neuro-blogo-sphere

Disorders of Childhood & Adolescence ADHD & Complex Illness

Speaking of Vermont adolescent Illingness...watch video

Thanks B!

On a need-to-know basis...

How common is childhood psychiatric illness?
20% of children 9 - 17 have a diagnosable psychiatric illness (~ 15 million), but very few get treatment. This can lead to a cascade of effects resulting from school drop-out, crime, etc.

Limbic disorders are not just genes or environment, but the interaction of a set of genes with a set of environmental factors. “almost all human diseases are complex-content dependent entities to which our genes make a necessary but only partial contribution.”

“What is inherited is the manner of reaction to a given environment”
Elmer Heyne, wheat geneticist, early 1900’s

How does the serotonin system function in anxiety?
Anxiety and depression are associated with environmental factors (trauma, abuse...) interacting with genetic predisposing factors (COMT, MAOA, 5HT1B, and SERT). There is a "short" and a "long" form of the SERT gene promoter. short/short are more likely to develop depression within a context of adversity or a stressful life event (SLE) and show reduced connectivity between amygdala and cingulate.

How does the dopamine system function in ADHD?
Two components of the dopamine system are the presynaptic dopamine transporter (DAT) that removes DA from the synapse, and the post-synaptic DA receptor that propagates the singal. The 10-repeat allele of the transporter DAT1 is hyperactive and the 7-repeat allele of the receptor DRD4 is hyposensitive thus in a sense reducing effective DA signaling, and both are associated with ADHD. People who have DA deficient brain will seek it out (addiction) because mesolimbic pathways to nucleus accumbens (which are dopaminergic) are hypofunctional so to get that "James Brown" feeling you feel you've got to enhance that signal. Additionally, methylphenidate (Ritalin) is a DA reuptake inhibitor that is commonly prescribed for ADHD.

Combining genomics with functional imaging studies allows identification of changes ocurring in psychiatric disorders.

For example, Catechol-O-methyl transferase (COMT) is an enzyme that breaks down catecholamines such including dopamine There are two genetic isoforms that depend on a single amino acid termed Val/Val, Val/Met, Met/Met Val has 4 times the COMT activity as the Met isoform which should then lead to lower dopamine levels in PFC in Val/Val individuals. This is thought to lead to increased activity of PFC "...neurons with valine-variant COMT show higher levels of activation during certain cognitive tasks, as they require higher levels of neuron firing to achieve the same level of post-synaptic stimulation." and a greater risk of ADHD and schizophrenia.

Coronal Sections

Try your hand at the Checkllist for Coronal Slices:
COMET has these lucites labled for reference...

corpus callosum (genu , body and splenium), cingulate gyrus
lateral ventricles (anterior, inferior, and posterior horns, body, and trigone, interventricular foramen) and septum pellucidum
caudate (head , body and tail), putamen, striatum
globus pallidus, lentiform
internal, external and extreme capsules, claustrum, insula,
internal capsule (anterior and posterior limbs), nucleus accumbens, basal forebrain area,
hypothalamus (boundaries),
amygdala, stria terminalis, hippocampus (Ammon’s horn), fornix (crus, body, columns and fimbria)
mamillothalamic tract
thalamus (anterior tubercle), massa intermedia , medial and lateral geniculates, pulvinar)
stria medullaris thalamicus, habenula, pineal gland, posterior commissure
subthalamic nucleus of the ventral thalamus

Then try your had at the limbic checklist:
Parahippocampal Gyrus
Hippocampal formation (Atlas figure 64, Hippocampus (Ammon’s Horn), Dentate Gyrus, Subiculum)
Fornix- crus, body, columns
Mamillothalamic tract
Thalamus (Anterior thalamic tubercle)
Anterior limb of the internal capsule
Cingulate gyrus & Cingulum
Prefrontal cortex (Dorsolateral prefrontal cortex, Orbitofrontal cortex)
Amygdala & Uncus & Stria terminalis
Anterior perforated substance (Basal forebrain area)
Nucleus accumbens
Stria medullaris thalamicus & Habenula
Hypothalamus (anterior commissure, hypothalamic sulcus, mamillary body, lamina terminalis)

Next up anxiety & panic disorders, anxiolytics and sedatives...

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What are some common anxiety disorders and their characteristic features?
Anxiety disorders are the most common psychopathology, examples of which include: panic disorder, geralized anxiety disorder (GAD), social phobias and other specific phobias, obsessive compulsive disorder (OCD, recurrent intrusive impulses), and post-traumatic stress disorder (PTSD, defined by exposure to a particularly traumatic life/death event).
Panic attacks typically show symptoms of heart palpitations, shortness of breath, diziness, fear of death/loss-of-control, derealization, etc. Panic disorders are recurrent panic attacks that produce persistent anticipatory anxiety and sometimes severe phobic avoidance (agoraphobia). In combination with depression and anxiety, panic disorder carries an increased risk for suicide.

What are the main neuroanatomical and neurochemical components of anxiety?

In terms of neuroanatomy, the amygdala plays a central role in anxiety circuits. Sensory input to these circuits arrives from both peripheral and interoceptive stimuli. And the fear response that is generated can actually precede conscious awareness. Connections to the hippocampus are important for formation of aversive (or traumatic) memories. And individuals who have reduced connectivity between amygdala to anterior cingulate (associated with a short allele for the 5HTT) are more prone to protracted negative affect.
In terms of neurochemistry, fear and anxiety involve CRH (via the HPA axis) and noradrenergic functions (from locus coeruleus), but also involves striatum (for motor escape), periaqueductal gray (for analgesia), etc. CRH stimulates ACTH from the anterior pituitary leading to cortisol release from adrenal gland. CRH also stimulates locus coeruleus to increase NE release. Cortisol provides negative feedback on both CRH and NE pathways to shut off signaling in the circuit. Inhibitory GABA Cl- channels are thought to be underactive in anxiety and depression, and benzodiazepines (BDZs) are used to augment effect of GABA.

Pharmacological Treatment for Anxiety Disorders
The goal of treatment for anxiety disorders is to reduce the anxiety without sedating. The classic anxiolytics are the benzodiazepines and barbiturates. Both bind to allosteric sites on the GABA channel to enhance GABA effects, so both still require GABA to be there to open the channel. They differ in that benzodiazepines increase the frequency of channel opening whereas barbiturates increase the duration of channel opening, and therefore have a more dramatic effect.
The benzodiazepines include diazepam, lorazepam, clonazepam, and triazolam. Benzodiazepines are used to treat GAD, social phobia, and acute instances of panic attack. BDZs undergo hepatic metabolism, but have long-half lives from 10 to >100 hours due to tissue redistribution. BDZs can produce drowsiness, and interact with other CNS depressants (eg alcohol). Long-term use of BDZs can lead to dependence and withdrawal symptoms with discontinuation. BDZs have a wider safety margin because they have fewer respiratory or cardiovascular effects than barbiturates. Additionally overdose of BDZs can be treated with flumazenil (a BDZ receptor antagonist).
The prototypical barbiturate is phenobarbital. Barbiturates are highly lipophilic, entering the CNS rapidly, and thus are prone to abuse. Overdose may depress medullary respiratory centers, so there is a low margin of safety, and no antidote. Barbiturates are used for sedation, and thiopental is a barbiturate used for anaesthesia.
Other drugs used as anxiolytics include buspirone and propanolol:
Buspirone is a selective anxiolyitc, less sedating but slow to act and so most useful for GAD. Buspirone interacts with MAOIs and is a partial agonist at 5HT1A receptors.
Propranolol is a β-adrenoreceptor antagonist used to treat anxiety in which sympathetic overactivity predominates (eg performance anxiety).

Hypnotics
The goal of treament is to produce sleep as close to normal as possible. Generally these are not for long-term use because tolerance develops with use, but they can help through short periods. Typically deep sleep ocurs early, and REM sleep later in the sleep cycle. Zolpidem or Eszopicloneare commonly preferred over benzodiazepeines because they have less effect on REM than do BDZs.

Next up, a series on mood disorders...

Moo'd Disorders

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Mood is "a person's sustained and predominant internal emotional experience; examples include depression and euphoria" def. Moods can be abnormal if they are excessive, prolonged, too easily provoked, etc. A primary mood disorder is when the quality or intensity of these abnormalities constitute the defining features of disease.

How are mood disorders classified?
There are two broad categories of primary mood disorder: unipolar (depressive) disorder and bipolar (manic-depressive) disorder. Major depressive disorder is the prototypic unipolar disorder. Bipolar I disorder is the prototypic bipolar disorder.

What is the difference between unipolar and bipolar disorder?
Major depressive disorder may be a single depression event, or recurrent (50% of those who have one episode have another, 70% of those have another, 90% of those have another...). Typically this constitutes a relapsing-remitting pattern, all down, but in rare cases depression is chronic.
Bipolar I disorder is essentially always recurrent, and may progressively worsen over time. Bipolar I is defined by at least 1 manic episode, but invariably depressive episodes occur as well. Mania and depression typically cycle, such that at any point in time a patient may be manic, depressed, or neither. Mixed states may also occur, especially in cases of rapid cycling. Both manic and depressive disorders may include psychotic symptoms that are generally mood congruent.

What symptoms define major depressive and manic episodes?
Depression and mania are thought to be diseases of dysregulation rather than a particular single causative excess or defieciency.
A major depressive episode is characterized by: depressed mood, anhedonia, psychomotor disturbance, weight change, sleep disturbance and fatigue, delusional worthlessness, and possible suicidal tendencies. A diagnosis requires five of these, one of which has to be depressed mood or anhedonia.
Manic episodes are in a sense a reverse of a depressive episode: expansive/irritable mood (required), hyperverbal, grandiosity, reduced need for sleep, racing thoughts, distractibility, and excessive involvement in pleasurable activities.

Which genetic and environmental factors are important in transmission of mood disorders?
Mood disorders are highly familial and heritable. A polymorphism in the 5-HT transporter is associated with susceptiblity to depression. The short allele of the 5-HT transporter is also associated with reduced volume and function in the perigenual anterior cingulate and reduced connectivity to amygdala. Reduced cortical inhibition may lead to increased amygdala reactivity and prolonged negative affect in response to adverse conditions. Environmental factors include losses and stressful life events.

What neurochemical and sleep abnormalities are associated with depression?
Neurchemistry of depression is hypothesized to involve catecholamines (NE, locus coeruleus, DA, ventral tegmentum) and/or indolamines (5-HT, raphe).

These models illustrate the difficulty in getting the proper balance of medications to address symptoms.
Neuroendocrinology of depression centers on a role for CRH as evidenced by: elevated CRH levels in CSF; blunting of ACTH response (due to downregulation of CRH receptor in anterior pituitary); nonsuppression of cortisol by dexamethasone challenge; elevated cortisol levels and adrenal hypertrophy.
Sleep abnormalities associated with depression include increased sleep latency, but decreased REM latency and decreased arousal threshold resulting in decreased slow-wave sleep.

What treatments are effective for mood disorders?
The goal of treatment is to reduce the signs and symptoms, resotre life function, and minimize recurrence.
Treatments form major depression include three classic antidepressants (TCAs, MAOIs, SSRIs), and psychotherapy including CBT and interpersonal therapy. However electroconvulsive therapy (ECT) remains the single most effective treatment for major depression, especially for refractory patients, but is associated with some degree of memory loss.
Tricyclic antidepressants (TCAs, eg imipramine) block reuptake of monamines (NE, NE & 5-HT, NE & DA). Because they act indirectly (not on receptors) they take 2+ weeks for full effectiveness. Initially increased NE may cause sedation due to effects through α2 and β inhibitory receptors ( I thought I heard this right in lecture, but I think beta receptors are Gs excitatory - hence beta blockers like propranolol??) but over time these desensitize such that the α1 excitatory receptor is thought to predominate in restoring NE function. However TCAs have a low margin of safety because NE increases in the periphery, combined with partial block of muscarinic receptors, can lead to arrhythmias/tachycardia in cases of overdose. (This would be good to keep in mind if the patient exhibits suicidal tendencies). However TCAs remain effective for those patients for whom SSRIs are not effective.
Monoamine Oxidase Inhibitors (MAOIs) are used for the same purpose to raise monamine levels, but MAOIs do this by reducing monoamine breakdown (eg phenelzine, which blocks both A & B MAO). MAOIs also have a low safety margin, but fatalities are rare compared to TCAs. However dangerous drug interactions can occur with certain foods that contain tyramine, which can build up to high levels and act like a sympathetic amine, potentially causing severe hypertensive crisis (the same can occur with efedrine or combined treatment with other antidepressants).
The last of the classical antidepressants are the
SSRIs (selective serotonin reuptake inhibitors). Compared to TCAs and MAOIs these have fewer side-effects because they function specifically by blocking 5-HT reuptake and have less effect on NE. Examples are fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil). All SSRIs have the same mechanism, but fluoxetine has a long (9day) half-life though in some cases exacerbates anxiety. Sertraline has a shorter half-life but may exacerbate mania. Paroxetine has the shortest half-life but can produce some withdrawal symptoms. There are still some side-effects associated with elevated 5-HT: blood vessel constriction (head ache), GI (nausea, diarrhea/constipation), CNS (sweating, sleep abnormalities, diminished sex drive). And serotonin syndrome can occur with multiple 5-HT meds leading to sympathetic hyperactivity (for which methysergide, 5-HT antagonist, may be useful). Finally, SSRIs carry a risk for aggression and suicide in children and young adults 18 - 25.
Atypical antidepressants include: Buproprion which blocks uptake of NE and DA and so is useful in smoking sensation by slowly enhancing DA in mesolimbic regions; SSNRIs (selective serotonin norepinephrine reuptake inhibitors) such as duloxetine and venlafaxine; nefazodone an SSRI and 5-HT2 partial antagonist; and mirtazapine an α2 presynaptic antagonist, and 5HT2 antagonist which produces sedation and weight-gain that also helps appetite for AIDS and cancer patients...

In terms of treatment of manic episodes, lithium is still the most useful treatment. The mechanism of lithium action is uncertain but thought to involve inhibition of phosphoinositide turnover in the PLC pathway. Presumably this would reduce Ca++ release from intracellular reserves in response to Gq signaling and thereby reduce neuronal excitability. Lithium is absorbed quickly, but slow to cross the BBB and 95% is excreted in urine. Lithium can be toxic producing fatigue, tremor, and thirst, overdose is treated by dialysis. Other treatments for mania include anticonvulsants (valproate and carbamazepine) and some antipsychotics (clozapine or risperidone). ECT is also effective, though used less frequently for mania than pharmacotherapy.

A classic Onion:
God Diagnosed With Bipolar Disorder
May 2, 2001 | Issue 37•16

Perhaps "the Almighty One" acould benefit from...

Cognitive Behavioural Therapy (CBT)
CBT is built on analysis of the problem, formation of specified objectives, and application of principals of conditioning to modify behaviour (namely exposure, reward/punishment).
The idea for CBT is based on the idea that childhood experiences coalesce into a set of core beliefs that we use to generate assumptions and responses to different situations throughout our lives. In cases of depression or phobia, early experiences have led to negative self-beliefs that impair functioning and so these thought patterns have to be repatterned to address the root cause(s). I always liked the approach, it's like it takes what the brain does best and puts it to the work it was supposed to do...
What are the components of CBT?
CBT is best used in combination with pharmacotherapy in which medications are used to reduce initial anxiety (from the bottom up) to the point where new thought patterns can be learned to reduce anxiety (from the top down). The first step is education: explaining the disorder and the rationale behind treatment so that the patient becomes a partner in treatment. They keep written records of events (eg panic attacks) and analyze their responses to them. Patients are taught relaxation techniques including progressive muscle relaxation, breathing, meditation, body scans, etc. to practice daily. Patients are also taught breathing techniques - especially important in panic disorder which is thought to involve sub-clinical hyperventilation. And finally, with incremental exposure in initially safe and then progressively more realistic environments, patients are taught to catch cognitive distortions and replace them with positive patterns. For instance to repattern a negative thought they are taught to ask 4 questions: 1. Does this thought contribute to my stress? Where did I learn this thought? Is this thought logical? Is this thought true? Though knowing the source of a negative thought is helpful, even if unknown it is important to restructure that thought regardless.
"Think of your mind as being like a bus"
"Who is driving your bus?"
Loretta Laroche

In line with getting to the root of a neurologic problem...

Different types of neuro exam are used in different situations: screening, extended, directed, or for unresponsive (coma) patients. The extended neurological exam has several assessments: 1) mental status, 2) cranial nerves, 3) motor-reflex function, 4) sensation, 5) cerebellar, and 6) station & gait.

1) The Mental Status Exam...
...is an assessment of emotion, cognition, and behaviour. A prerequisite for this exam is a proper raport witht the patient (my first doctor as a kid was Dr. Rapaport!). The mental status exam is designed to be a systematic method of making and recording observations., but is best if the exam is more conversational than contrived. It can begin simply with an evaluation of appearance, general behaviour and attitude. While talking, you can note the quality and quantity of speech. In asking about the patient's mood, activities, past, etc. you can assess the range and appropriateness of mood, perception, thought content and thought processes. Throughout the exam, evaluation of cognition involves assessment of sensorium (level of alertness), orientation (to person, place, time, & purpose), memory (immediate, short-, and long-term), attention, abstract thinking, language function, visuospatial tasks (eg clock drawing), judgement and insight.

2) Testing Cranial Nerve function:
The eye exam will test CN II, III, IV, VI and starts with general exam of eyelids (ptosis), globes (protrusion/sunken), and sclera (injection, discharge). Visual acuity is typically tested with a Rosenbaum near card with correction for each eye individually. Visual fields are tested by first checking both eyes in 4 quadrants using finger waving with your hands half-way between you and the patient so you can compare your visual field to theirs. If you suspect a deficit, check they eyes individually for counting fingers (have to have your hand considerably closer for this). Test occular movments by taking eyes vertically at mid and both lateral extremes, then testing accomodation. Look for conjugate gaze with no more than a few beats of nystagmus. Pupillary reaction should be assessed in a dim room by shining light in one pupil at a time and looking for equal reactivity to light. Fundoscopic exam should also be assessed in dim light, have the patient look distant and get close to the pupil (can rest hand on cheek) while looking somewhat toward nasal retina . Look for a flat optic disc with good margins and check retinal vessels for normal ICP (pulsations in 3/4 patients).
Testing facial power tests CN VII by checking symmetry of palpebral fissures, nasolabial folds, wrinkled forehead, eye closure, and smile.
Testing hearing tests CN VIII by observation during the interview itself, and with finger rubbing (high-freq) normally audible at 3' , but if not move progressively closer to the ear. If abnormal can test Weber or Rinne.
Palatal elevation tests CN IX and X by using a tongue depressor for what it was actually made for... while patient says "Ahhh" can assess symmetry of palate/uvula elevation. If abnormal can test gag reflex for symmetry on both sides (especially if patient has a swallowing problem).
Tongue protrusion tests CN XII by having patient protrude the tongue and looking for deviation or atrophy. If you suspect weakness you can have patient push against each cheek (will be weaker on lesioned side).

3) Testing Motor Function & Reflexes
This series tests cortex, CST, peripheral nerves, NMJ, and muscle.
In assessing motor function you are looking for atrophy and power in select muscle groups. In UE examine shoulder (abduction), elbow, wrist, and finger. In LE examine hip, knee, and ankle. When checking strength stabilize above the joint (usually 90 degrees) and try to overcome the patient from a point below the joint (except in the test of shoulder abduction which is easiest tested together). If you suspect a subtle weakness of cortical origin in the UE you can have the patient extend their arms palms up and close eyes for 30+ seconds looking for pronation and drift downward. When checking tone have the patient completely relax the muscle and assess how freely it moves across the joint. For the legs while sitting you can let them swing like a pendulum, or while lying down just raise at the knee and allow to slide back down. In particular look for signs of distal atrophy.
Testing DTR's
Here moving the reflex hammer with a quick flick of the fingers and wrist produces the best results. You want the limb really relaxed, but since the patient will tense to varying degrees, do a series of trials and take a mental average. Sites to be tested are tricep tendon (with supported arm), biceps tendon (wtih your thumb firmly over, feeling for contraction), brachioradialis (with arm at mid-prone position, tapping midway up), patellar, and ankle (hold foot dorsiflexed while tapping Achilles' and feeling for plantar flexion. Testing for a Babinski response requires scratching the sole with a semi-blunt object from the heel to toe in a lateral to medial arc with increasing pressure. Normally toes will curl down, or foot will withdraw - but is abnormal if big toe extends (and toes fan?). Rate reflexes on a scale 0 - 5 0 being absent, 2 normal, and 4-5 clonic. If the patient is hyporeflexive you can employ the Jendrassik maneuver to facilitate the reflex (have the patient pull at both wrists, make a contralateral fist, clench jaw, etc.). Look for abnormal reflex asymmetry, clonus, or spread.

4) Testing Sensation
Here you are testing distally for signs of neuropathy, for example at the interphalangeal joint of the hallux. When testing vibration, use a 128 Hz fork and first demonstrate vibration for the patient at a spot you know they will feel normal, then place it distally. You can dampen the vibration with your finger to speed the process, and when the patient reports that they can no longer feel it make a note of how much vibration remains (their threshold). If there is no sensation distally, continue to move proximally until the patient does have sensation (medial malleolus, shin, knee). Test sharp sensation with a toothpick-type thingy and try not to draw blood I guess!

5) Cerebellar Testing
The finger-to-nose test (make sure they patient stretches the arm full out) and look for end-point tremor or misses. Check rapid alternating movements for rhythm.

6) Station and Gaint
For the Romberg test the patient stands eyes open, feet together, then closes their eyes and you'd look for swaying/falling. To test gait have the patient walk on heels, toes, and heel to toe.
Refer patients as needed to the Ministry of Silly Walks

YouTube video's here for a study break!
Notice the characteristic asymmetry in John Cleese's silliness...

This photo had me thinking...
flattened affect??
"cat"-atonic??
disordered thought patterns??
auditory hallucinations??
Clearly cats fall neatly into one of the schizophrenias - perhaps schizofeline disorder??

What are the symptoms of schizophrenia?
Delusions (fixed false beliefs) hallucinations (perceptions that are not real, commonly auditory), disorganized speech, disorganized thinking or catatonia behaviour, affective flattening, alogia (lack of words), avolition (lack of motivation), deterioration of social/occupational function, mood symptoms (if present are brief). Schizophrenia can be divided into positive and negative symptoms. Positive symptoms are qualities that are normally absent (hallucination), negative symptoms are the absence of things normally there (withdrawal). If you have 2 positive symptoms that last 1 mo and some complex of symptoms that last 6 mo that's schizophrenia.

What abnormalities are found in imaging studies of schizophrenia?
Imaging studies of schizophrenia show enlarged lateral & 3rd ventricles, impaired activation of frontal lobes, and reduced anterior hippocampus volume.

What are the genetics and environmental risk factors for schizophrenia?
Schizophrenia occurs in 1% of the population. Onset is typically in late adolesence, though later for women. Outcomes vary - some have no further instances, half will have episodic schizophrenia, and a third will show marked deterioration. Among 1st degree relatives incidence is ~ 10% and ~50% for monozygotic twins, so there is some genetic component. Environmental (prenatal) factors correlated with schizophrenia include: Rh incompatibility, nutritional deficiency, and pre-eclampsia

How is schizophrenia treated?
Schizophrenia is generally treated on an outpatient basis but with community outreach and supported housing. However, treatment is complicated by lack of insight. Most antipsychotic medications have some effect on dopaminergic systems. The more potent the effect on D2 the more effective the antipsychotic:

Additionally, dopaminergic drugs can induce psychosis (L-DOPA, amphetamines), however no direct evidence of a hyperdopaminergic state has been found. If I have it right, there is dopaminergic drive to prefrontal, and prefrontal is inhibitory to limbic, so the idea is that lost mesocortical pathways leads to a loss of inhibitory feedback. Hyperactivity of mesolimbic pathway then may cause positive symptoms, while loss of mesocortical inputs causes negative symptoms. see Dopamine hypothesis of schizophrenia...

In an alternate model, effects on dopamine may be secondary to NMDA receptor hypofunction. NMDA antagonists like PCP also cause psychosis. Since NMDA pathways develop relatively late, this may explain adolescent onset of schizophrenia. Support for this model comes from the fact that ketamine (which binds the NMDA receptor) causes psychosis in adult but not in children. But if you can connect NMDA with DA (other than NM"DA") let me know...

In parting, a punk classic from Sonic Youth...

The Reward Pathway
Mesolimbic dopaminergic neurons project from the ventral tegmental area (VTA) to the nucleus accumbens (NA). Of course nucleus accumbens receives many other inputs as well (eg prefrontal cortex, amygdala), but it's output is predominantly inhibitory GABAergic.

The reward pathway is strongly tied to theories of addiction. In this series we look at alcohol, opiod, and cocaine addictions...

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What are the "signs" of alcohol abuse?
Alcohol acts via multiple neurotransmitter pathways including activation of the VTA-NA reward pathway. Signs of alcohol use are obviously slurred speech, discoordination, impaired memory, etc. But to determine when a patient has alcohol abuse questions might include: When was your last drink? How much? Is that typical for you? Has anyone felt you have a problem with alcohol? etc. From things I've seen, a quick check for alcoholism could be helpful in terms of preventing really bad stuff from happening down the road... There are other screening methods available as well, such as the Michigan Alcohol Screening Test (MAST) mentioned in lecture.

What are possible treatments for alcoholism?
Disulfiram when taken preventatively will cause negative consequences with drinking - basically an instant-hangover as a form of negative conditioning - but then compliance is especially a problem. Naltrexone has been shown to decrease cravings, and acamprosate is thought to reduce withdrawal - less withdrawal being more conducive to successful cessation.

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What are the "signs" of opiod abuse?
Opiods are drugs with morphine-like action, opiates are the derivatives of opium itself (morphine and codeine, and heroin). Opiods produce analgesia, drowsiness, constipation, pupillary constriction... Tolerance tends to develop to analgeisa and euphoria more than for constipation and pupillary constriction. Withdrawal peaks in 24 - 28 hours, but generally is not life-threatening. Opiods act primarily via the μ-receptor in the reward pathway (VTA - NA) and pain pathways. The current trend of opiod abuse is an increase in illicit use of prescribed opiods by younger populations (eg hydrocodone, oxycodone).

How is opiod abuse treated?
There is one antagonist and 3 opiod agonists used to treat opiod abuse. Naltrexone is an opiod antagonist that prevents binding to opiod receptors, but compliance rates are very low (except in certain highly-motivated patient populations). More commonly opiod abuse is treated with an opiod agonist. Methadone blocks exogenous opiods but prevents withdrawal and is given daily as a liquid in a clinical setting (due to safety and diversion concerns). LAAM is similar to methadone. Buprenorphine "bupe" is a partial opiod agonist that also blocks exogenous opiods but is longer lasting and more conducive to detox paradigms. Additionally the treatment can be office based by certified MDs, and so is good for patients who do not need "wrap-around services".

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Cocaine Addiction
Cocaine acts as a CNS stimulant, elevating dopamine levels by blocking dopamine reuptake, especially acting on the reward pathway (VTA-NA). Currently there is no effective treatment for cocaine dependence, so treatement is based on behavioural approaches.

Behavioural approaches to substance abuse
Behavioural approaches are based on the idea that reinforcement/punishment modulates all our behaviours, and drug abuse is no different. Drug use is self-reinforcing because use is rewarded (euphoria) and withdrawal is punished. Treating dependence involves turning addiction around such that punishment is now tied to use, and reward tied to abstinence. This is known as "contingency management" as in your are making reward contingent on abstinence. Studies here at UVM by Higgins et al have shown that a voucher system based on this model can yield dramatically better outcomes than the traditional 12-step program.

Certain populations of schizophrenic patients are at increased risk for substance abuse, for review. And the mesolimbic pathway is one of the targets for antipsychotic medications.

Antipsychotic Medications

What is a classical antipsychotics, its mode of action and risk?
All classical antipsychotics block the D2 dopamine receptor. Haloperidol is the classical classical antipsychotic. However any drug that blocks D2 can produce "extrapyramidal" side effects - tremor, akinesia, and potentially tardive dyskinesia (which may be permanent). Additionally there is risk for neuroleptic malignant syndrome (an autonomic dysregulation) thought to be due to decreased levels of DA signaling and so treated with the DA agonist bromocriptine. Classical antipsychotics are more effective at treating the positive symptoms of schizophrenia (hallucinations, paranoia...)

What are the atypical antipsychotics and their modes of action/risks?
Clozapine blocks a variety of receptors, but not as much D2 so there is less risk of extra-pyramidal side effects. However clozapine carries an increased risk of agranulocytosis (WBC toxicity) so is somewhat reserved for patients who are experiencing extrapyramidal effects.
Risperidone blocks DA but also 5-HT receptors so it has good effects on both positive and negative symptoms. It would be the drug of choice, but treatment is more expensive than haloperidol.
Olanzapine blocks a broad spectrum of receptors as well, including D2 and 5-HT2 receptors, so it is also useful in treating + and - symptoms of schizophrenia.
Quetiapine blocks D1, D2 and 5HT1A, 5HT2 receptors.
Antipsychotics are also useful for treating Tourette's and Huntingtons.

Yesterday we ended with SY, so maybe today we'll end with The Pixies...
Where is my mind?

Rousseau, The Sleeping Gypsy, 1897 image

How are cortical inputs organized in terms of depth?
Cortex is organized into vertical columns based on the radius of a given pyramidal cell. Recurrent axon collaterals from pyramidal cells function in lateral inhibition and negative feedback (RC). Cortical inputs to the pyramidal cell synapse in superficial layers II/III (CC); specific thalamic inputs are deeper in layer IV (SA) and non-specific afferents from thalamus, locus coeruleus, raphe, etc. synapse in all layers (NSA).

How does an electroencephalogram work?
An electroencephalogram (EEG) measures the sum of many superficial synaptic events occuring beneath an electrode by recording changes in extracellular potential. When increased extracellular negativity is detected, it means that positive ions have moved into (depolarized) a bunch of neurons beneath the electrode. So this increased extracellular negativity is indicative of increased depolarizing synaptic activity in the region, and therefore the convention is to represent this as an upward trace.

What brain states are visible by EEG?
At basal levels of activity the brain shows a relatively low frequency, high amplitude wave of activity, the α wave. When a stimulus causes an "alerting response" the rhythm changes to lower amplitude, higher frequency wave. Consciousness is driven by the reticular activating system (RAS) in the brainstem. Damage to the RAS at the level of the midbrain produces coma (which differs from the more metabolically active state of normal sleep).

first we'll look at issues related to coma, and finish with sleep and sleep disorders

What are the differences between coma, persistent vegetative state, locked-in state, and clinical death?
Death is no breathing, no reflexes, no EEG, no evoked potential, and no metabolism. Coma is no awareness and no wakefulness, but retains some degree of respiratory function, reflexes, evoked potentials, and metabolism. Persistent vegetative state is no awareness but intact wakefulness (sleep/wake cycles), and some levels of respiratory, reflex, evoked potentials, and metabolism. Locked-in syndrome is not a loss of consciousness, but an inability or great difficulty in communicating consciousness due to quadraplegia & pseudobulubar palsy.

The first symptoms examined in a comatose patient are cardiovascular and respiratory to check for adequate perfusion and oxygen supply...

What breathing signs are associated with damage to different levels of brainstem?

Cheyne-Stokes (periodic) breathing may occur when cerebrum is affected bilaterally (eg a metabolic encephalopathy). Hyperventilation can occur in midbrain lesions. Apneusis (pausing at full inspiration) can occur with lesions to rostral pons. Ataxic breathing may occur with damage to caudal pons, and may evolve into respiratory arrest which occurs with damage to the rostral medulla.

What pupillary signs are associated with CNS damage at different levels?

If pupils are large and unreactive (to light) then damage is probably to pretectal region (eg pineal tumor affecting Edinger-Westphal). If only one pupil is starting to dilate then CN III is probably being compressed, either due to uncal herniation or aneurysm (commonly superior cerebellar artery). If pupils are small but reactive, then damage is likely to di or telencephalic structures because sympathetic tone is decreased but midbrain is still intact. If both pupils are "pinpoint", thus only imperceptibly reactive, then damage is to pons - taking out all sympathetic drive both direct hypothalamic and drive to RVLM.

In contrast to coma, sleep is only a "periodic suspension of consciousness"

Sleep States
There are two distinct sleep states REM and non-REM (NREM). NREM sleep is associated with the RAS, muscles are not paralyzed and dreaming rarely occurs. REM sleep , is associated with the nucleus reticularis pontis oralis/caudalis (NRPO). Groups of neurons within the NRPO generate the characteristics of REM sleep: ponto-geniculo-occipito (PGO) waves, rapid eye movements, muscle atonia, and the shut-down of NE and 5-HT signaling. Conversely, REM is turned off by noradrenergic (locus coeruleus) and histaminergic (hypothalamus) signals.

Sleep/Wake Cycles
Circadian rhythms originating in the suprachiasmatic nucleus of hypothalamus are entrained by sunlight to keep a 24 hour cycle. Timing of sleep/wake cycles are normally tied to this circadian rhythm. Alertness is high in the morning, dips in mid afternoon then peaks again briefly before dropping at night. The peak in wakefulness a couple hours before bed time is the "forbidden zone" when sleep is all but impossible (perhaps evolutionarily this was a time to find the best place to sleep).

Sleepless in Seattle
not necessarily my favorite movie but David Hyde Pierce has a good line in it,

"Annie, when you meet someone and you're attracted to them, it just means that your subconscious is attracted to their subconscious, subconsciously. So what we think of as chemistry is just two neuroses knowing that they are a perfect match."

During periods of sleep deprivation you initially continue to follow circadian rhythms of wakefulness/sleepiness but by the 3rd day sleep tendency is maximal and overtakes any chronicity in sleep/wake cycles.

Dreaming
Dreaming can occur even in relaxed wakefulness, but is usually considered part of REM sleep. Dreams often contain illogical content, but uncritical acceptance of that content. Normally dreams are not remembered unless they are associated with strong emotion (eg anxiety). External stimuli can be incorporated into dreams to a limited extent, but interestingly pain is rarely incorporated, even in patients with chronic pain. In cases of acquired blindness, people dream not only about faces they have seen before they lost their sight, but also about the faces of people whom they have met subsequently!

What types of sleep disorders bother patients?
Hypersomnia (excessive sleep), parasomnias (abnormal sleep patterns), circadian abnormalities (early-bird vs night-owl), and insomnia. Insomnia is usually a primary condition, if left untreated it can lead to anxiety and depression. Diagnosis may involve patients keeping a sleep log or automatic recording by actigraphy & criteria are inability to fall asleep at least 2 nights/wk for 2+ weeks.

How are sleep disorder's treated from a behavioural standpoint?
First, identify and eliminate the underlying cause. Then behavioural therapy is most effective and longest lasting, but also the most time-consuming. Advice on good sleep hygeine includes basically no stimulating substances (cafeine) or activities (exercise) before bed.
Stimulus control therapy involves breaking associations of wakefullness with the sleep environment - otherwise the body will become conditioned to think its "awake time" in the bedroom.
Another behavioural approach involves sleep restriction. First a log is kept to determine how much the patient sleeps currently, then they are only allowed to be in bed for that amount of time. If they don't sleep much during that time, tough luck! they've got to get out of bed. After a couple of nights they'll be so sleep deprived that they'll sleep 90% of the allotted time, then you can slowly progress to a more normal sleep interval.

Then you can Sleep Better - Pete Yorn

How is insomnia treated pharmacologically?
Usually pharmacological treatments are reserved for short-term treaments. Hypnotics include benzodiazepines (temazepam), non-BDZ (zolpidem), antidepressants (trazodone) but not over the counter hypnotics. Melatonin is good for jet lag but not insomina; however the melatonin receptor agonist ramelteon has been shown effective. Trazodone suppresses REM, increases slow wave sleep, and can produces withdrawal and rebound with cessation. BDZs for short periods are less of a problem, but long-term can also suppress REM and cause rebound. Zolpidem is better for sleep quality but can rebound, while ramelteon also has few side-effects but its efficacy is very mild.

On the other end of the spectrum from insomnia, hypersomnia is also quite common...

What is hypersomnia? What is narcolepsy and how is it treated?
The most common cause of excessive daytime sleepiness (EDS)? Lack of sleep. Narcolepsy is a special case where symptoms include EDS plus sleep cataplexy (sensation of weakness and increased emotion as REM intrudes into wakefulness with commensurate REM paralysis), and the associated sleep paralysis and hypnogogic hallucinations (waking dreams). "Sleep attacks" are not a marker of narcolepsy. Narcolepsy is due to an absence of hypocretin that leads to decreased DA and increased cholinergic signaling. Currently there is no cure - treatment is symptomatic for EDS modafinil while TCAs can be used to suppress REM during the day.

tomorrow a bit more about sleep disorders, and then CNS infections...

Fuseli's Nightmare

Polysomnography (PSG) is a recording of changes that occur during sleep using electrodes to measure eye movements, brain wave patterns, and muscle tone. PSG records: eye movements (EOG) with one electrode a little above the eye and the other a little below; brain waves (EEG) with a center and an occipital electrode; and muscle tone (EMG) from a submental electrode. The EOG works because the eye is a polarized organ (the retina is more negative and cornea is more positive), so when you blink and your eye moves down, the electrode a little above the eye records a negative (from retina), and the electrode below records a positive (cornea). The EEG may record three basic waveforms: alpha waves in relaxed wake state (with eyes closed), maximal in the occipital electrode; theta waves common in stage 1 and 2 sleep, strongest in central electrode; and delta waves in stage 3/4 sleep, usually in frontal lobes. On a typical PSG recording, the upper two traces are left & right eyes, then EEGs central (for strongest theta) and occipital (for strongest alpha), and the lowest trace is the EMG:

EOG
EOG
EEG (central)
EEG (occipital)
EMG

Waking State

EOG is flat with eyes closed, sometimes slow rolling
EEG shows alpha waves with eyes closed (no theta)
EMG shows muscle tone

Stage Uno

EEG shows > 15sec of theta waves (common in drowsy state)
EMG shows some muscle tone

Stage Two

EOG is silent for occular movements, but now underlying frontal brain waves are picked up.
EEG shows characteristic sleep spindles (bursts) and K-complexes (giant biphasic waves) in theory these represent responses to intrinsic stimuli.

Stage Three & Four

EEG shows slow delta waves for 20% - 50% of page (15sec out of 30sec page). When these large amplitude delta waves are >50% of page that's stage 4 sleep, otherwise there's no physiological difference between 3 and 4.

Phasic REM

EOG indicates REM
EEG is mixed, mostly theta, sometimes a characteristic "saw-tooth" wave
EMG is flat (REM paralysis)
Tonic REM is similar but eye movements are paralyzed (flat EOG).

Normally 50% of sleep is stage 2, broken up in three or four periods of ~1hr. Another 20% is stage 3/4 in one block early in sleep. REM takes up 20 - 25% of sleep, in blocks from a few minutes to half-hour long later in sleep.

PSG is the only certain diagnosis for obstructive sleep apnea...

Obstructive Sleep Apnea
Apnea means "without breath", sleep apnea is, well, stopping breathing while sleeping. The number of times there's no airflow or reduced airflow (hypopnia) for > 10 sec per hour sleep (the AHI, apnea-hypopnea index) becomes significant past 5/hr. Apnea can lead to awakening which is why it is associated with hypersomnia. Apnea carries a two-fold increase in risk for pulmonary hypertension. Sleep apnea can be obstructive (throat closes but there's still effort) or central (there's no signal to breathe). All patients with obstructive sleep apnea will snore (though not everyone who snores has sleep apnea). Generally obstruction occurs in all body positions because it is a functional rather than primarily structural problem. Since the problem is one of obstruction of the airway, the goal of treatment is to keep the airway open. Possibilities include CPAP (continuous positive airway pressure) which is 100% effective, as well as: oral plates, surgical U3P (cutting uvula, soft palate, tonsil & adenoid, and advancement of genioglossus), breaking & resetting the jaw, or tracheostomy in extreme cases.

Chronic CNS Infections
Here we look at examples of bacterial, fungal, and viral infections
First up bacterial - tuberculosis, syphilis and Lyme...

Mycobacterium tuberculosis is the leading cause of death by a single infectious organism. TB is slow growing (2 - 8 week prodrome), entering the lung and travelling to the meninges and brain parenchyma. So signs and symptoms are those of meningitis or encephalitis, as well as stroke (due to vasculitis) often with CN palsies because it's not uncommon for vasculitis to center on brainstem. The LP will show increased opening pressure and WBCs. Treatment then requires anti-mycobacterials ( ethambutol or streptomycin then isoniazid and rifampin).

Lyme Disease is another slow growing infection, this one a tick-borne spirochete (Borrelia burgdorferi). An early sign can be erythema migrans (bull's eye rash). In subsequent days/months you might see carditis, facial palsy similar to Bell's palsy, and peripheral neuropathies. In late/chronic stages you may see monoarthritis (commonly in knee) and chronic encphalopathy with mild cognitive problems. The diagonsitic is Lyme antibody in serum. Treatment involves doxycyclin or amoxicilin in inital localized cases, IV ceftriaxone or Pen G in later cases.

T. pallidum

Syphilis is also due to a spirochete - Treponema pallidum. These can be seen in biopsies from chancre with black light and is diagnosed by VDRL of the CSF. There are 4 forms of neurosyphilis: asymptomatic CNS syphilis, acute syphilitic meningitis (fever, HA, CN palsies...), meningovascular syphilis (presents with stroke), and parenchymatous syphilis (dementing long-standing form of syphilis). Treatment is with doxycyclin or Pen G

moving on to viral CNS infections - West Nile and JC Virus...

West Nile Virus is a mosquito-borne ssRNA virus that can directly invade neurons. However, only 20% are symptomatic and <1% of these are neuroinvasive. If the CNS is affected, patients may present with fever and headache; or if anterior horn cell infected may have flaccid paralysis; or with Guillain Barre Syndrome. Most cases showing meningitis have a full recovery, but only 20% survival with those showing encephalitis or flaccid paralysis.

Progressive Multifocal Leukoencephalopathy (PML) is a demyelinating condition that results from infection of oligodendrocytes with ds-DNA JC virus. JCV is almost an obligate viral infection (70-80% of the population) but becomes an issue in AIDS and with natalizumab treatment for MS. 90% of patients die in <12 months.

on to fungal infections - cryptococcus & aspergillus...

Symptoms of fungal CNS infections are mostly those of meningismus (fever, head ache, stiff neck). Cryptococcosis due to inhalation of a yeast C. neoformans is the most common, and appears in MRI as "soap-bubbles" in deep brain around basal ganglia. Aspergillosis is caused by A. fumigatis and is essentially isolated to immunosuppressed patients. Diagnosis uses a cryptococcal antigen. Both are treated with amphotericin B.

Now for a closer look at...

Bacterial Meningitis

What is the pathophysiology of bacterial meningitis?
Bacterial meningitis is infection of the meninges - arachnoid & pia - due to bacteria in the subarachnoid space. This is rare because even in cases where bacteria get into the bloodstream the BBB (tight junctions and rare pinocytosic vessicles) normally prevents them from entering the CSF. However, cytokines such as TNF α IL1 and IL6 can recruit WBC to sites of infection leading to breakdown of the BBB. When the vessel walls become leaky it allows CSF pressure to elevate in that space, compressing blood vessels and leading to progressive mental status deterioration. The CNS is an immune incompetent area (minimal Ig, low complement, low WBC...) so when bacteria get in they can replicate very quickly. Bacterial meningits is relatively rare, but shows ~25% mortality and 50% permanent neurological damage.

How is bacterial meningitis diagnosed?
If a patient comes in with two out of the four - headache, fever, stiff neck, or change in mental status - that's a start. Apparently the neck can be so stiff that you can lift them off the bed! Also bacterial meningitis is rapid, if the patient is still talking after 24 hrs it's probably viral instead. But if you think it may be bacterial, before drawing a CSF sample, you have to think about whether there may be a brain abscess. One way to do this is to look for "contiguous foci" of infection - otitis, mastoiditis, sinusitis, odontogenic, ... Other signs to look for might include meningococcal rash, a change in mental status, focal neurologic deficit, recurrent seizure, history of CNS lesion, or immunosuppression. If you do decide to get an image, start antibiotics while waiting, it won't affect subsequent interpretation of the CSF sample that much.
When you do the LP you're looking for opening pressure, and then in the sample looking for cells, glucose, protein, and infection by gram stain and culture. Additionally, you may do a viral culture (particularly in the fall), or look for cryptococcus if the patient is immunosuppressed, and sometimes test for syphilis (VDRL). If bacteria are in the subarachnoid space you classically see an opening pressure > 200 mm H20, WBC > 1000, protein >75%, glucose < 45 mg%, and presence of bacteria in culture/gram stain. There's also a reasonable chance of picking up the pathogen from a blood sample too (since that's likely how it got into the CNS originally if not due to trauma/surgery).

How is bacterial meningitis treated?
Most often bacterial menigits is due to S pneumoniae (gram pos), N. menigitidis (gram neg), and in patients >50, or if immunocompromised, Listeria monocytogenes (gram pos). Though cases that develop in the hospital (nosocomial) may be staph. So treatment of course involves antibiotics, but since tbe CSF is basically immune incompetent, you specifically want antibiotics that kill (eg β-lactams) like ceftriaxone in conjunction with vancomycin. Steroids are also important for this reason because you want to reduce cytokine release that will result from the initial phase of bacterial death and lysis. A short course of dexamethasone (decadron) given coincident or even just prior to antibiotics will not immunosuppress too much.

and we finish off with...

Brain Abscess

What is the pathophysiology of a brain abscess?
In addition to signs of contiguous spread that we looked for above (mastoiditis, peridontal abscess, etc.) haematongenous spread and trauma/surgery are other routes in brain abscess formation. Especially in cases of IV drug use, if infected needle introduces bacteria into the venous system, they will settle down on the first valve they see - tricuspid (they try before they buy). Here endocarditis can lead to formation of infected emboli that can spread to the brain. In cases of penetrating or post surgical infection you generally have staphylococcus, otherwise microaerophilic streptococcus is common in communicated infection. Other infectious agents that can lead to abscess formation include mycobacterium, aspergillus, toxoplasmosis, neurocysticercosis
A brain abscess itself is an accumulation of pus-filled (suppuration) in a space encapsulated by a thin wall of gliosis and collagen laid down by fibroblasts. Reactive WBCs cause hyperaemia and leaky vessels around the abscess which compresses parenchyma and blood vessels in the vicinity. The wall is usually thinner deep near the ventricles, so rupture here will cause intraventricular rupture of brain abscess (IVROBA). However brain herniation due to elevated intracranial pressure is the cause of 2/3s of the mortality.

How is a brain abscess recognized by imaging?
While fluid is still enclosed, diffusion weighted imaging (DWI) will show restricted water very brightly and can be used to help identify abscesses, however strokes also look like this since H2O is sequestered indying cells. MR-spectroscopy can distinguish the chemistry of the parenchyma from that of an abscess. An empyema in contrast to an abscess is not encapsulated; an infection in potential space (or body cavity) will have somewhere it can go. If it is an epidural empyemea it is limited by the sutures, but if it is a subdural empyema it can go pretty much anywhere.

A bit more on meningitis & encephalitis on Monday, plus general anaesthetics

Asceptic Meningitis

What is asceptic meningitis?
It's a bit of a misnomer since a wide variety of infectious organisms can cause asceptic meningitis. It's also sometimes called "viral meningitis" or "non-bacterial meningitis" (to distinguish it from the acute, life-threatening condition). Asceptic meningitis is characterised by signs and symptoms of meningitis and encephalitis, so to varying degrees: fever, headache, stiff neck, altered mental status, seizure, and/or neurologic deficits.

How is asceptic meningitis diagnosed?
When taking the history it'd be useful to ask about: Other infectious disease? Immunization history? Use of IV drugs? Current medications? In the exam you're looking for signs of meningeal irritation, focal neurologic deficits, mental status changes, meningococcal rash, or signs of contiguous infection. But when they come in all these patients get antibiotics to treat the most common bacterial pathogens while tests are performed. CSF analysis in asceptic meningitis will generally have a lower cell count, predominantly lymphocytes (as opposed to neutrophils), protein will be mildly elevated, glucose normal to low (2/3 serum glucose), culture & gram stain will be negative. (The WBC counts may need to be corrected if excessive blood is present in the sample from the LP - as a rule of thumb the correction is 1 WBC/ 700 RBCs).

What can cause aseptic meningitis?
Most causes are viral (enteroviruses, herpes, HIV, mumps, arboviruses, lymphocytic choriomeningitis LCM, etc), but may also be bacterial (rickettsiae/ mycobacterium tuberculosis), spirochetes (T. pallidum and B. burgdorferi), fungi (cryptococcus, histoplasma, coccidiodes) or due to other causes (endocarditis, vasculitis, etc). Turns out enterovirus accounts for ~90% of asceptic menigitis (especially in late summer). PCR of the CSF for enterovirus is generally the best diagnostic, but mostly this is self-limiting disease.

What can cause asceptic encpehalitis?
Causes include equine encephalitis (EEE, WEE), WNV, mumps, rabies, and herpes virus. An important consideration however is Rocky Mountain Spotted Fever (RMSF), if the history is suggestive of it even if there is no rash, due to the severity of this disease. Herpes virus HSV1/HSV2 is the most common cuase of sporadic encephalitis, and is very treatable. So all patients with encephalitis get treated for Herpes (acyclovir). PCR of CSF gives the diagnosis, and MRI often shows enhancement within temporal lobes. Rabies is a special case of progressive encephalomyelitis where once a patient develops symptoms the disease is 100% fatal, so post-exposure prophylaxis is key. This involves wound care, infiltration of the area with rabies Ig, and a series of rabies vaccine. If possible the animal is sac'd and you look for Negri bodies in the brain to confirm rabies. The CDC maintains a rabies hotline at # 877 554 4625.

CNS Infection in immunocompromised patients - particularly HIV

In the case of immunodepressed patients (HIV, transplantation, chemotherapy), the kind of CNS infections that are seen generally depend on the type of immunosuppresion: humeral, cell-mediated, or phagocytic:
Humeral immunodeficiency involves a decrease in B cells, antibodies/immunogblobulins. Causes of humeral deficits include chronic lymphocytic leukemia (CLL), splenectomy, and multiple myeloma. Pathological agents are generally viruses or encapsulated bacteria. Post-splenectomy sepsis (PSS) almost always involves pneumococcus because splenectomized patients cannot clear encapsulated organisms. For this reason all these patients should get pneumococcal vaccination.
Cell-mediated immunodefficiency involves a deficit in antigen-specific adaptive T-cell response. Causes of cell-mediated immunodefficiency include HIV/AIDS, lymphoma, organ transplantation (with subsequent steroids, cyclosporin, and/or tacrolimus to prevent rejection). Pathological agents commonly include fungi (cryptococcus, aspergillus), viruses (CMV, JCV, VZV), or parasites (toxoplasma). Multiple ring enhancing lesions in an AIDS patient are generally toxoplamosis, and empirical treatment (sulpha based) that shows improvement will give a clinical diagnosis. The main "confounder" is CNS-lymphoma which can appear similar in imaging.
Phagocytic immunodefficiency involves a deficit in neutrophil or macrophage function - a lack of superoxide respiratory burst. Causes of phagocytic deficits include neutropenia, Acute myelogenous leukemia (AML), and chemotherapy. Pathological agents are generally bacteria (staph) or fungi and less likely viral.

So, to recap: when considering CNS infection in immunocompromised patients...
What is the type of immunosuppression?
What pathogen(s) are likely?
Does the situation require emergency or empiric therapy?

moving on now to...

General Anaesthetics

What is anaesthesia?
Anaesthesia is a drug-induced, reversible depression of CNS that results in loss of response and loss of perception. Anaesthesia can be divided into 4 components: unconsciousness, amnesia, attenuation of autonomic reflexes, and immobility. Anaesthesia has also be divided into levels of sedation: where stage 1 is analgesia, stage 2 shows agitation, and stage 3 is what you're shooting for. Defined in terms of levels of sedation, with minimal to moderate (aka "conscious") sedation patients are still responsive and able to maintian adequate ventilation and cardiac function. But things get more difficult if patients slip into deep sedation where they may require ventilation. General anaesthesia is one step beyond that.

Where do anaesthetics work?
Actually no one really knows - though it is certain they do not act at the level of sensory receptors. Effects at the spinal cord level are known to affect immotility as shown by experiments with decorticate animal studies and effects on the f-wave in EMG. Effects of anaesthetics on the SC are also important in controlling autonomic responses. In terms of suppressing specific functions...
Campagna, 2003
Note the difference between perceptive awareness and explicit memory. This difference is exploited in a "wake up" test in which a patient is brought out from under anaesthesia just enough that they can respond to test motor function during surgery, and yet have no memory of the event.

How do anaesthetics work?
Most act on receptors, either facilitating inhibition (GABA) or inhibiting excitation. MAC (minimum alveolar concentration) is a measure of potency for inhaled anaesthetics. "MAC for movement" is the point at which 50% of patients can still make a purposeful movement in response to a noxious stimulus; at 1.3 X MAC no patient will move. "MAC-BAR" is suppression of autonomic reflexes (sympathetic response). Note that if you give two anaesthetics (as is commonly done with NO) their MACs are additive. Inhaled anaesthetics also show a concentration effect; as you increase the inspired concentration it causes (somehow) reduced lung volume and augmented tracheal flow which increases the effect of the anesthetic. Once the patient expires as much anaesthetic as the inspire, that's equilibrium. The rate of rise to equilibrium is faster at higher concentrations.
The blood:gas partition is the ratio of anaesthetic concentration in the blood vs concentration in the alveolus. eg halothane 2.54 versus NO 0.46. This means that a less soluble drug has a smaller "sink" to fill so acts quicker but is less potent, and more soluble has a larger "sink" to fill so it is slower to act but more potent. As you'd expect, increased alveolar ventilation has less of an effect on very insoluble (NO) agents than more soluble ones (halothane).

What are the common anaesthetic agents?
Nitric oxide solubility is low, so induction is fast but potency is low (its MAC > 100%) so NO is mostly used as an adjunct.
Halothane is more soluble so it is more potent, but may cause liver damage (hepatitis) and is a myocardial depressant
Isoflurane is a vasodilator, and not a myocardial depressant.
Desflurane is poorly soluble so less potent but boils at RT so requires a special vaporizer
Sevoflurane also has low solubility and so rapid induction

IV Anaesthetics
With IV you want a more soluble anaesthetic so you have a quicker "vein to brain" time.
Fentanyl has a short half-time when given for brief periods <2hrs, but becomes extremely long with extended infusion.
Thiopental (pentathol) is an induction agent, it is a barbiturate so it gets to the brain quickly and acts as a GABA agonist. Thiopental also appears to be cerebral protective, possibly due to metabolic suppression of neural function. Thiopental is redistributed to muscle and fat, which leaves a hangover effect.
Propofol is also very lipid soluble (in fact it comes as an emulsion which is where it get's the nickname "Milk of Amnesia"). Most commonly propofol is used ans an IV induction agent. It is cleared by the body, rather than redistributed, so its side-effect profile is lower than pentathol. But propofol does lower blood pressure. Propofol have a predictable half-time no matter how long they are given. Interestingly, different doses of propofol affect different parts of the CNS, light doses affect frontal cortex, then deeper thalamus and RAS, then spinal cord (immobility).
Entomidate is used for induction but not maintanence because it suppresses the adrenal. However it is very cardiovascular stable and so used for trauma or other patients with unstable blood pressure.
Ketamine is an NMDA antagonist that causes a dissociative state, and is also a very good analgesic. Benzodiazepines are often given in combination to attenuate psycomimetic effects. Ketamine too increases blood pressure and heart rate which can be helpful in some situations.

On to the last day of lecture...

Growth Cone Dylan T. Burnette

We pick up neural development where we left off earlier having completed nerulation, prosencephalic cleavage (5 vessicles at 5 weeks), neuronal proliferation and migration (eg along radial glia).
At birth then you have essentially all your neurons (with the exception of cerebellum and hippocampal structures). What you do after you're born is alter their connectivity (and add myelin). The process is strikingly similar among vertebrates: early embryonic stages look very similar and major aspects of molecular developmental pathways are often conserved. One of the big differences in human development is not so much a difference in gene number, but the modification and control of those genes.

Homeobox (HOX) Genes
HOX genes are an example of this conservation in vertebrate development. In flies these genes encode transcription factors important in telling tissues within a given body segment what to become (ie antennae or leg). A homeotic mutation abnormalities like antennapedia. In humans these genes function similarly, telling neurons in brainstem & spinal cord segments what to become (eg what target to innervate). For instance, trigeminal nerve usually forms at level 2 of the rhombencephalon (r2) and facial nerve usually forms at r4, but if you alter HOX expression such that r4 now thinks it's r2 you get a second trigeminal nerve at r4; it innervates the targets of trigeminal - so somehow it was programmed to respond to cues to guide it to a trigeminal target.

Axon Guidance
The tips of growing axons are highly dynamic. They extend lamellapodia and microspikes that sample cues in their environment. These cues can be chemoattractive or repulsive, and may act as long-range soluble molecules or short-range contact molecules (stuck to ECM or onto cell surfaces involving cell adhesion molecules and integrins). Often signals are set up in gradients to push and pull axons along. But axon guidance can only occur over relatively short distances, and so is largely confined to periods in early development when the embryo is still small.

Cell Death & Trophic Factors
In general, more neurons are made than are needed to innervate their target structures. For example, with innervation of limb muscle many axons will grow out initially and synapse with their target. Before contacting the target these neurons can survive without growth factor, but upon exposure to growth factor (released by the target) neurons become dependent on that factor from then on. Since you'd want more innervation of larger and/or more active structures, it makes sense that more muscle would produce more growth factor and maintain more neurons. But since you generally have more neurons than you need, you don't have enough growth factor to keep them all supplied and the remaining neurons apoptose (programmed cell-death). Though the specific growth factor involved in intial motor innervation is unknown, there are many classes of trophic factors, of which we discussed 5 today: NGF, BDNF, and NT3 (which preferentially bind to Trk-A, Trk-B, and Trk-C respectively and all 3 bind to the low affinity nerve growth factor receptor p75 receptor); CNTF (ciliary neurotrophic factor) produced by Schwann cells; and GDNF (glial derived neurotrophic factor) signals through GFR-α to activate RET kinase.
Similar to the control of cell number, you also make more synapses than you need, and these are pruned in a process called synapse elimination that also depends on activity and limiting amounts of trophic factors.

Hormonal control of neural development and sexual differentiation
In addition to guidance cues and growth factors, the brain also develops in response to hormones. In the case of sexual differentiation, these hormones depend on which genes you get from sex chromosomes. If you have no sex hormones, the default state is (basically) female; the male brain results from both masculinizing and defeminizing processes. The specific region on the Y-chromosome that determines male characteristics is called the TDF (testis determining factor) also called Sry (sex-determining region on Y). You can get cross over of this region with TDF on XX individuals who will be genetically female but have male phenotype, or conversely XY individuals who lose the TDF, are genetically male, but with female sex characteristics. In males the TDF tells the gonads to become testis, and testes in turn make testosterone and Mullerian-inhibitory hormone (MIH). (The actual signaling molecule is di-hydro-testosterone DHT, which is synthesized from testosterone by 5 alpha reductase).
Steroids can affect neurons directly via steroid receptors (eg within the sexually dimorphic nucleus of the hypothalamus), or indirectly as in the spinal nucleus of the bulbocavernosus muscle in rat. In the later case, testosterone acts on receptors on the smooth muscle which causes growth of the muscle & release of more growth factor and thereby maintains more of its innervation (anterior horn cells). In the female rat, testosterone receptors are also present on muscle initially, but in the absence of testosterone the muscle remains smaller and loses much of its motor neuron innervation.
Steroids also affect sexual behaviour, for instance testosterone is converted to estradiol by aromatase, and estradiol acting via PGE2 can generate male sexual behaviours in female rats (when administered during the appropriate critical perio. Converseley blocking PGE2 in males leads to more female-like behaviours. Steroids can also affect neural development in other ways, for example regulating dendritic spine density (here estradiol and PGE2 appear to have similar effects).

Tiger Swallowtail (Papilio glaucus) gynandromorph (left half male, right half female), © James Adams, 2004.
Collected at: Pigeon Mountain (west side), Walker Co., Georgia, April 16, 2004.

photo