myelin, gets discussed a lot because the severe forms are in the "diff" of a profoundly retarded baby. Contrary to "Big Robbins", many adult-onset cases are known. Remember tiger-striping of the white matter.

Adrenoleukodystrophy is an X-linked disease in which cholesterol esters accumulate. We discussed the whole cruel "Lorenzo's oil" business (by now, it's clear that it doesn't do what it was supposed to do) under "Adrenal gland diseases". It is now being treated with some success using bone marrow transplantation (Lancet 356: 713, 2000).

* Canavan's disease, lack of aspartoacylase, features Alzheimer II glia all over the white matter. (Contrast states with elevated blood ammonia, where you see them best in the gray matter.)

Radiation necrosis of the brain sometimes occurs.

Acute radiation necrosis features widespread necrosis of cells, especially oligodendroglia and the granular cell layer of the cerebellum.

Delayed radionecrosis may occur in therapeutic-range radiation, after months or years.

In the white matter, all of the cells die. Whatever vessels remain exhibit radiation-type changes.

At the edges, look for axonal spheroids. It is likely to be worse if the patient has also taken methotrexate.

{01909} radiation necrosis

PERIPHERAL NERVE

Peripheral Nerve Text and pictures From "Big Robbins"

Peripheral Nerve Exhibit Virtual Pathology Museum University of Connecticut

Hydroxychloroquine neuropathy Pittsburgh Pathology Cases

Acute motor axonal neuropathy Pittsburgh Pathology Cases

Dysmyelination of peripheral nerve Wash. U., St. Louis Illustrated notes

Bell's Palsy EMBBS

Fiber type grouping Wash. U., St. Louis Illustrated notes

Chronic demyelination of nerve Wash. U., St. Louis Illustrated notes

Axonal loss Wash. U., St. Louis Illustrated notes

Axonal swellings Wash. U., St. Louis Illustrated notes

Nerve biopsy Wash. U., St. Louis Illustrated notes

The anatomic pathology of the peripheral neuropathies is the most arcane area in pathology. Don't worry about it.

Guillain-Barré syndrome (Lancet 352: 631, 1998; Lancet 363: 2136, 2004) is a relatively common (1 person in around 70,000 gets it per year), serious, generally non-fatal, autoimmune disorder of the motor roots.

Patients experience ascending paralysis and areflexia. If they can be supported through weeks or months of paralysis ("You see, I did hear everything you said!"), survival is the rule, though there may be some permanent weakness. In the 15% of cases in which death occurs, pathologists note demyelinization of the motor rootlets.

The disease typically follows some viral (notably CMV) or other (notably Campylobacter jejuni) infection. The good animal model involves immunizing creatures with P2-myelin antigen. Review: NEJM 326: 1130, 1992. The antigen itself is GQ1b, the same thing botulism and tetanus toxins bind to. Guillain-Barré variants involve local weakness: Arch. Neuro. 51: 671, 1994.

Therapy with intravenous IgG (Br. Med. J. 313: 376, 1996); this is now standard.

Other peripheral neuropathies form a bewildering array. Remember:

• alcoholism / thiamine deficiency (numb fingers and toes even after years of sobriety)
• diabetic neuropathy (often painful, dysautonomia common, complex etiology)
• lead poisoning (limp wrist? have you drunk moonshine?)
• arsenic / thallium poisoning (is there someone who doesn't like you / has an insurance policy on you? South. Med. J. 96: 632, 2003)
• Charcot-Marie-Tooth disease (hereditary selective atrophy of the lower extremities due to damage to myelin and/or axons of the peripheral nerves, sparing the neurons; there are at least four different genes that produce this syndrome: Neurology 42: 597, 1992; NEJM 329: 96, 1993; * the X-linked form is mutated connexin, the gap junction protein Science 262: 2039, 1993; the two classic types are mutated myelin proteins zero and 22: Proc. Nat. Acad. Sci. 90: 10856, 1993; a new variant Nat. Gen. 18: 382, 1998; yet another Am. J. Hum. Genet. 72: 722, 2003.)
  * Ascorbic acid helps an animal model: Nat. Med. 10: 396, 2004.
• *Kugelberg-Welander disease ("spinal muscular atrophy III"; gradual disappearance, first obvious in the teens, of anterior horn cells with eventual profound weakness)
• Werdnig-Hoffman disease ("spinal muscular atrohpy I"; hereditary disease with disappearance of anterior horn cells early in life); same locus as Kugelberg-Welander (SMN)
• paraneoplastic neuropathies (many variants)
• autoantibodies against acetylcholine receptors in the ganglia produce an autonomic neuropathy: NEJM 343: 847, 2000.
• hereditary sensory neuropathy (* misdiagnosed as "proof of child abuse", of course: Pediatrics 93: 842, 1994)
• after torture "intended not to leave marks", as in the limb-constriction devices used on U.S. servicemen in Vietnamese POW camps JAMA 276: 375, 1996.
• Bell's palsy (facial nerve palsy) has many causes, including old zoster infection. Most recently, a quacky intranasal 'flu vaccine caused an epidemic in Switzerland: NEJM 350: 896, 2004. Most often, Bell's palsy is idiopathic.
• chronic inflammatory demyelinating polyradiculoneuropathy, a mixed sensory and motor neuropathy that lasts for several years and is very debilitating; look for myelin loss and onion bulbs;
• Gulf War neuropathy in soldiers returning, very likely from the botulinum and anticholinergics given for protection from Saddam Hussein's weapons of mass destruction (Br. Med. J. 312: 797, 1996 -- your lecturer isn't an expert here but thinks it's easy to believe). Neuropathies are hard to diagnose, when there's a functional overlay it gets harder. Stay tuned on this.
  Gulf war syndrome update: BMJ 318: 274, 1999; a subtype perhaps with basal ganglia atrophy Arch. Neurol. 57: 1280, 2000; Radiology 215: 807, 2000. No clear single cause. Patients with "impaired cognition" are especially likely to remember having used flea collars; patients with "confusion-ataxia" and patients with "central pain" are especially likely to remember having been made very sick by pyridostigmine, suggesting some biochemical quirk.

*For painful neuropathies, try topical capsaicin, the stuff in hot peppers (it acts by opening sodium and calcium channels, and somehow depletes substance P).

Neurilemmomas ("schwannomas") arise from the fibrous tissue surrounding nerve bundles. The nerve is at the edge of the lesion.

As a result, the nerve runs along the edge of the tumor, and resection is generally possible.

Ask any pathologist to show you "Antoni A" (palisaded spindle cells forming "Verocay bodies", supposedly in imitation of Pacinian corpuscles), and myxoid "Antoni B" areas.

{01846} schwannoma
{01849} schwannoma
{15694} eighth-nerve tumor

Peripheral Nerve Tumors From Chile In Spanish

Schwannoma WebPath Photo

Acoustic "neuroma" WebPath Photo

Two phases of a schwannoma WebPath Photo

Schwannoma Looks like a generic benign spindle-cell tumor. WebPath Photo

Acoustic neuroma Pittsburgh Pathology Cases

Infarct with petechiae WebPath Photo

schwannoma WebPath Photo

schwannoma WebPath Photo

Click on the acoustic neuroma! Gross specimen WebPath Photo

Click on the acoustic neuromas Scan. WebPath Photo

Trigenimofacial malignant epithelioid schwannoma Pittsburgh Pathology Cases

Schwannoma Electron micrographs VCU Pathology

"Acoustic neuromas" are schwannomas of the eighth cranial nerve. This is a common location. Especially if multiple, ask about neurofibromatosis (especially type II, schwannomin gene: Nat. Genet. 18: 382, 1998).

*The NIH acoustic neuroma consensus conference: Arch. Neuro. 51: 201, 1994.

{11031} eighth-nerve tumor
{15693} eighth-nerve tumor

Plexiform neurofibromas arise from the fibrous tissue within nerve bundles. They are traversed by the nerve fibers, and resection will require sacrificing the nerve. They usually mean neurofibromatosis.

Most of the neurofibromas in classic neurofibromatosis are cutaneous neurofibromas, subcutaneous bumps. While these look strange, they have very little malignant potential. Anyone can get a lone cutaneous neurofibroma, but in neurofibromatosis, there can be hundreds.

*"Diffuse neurofibroma" looks like thick nerve trunks with chunks of collagen ("Wagner-Meissner bodies"). It's thoroughly benign.

A "triton tumor" is a neurofibroma that makes rhabdomyoblasts. This really happens -- something about the Triton salamander regenerating its legs, remember from biology?

{01843} von Recklinghausen's of cauda equina
{01854} neurofibroma, trust me

Thoracic neurofibroma

Virtual Hospital

*Despite conventinal wisdom, and the fact that skin over big neurofibromas can get to be elephant-like, the "elephant man" probably had Proteus syndrome instead.

Paraganglioma
Pittsburgh Pathology Cases

The tendency today is to call nerve sheath sarcomas "malignant peripheral nerve sheath tumors" rathan than "malignant schwannomas", "neurofibrosarcomas", etc.

* MIND AND BRAIN {18601}

[Gilgamesh, the warrior-king, has left his kingdom to find an answer for death. On his journey, he meets a barmaid. She tells him:] Gilgamesh, where are you hurrying to? You will never find the answer for which you are looking. When the gods created humankind, they allotted us to death, but life they retained in their own keeping. As for you, Gilgamesh, fill your belly with good things; day and night, night and day, dance and be merry, feast and rejoice. Let your clothes be fresh, bathe yourself in water, cherish the little child that holds your hand, and make your wife happy in your embrace; for this too is the lot of humankind. -- 2600 B.C. [Gilgamesh finally found his answer, though it was not the one he was looking for. The entire conversation between Gilgamesh and the barmaid has been repeated billions of times since.]

I have concluded that what we call "a person" is fundamentally a spiritual process. After reviewing what evidence I could find, it seems most reasonable to me to think that we inhabit our human bodies and human brains (the products of Darwin's world) only temporarily. This doesn't bother me as a man of science, since I'm impressed by anecdotal accounts of phenomena that do not fit the familiar scientific paradigms but that have resisted systematic study. Relativity and quantum theory have satisfied me that the universe is stranger than we think, or even than we can think, even before we consider the riddle of consciousness. Considering spirit and body to be distinct helps me deal (though not in full) with questions of religious faith in Darwin's world. Why spirit and body have been joined remains the great question, which I will pass along to you. Like Socrates, I've heard it whispered that the answer involves "Love" with a capital "L".

Humankind began performing ceremonial burials at least 50,000 years ago, and we may assume that we've been contemplating our own mortality at least since that time. While discovering the relationship of mind and brain would seem a key to determining the true nature of human beings, there seems to be no easy answer. Philosophers regard this as a key problem, and (to my knowledge) all the great world-faiths allow considerable room for discussion.

The mind and the body (brain) might be related in any of several ways. This is a short survey of the principal positions; my amateur effort made it past a philosophy professor when I first prepared it in 1984.

Interactionism describes the mind and brain are distinct and equally real; during life, the mind effects changes in the material brain (presumably by telekinesis). Philosopher Karl Popper and neurosurgeon Sir John Eccles currently maintain this view. Popper says "the mind plays on the brain as the pianist plays on the keyboard". Parapsychology has failed to demonstrate any such force to most people's satisfaction. Neuroscience hasn't found it, either (nor can I imagine how we could, at present). Physical causation is easily demonstrated in our world, but no case of non-physical causation been demonstrated. (But psychologists do continue to study mind as if it obeyed causal laws.) Of course, interactionism probably violates the laws of conservation of energy, momentum, and so forth. Niels Bohr (of the Bohr atom and much more) pointed out that the microprocesses of the brain are of an order of magnitude where quantum indeterminacy should make a difference. Anyway, the laws of physics have never really been tested for neurons. An interactionist may believe (but does not have to believe) that all mental events are accompanied by physical change in the brain. NOTE: Some people (especially those interested in parapsychology) talk about "a different kind of matter", unknown to conventional science, which forms a second body for spirits, the dead, etc. (Popularized in Ghost.... and there are some interesting anecdotes.... but no convincing demonstrations have been forthcoming from the parapsychologists, despite decades of trying.) Dante (Purg. canto 25) describes how ontogeny recapitulates phylogeny (this will surprise those of you who believe that the medieval mindset was anti-science -- that's simply wrong) and follows this discussion with an account of interactionism (following Aquinas, Dante believed that God creates and infuses the soul when, and only when, the brain is prepared). After death, a new body is created from the matter of the spiritual realms. Philosophically, this is unrelated to interactionism (and not so interesting); the problems of how "mind" can be related to "subtle matter" are as difficult as defining how mind and brain interact.

Parallelism regards both mind and matter as closed systems, each with states determined by its own laws. However, they have been set in motion so that, in the course of time, every change in one corresponds to a change in the other. Leibnitz (co-discoverer of calculus) compared mind and brain to two clocks set in motion simultaneously. Though they always show the same hour, neither influences the other. I don't know anybody who believes this nowadays, or why anybody would.

Epiphenomenalism sees mind as real and different from brain, but as dependent on brain and exerting no causality it. I suspect this is the practical view of most medical doctors.

Materialism sees matter as possessing an ontological priority to mind. (Brain is ultimately "more real than" mind.) The assumption is that as neuroscience advances, it will become possible to explain all behavior without postulating mental causes. Interactionists assume the opposite, of course. Radical behaviorism, as explained by B.F. Skinner, defines behavior as the set of observable responses of an organism to stimuli. Skinner was unconcerned with non-observable mental states, denied that mental states are causes, are real, etc. Most of us, however, find being conscious interesting. For specialists: Reductive materialism describes the mental as no different from the physical. Emergentist materialism views mental events as a special set, though a distinguished set, of brain states. Eliminative materialism denies the reality of mental states at all. Logical behaviorism defined mental states in terms of dispositions to certain behaviors (although it might be hard to define these behaviors completely). It is hard for logical behaviorists to explain how one mental state causes another, or how a mental state can result in no behavior. Central-state identity theory views mental events as real and as causes, but they are identical with microstates of the brain. Some theorists claim (and I have no idea why) that all the mental events that could possibly exist must correspond to neuronal states. Others claim only that all known mental events correspond to neuronal states. The former theorists deny that a machine or a disembodied spirit or a Martian could think; the latter theorists consider this possible.

Functionalism, based on information theory and work in artificial intelligence, seeks to avoid the difficulties of both interactionism and materialism. This view compares mind to computer software, brain to computer hardware. The "personal self" is the self-organizing portion of the program within the computer of the brain. Thus, it is meaningful to talk about mind affecting brain, whether or not we believe in the ultimate physical determinacy of the brain. The mind obeys its own set of laws. Exactly what "consciousness" has to do with all of this is unclear. Most of us do not think "consciousness" is the same as a computer program's ability to edit itself. Functionalists do not care whether all mental events are related to changes in neurons, or whether the same organization might be operative in other systems (machines, disembodied spirits, etc.) A personal after-life requires only that the same software be run on a different machine. David MacKay thinks this is quite possible; Roger Sperry is pessimistic....

Further reading for physicians on mind and body:

Churchland, P.S., "Mind-Brain Reduction: New Light from the Philosophy of Science", Neuroscience 7: 1041-7, 1982

Fodor, J.A., "The Mind-Body Problem", Scientific American 24: 114-123, Jan., 1981.

Friedman, D.X. "The Search: Body, Mind, & Human Purpose", Am. J. Psych. 149: 858, 1992. Not hard metaphysics like some of the others, but thoughts on what psychiatry is all about. Good quotation from Claude Bernard.

Greyson, B., "Distressing near-death experiences", Psychiatry 55: 95, 1992. The title is understated. Echoes of "Revelation" or Dante.

Greyson, B., "Varieties of Near-Death Experience", Psychiatry 56: 390, 1993. Prevalence and impact. The impact on a person's behavior is generally salutary. Dutch 13-year prospective study of near-death experiences: Lancet 358: 2039, 2001. The authors discussed whether it could be paranormal, and noted if it were just physiology, there should be some identifiable correlates with duration, medication, attitudes, and so forth -- but there was not.

Hebb, D.O., "Consider Mind as a Biological Problem", Neuroscience 6: 2419-2422, 1981. I couldn't follow this one.

Lukoff, D., et. al., "Toward a more culturally sensitive DSM-IV", J. Nerv. Ment. Dis. 180: 673, 1992. Despite the trendoid title, this is a past-due call for psychiatrists to deal more intelligently with religious issues, whether "cultural" or the spontaneous religious experiences that happen to lots of people.

MacKay, D.M., "The Interdependence of Mind and Brain", Neuroscience 5: 1389-91, 1980

-, "Ourselves and Our Brains: Duality Without Dualism", Psychoneuroendocrinology 7: 285-94, 1982.

Owens, J.E., et. al., "Features of the near-death experience in relation to whether or not patients were near death", Lancet 336: 1175, 1990. (It's much more likely to happen if you're really near death than if you just think you are. The author thinks this favors "the transcendent hypothesis".)

Sabom, M., Recollections of Death, now out of print. Formerly the chief cardiologist at the Atlanta VA Hospital, Dr. Sabom told me in 1980 that, in his series of dozens of patients who reported having watched their resuscitations, they were uniformly accurate, without a single major error. He played a great tape for me ("The blood went in that doctor's shoe" and indeed it had, etc.; upon seeing his own heart, the guy made the two classic observations a medical student makes at an autopsy.) This strikes me as more impressive evidence for "the transcendent hypothesis" (instead of "hallucinations from lack of oxygen to the brain" or whatever) than do the stories about "light, love, and meaning", though Dr. Sabom records these, too. Dr. Sabom was subsequently fired, supposedly for his interest in parapsychology, but today's skeptics (understandably) consider him the most respectable near-death experience researcher.

Sperry, R.W., "Mind-Brain Interaction: Mentalism, Yes; Dualism, No", Neuroscience 5: 195-206, 1980.

Stevenson, I., Journal of Nervous and Mental Diseases 165: 152-70, 1977. The guy who investigates reincarnation claims around the world, and is also a psychiatry professor at Virginia, writes about the empirical evidence for and against survival after death. Still interesting, though you won't find a definitive answer here.

"Can science explain consciousness?" Sci. Am. 271(1): 88, July 1994. I didn't understand this one, either.

The grave is the first stage of the journey into eternity. -- Mohammed

NOTE: Studying for the licensure examination in basic sciences? Around this time, students often ask "What's the best way to review for 'National Boards' in Pathology"? The answer is, "Whatever book or set of notes you can read with comfort, comprehension, and interest." This might be anything from re-reading "Big Robbins" (generally favored by students who feel stronger), the "ERF handouts" or a review book, to various quiz books and quiz banks (generally favored by students who feel too weak to remain focused on a text; but be sure you look up why answers are right or wrong!). Only you can tell what feels right for you.

*ADVANCE DIRECTIVES

Unless you are VERY confident that your family knows what you want, or that you will want whatever they decide for you, and that they are MORE comfortable making decisions than letting you be responsible for them... prepare your advance directive now.

Mine has been essentially the same since 1973. Now that I've hit fifty years of age, make that percentage odds business equal to my chronolocial age.

In case of serious disease or serious injury leaving me with less than a 50% chance of a return to meaningful life, institute no therapy except for hygiene and relief of pain and respiratory distress. If intravenous, endotracheal, or stomach lines are already in place, you must remove them. "Meaningful existence" means able to say, write, sign, or fingerspell the Lord's Prayer at the right time in a church service. This is a carefully considered definition that after over 25 years still meets every contingency of which I can think. Specifically, in case of an acute subarachnoid hemorrhage with coma, do not initiate any life-maintaining intervention. Administer analgesics and other comfort measures only. When there is less than a 50% chance of a return to meaningful life, allow me to die of dehydration if active euthanasia is not feasable. I have experienced prerenal azotemia with BUN near 100 and it is not really so unpleasant. [I added this in 1977.] If I have less than a 50% chance of returning to work, or if I am fully retired, do not administer antibiotics. In an unwitnessed cardiac arrest or if I am fully retired, do not begin CPR or continue it if begun. In all circumstances, let the above serve as a guide to my thinking.

I have previously remarked that as an invalid not able to contribute further to those around me, it would be unconscionable for me to allow other living things to be killed to feed me. I have given myself out to be a mainstream Christian throughout my entire adult life. All spiritual values proceed from relationships among people -- in fact, even the Good Lord is a community of three Persons. Without the ability to act in relationships, my natural life has no value. My body goes for anatomic dissection and/or my organs are to go for transplantation as appropriate for my manner of death. You may consider me legally dead when I have no reflexes off medication. Although I am a gentle soul and have actually helped anti-death penalty activists, I have never opposed the death penalty itself. Let this be remembered in the unlikely event that I am murdered. My last will (2004) is in the possession of my house buddy and executor, Lewis Burton. Memorial services follow the rite of the Episcopal Church, with white vestments please, as was the custom among the ancient Christians. Keep the tone light and humorous as I would have done, and remember that "All Creatures of our God and King" was my favorite hymn. There's a video of my reading Plato's "Phaedo" somewhere that people would enjoy on this occasion. After dissection (anatomy class, autopsy, or organ donation plus autopsy), my body is to be cremated and my ashes are to be scattered by other skydivers as per our custom. Have a nice day.

*SLICE OF LIFE REVIEW

{01152} brain, immature but normal
{01215} oligodendrocyte, normal
{01221} microglia, resting in normal cortex
{01222} dorsal root ganglion, normal
{01228} eye, normal
{01230} frontal lobe, normal cerebral cortex
{01231} occipital lobe, normal cerebral cortex
{01239} pineal gland, normal
{01273} neuron, normal
{01351} neuron, normal with glia
{01356} astrocytes, foot processes on capillaries
{01408} oligodendrocyte, normal nerve tracts
{01409} oligodendrocyte, normal
{01410} oligodendrocyte, normal
{01435} myelin, normal
{03695} transverse sinus ligament of marshall, normal
{04442} leptomeninges, normal over cortex
{04727} cerebellopontine angle, normal
{07194} trauma chemical injury, brain normal and carbon monoxide 7-4-112
{11369} pons, normal
{11402} vertebral basilar artery, normal
{11405} vertebral basilar artery, normal
{11408} vertebral basilar artery, normal
{12833} internal carotid artery, normal anatomy
{12836} internal carotid artery, normal anatomy
{12839} internal carotid artery, normal anatomy
{1209} neurons
{1224}{1226}{1228} cerebellum
{14597} microglia, normal
{10598} microglia, normal
{14599} microglia, normal
{14600} microglia, normal
{14601} peripheral nerve, normal
{14602} peripheral nerve, normal
{14603} peripheral nerve, normal
{14604} peripheral nerve, normal
{14605} schwann cells, normal
{14606} schwann cells, normal
{14608} nerve, normal
{15061} pineal gland, brain sand
{15062} pineal gland, brain sand
{15063} pineal gland, brain sand
{15064} pineal gland, brain sand
{15146} neuron, nissl substance (rer)
{15153} pyramidal cell, cerebral cortex
{15156} cerebellum, immature
{15157} neuron in a brain stem nucleus, #31 arrow on neuron cell body
{15158} choroid plexus, fetal brain of animal #31
{15159} dorsal root ganglion, #32
{15161} dorsal root ganglion, #32 arrow on bipolar cell
{15165} nerve, normal
{15314} pacinian corpuscle, finger tip
{17663} wernicke's encephalopathy, comparison with normal *mammillary bodies
{17859} brain, normal
{17860} brain, normal
{17861} brain, normal
{17862} brain, normal
{17863} brain, normal
{17864} brain, normal
{17865} brain, normal
{17866} brain, normal
{17872} infarct, brain frontal lobe looks normal
{19970} brain 32 weeks, normal
{19971} brain 32 weeks, normal
{19990} pineal gland with cyst, normal
{20155} brain, normal
{20713} pineal gland, brain sand
{20714} cochlea, normal
{20715} ciliary process, normal eye
{20716} optic nerve head and retina, normal
{20767} cerebral cortex of newborn, arrows in large cells layer v; note columnar arrangement
{20768} pyramidal cell in developing cortex, pial surface is toward bottom
{20769} choroid plexus, newborn
{20770} dorsal root ganglion, reduced silver
{20771} dorsal root ganglion, reduced silver
{20774} perineurium, transverse
{20775} nerve, longitudinal section
{25686} white matter, normal brain
{25687} cerebral cortex, normal
{30242} cranial nerves, normal
{30243} cranial nerves, normal
{30985} internal capsule and corona radiata, normal 1/10
{31018} cerebral cortex, normal
{31024} cerebral cortex, normal
{31027} skull, norm`l
{31030} skull, normal
{31045} posterior fossa, normal anatomy
{31048} vestibulocochlear nerve in cp angle, normal
{31051} cisterna magna and pons, normal brain
{31111} tentorial notch contents, normal
{31174} thalamus, normal
{31210} brain, normal
{31219} brain, normal
{31243} brain, normal
{31330} sella turcica, normal
{31339} brain, normal
{31354} brain, normal
{31358} skull, normal plain anatomy
{31361} skull, normal plain anatomy
{31364} frontal sinus, normal plain anatomy
{31370} lumbar spine anatomy, normal
{31373} lumbar spine anatomy, normal
{31376} lumbar spine anatomy, normal
{31385} lumbar spine anatomy, normal
{31388} lumbar spine anatomy, normal
{31418} internal carotid artery anatomy, normal
{31421} circle of willis anatomy, normal
{31433} venous drainage, brain normal anatomy
{31445} straight sinus joining torcula or *conflnormal venous anatomy - with arrows
{31451} middle cerebral artery, normal anatomy
{31454} middle cerebral artery, normal anatomy
{31460} internal carotid artery anatomy, normal
{31463} vertebral basilar circulation, normal
{31466} basilar artery, normal
{31469} posterior cerebral artery, normal
{31475} vertebral basilar circulation, normal
{31490} vertebral basilar circulation, normal
{31511} spinal cord, normal
{31517} spinal cord, normal
{31575} down's syndrome, cerebral atrophy/normal
{31583} substantia nigra midbrain, normal
{31589} substantia nigra, normal confusing because melanin isn't black
{31631} caudate, normal histology
{31640} neuron and astrocytes in putamen, normal
{31642} cerebellum, normal & disrupted
{31760} wernicke's encephalopathy, normal mammillary body for comparison
{32912} cavum septum pellucidum, normal
{34331} dorsal root ganglion, normal
{34334} dorsal root ganglion, normal
{34337} dorsal root ganglion, normal
{35819} pineal, normal
{35822} pineal, normal
{35837} area postrema, normal
{35861} cerebral cortex, normal
{35870} neuron, normal cells in caudate
{35876} locus ceruleus, normal
{35915} purkinje cell, normal
{37284} alzheimer's disease, normal neuron
{37335} caudate, normal for comparison
{37338} huntington's disease, normal brain on top for comparison
{37500} germinal matrix, normal
{37513} germinal matrix, normal
{37515} germinal matrix, normal
{37609} brain, normal
{37665} brain, normal for comparison
{37678} aqueduct, normal midbrain
{37679} aqueduct, normal
{37680} aqueduct, normal
{40144} brain, normal
{49534} *cerebellum, normal
{53716} EEG, normal
{53809} hurler's syndrome - purkinje cells, normal cells / engorged cells

Visitors to www.pathguy.com reset Jan. 30, 2005:

Drop by and meet Ed

Ed says, "This world would be a sorry place if people like me who call ourselves Christians didn't try to act as good as other good people ." Prayer Request

Teaching Pathology

PathMax -- Shawn E. Cowper MD's pathology education links
Ed's Autopsy Page
Notes for Good Lecturers
Small Group Teaching
Socratic Teaching
Preventing "F"'s
Classroom Control
"I Hate Histology!"
Ed's Physiology Challenge
Pathology Identification Keys ("Kansas City Field Guide to Pathology")
Ed's Basic Science Trivia Quiz -- have a chuckle!
Rudolf Virchow on Pathology Education -- humor
Curriculum Position Paper -- humor
The Pathology Blues
Ed's Pathology Review for USMLE I
Part I
Part II

How many psychiatrists does it take to screw in a light bulb?
What do YOU think?

Pathological Chess

Taser Video 83.4 MB 7:26 min