MBB1: REVIEW OF WEEK 3 (These notes should serve as a framework for studying this weeks lecture notes.) I.

Mechanisms of pain A. Acute high intensity stimulation leads to one type of physiological or nociceptive pain. The stimulus may be thermal or mechanical. This is largely review. Note the parallel pathway by which pain information is projected to the anterior cingulate gyrus so that the emotional component of pain can be perceived. Remember that pain is the only sensation that always has a negative valence regardless of the intensity of the stimulus. B. Tissue injury/ inflammation leads to a different and more problematic type of physiological or nociceptive pain. Tissue injury is associated with an ongoing pain sensation, an enhanced repose to stimuli at the site of injury (primary allodynia and primary hyperalgesia) and an enhanced response to stimuli applied to adjacent uninjured regions (secondary allodynia and secondary hyperalgesia). Allodynia a normally non-painful stimulus is now painful. Hyperalgesia a previously painful stimulus is now more painful than it used to be. C. Many injuries of the nervous system lead to neuropathic pain. 1. Injuries to the peripheral sensory axon can lead to neuropathic pain. Spontaneous pain is due to ectopic (in the wrong place) activity from the traumatic neuroma at the site of injury and from the dorsal root ganglia associated with the injured axons. Evoked pain appears to arise from activation of A touch axons that in turn activate second order pain neurons in the dorsal horn due to a loss of local inhibition. 2. Some demyelinating lesions of the PNS or the CNS are associated with neuropathic pain due to abnormal mechanosensitivity in a region of demyelination. a. Tinels symptom occurs at a site of peripheral demyelination. b. Lhermittes symptom occurs with a region of demyelination in the dorsal columns of the cervical spinal cord. 3. Some regions of demyelination appear to lead to cross talk from demyelinated axons that are appropriately conducting trains of axon potentials (with some slowing that is not clinically significant in this region) to adjacent similarly demyelinated axons that should be silent. For example, in the condition trigeminal neuralgia, there usually is a region of demyelination in the trigeminal nerve close to where it enters the brain stem. The patient often reports that they have a small trigger point somewhere within the distribution of one of the divisions of the trigeminal nerve. When that point is touched, they experience a very severe, sharp, shooting pain often throughout the dermatome of that division. At other times that experience apparently spontaneous identical pains, which we presume were came from similar crosstalk that originated from normal afferent activity of which they were unaware. 4. Some destructive lesions in the ascending pain pathways produce neuropathic pain. The thalamic pain syndrome due to a lesion in the VP nucleus of the thalamus is the most common example.

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5. D.

Phantom pain is thought to at least partially be due to the formation of a neuroma in the region of the stump with ectopic activity originating in the neuroma. Peripheral and central modulation of the pain system (some of this is new) 1. The first order neurons use the transmitter glutamate and co-transmitters substance P, CGRP, and probably other neuropeptides. When these afferents are stimulated the neuropeptides are released both in the dorsal horn and by the peripheral processes in the periphery. The peripheral release may trigger local neurogenic inflammation. 2. There is a pain amplification system. Certain prostaglandins probably sensitize the peripheral nerve endings to pain stimuli by lowering the threshold of nociceptors. Certain prostaglandins also may increase the excitability of pain transmission in the dorsal horn. 3. There are capsaicin (also termed vanilloid) receptors at the peripheral terminals of the pain afferents. These receptors also respond to noxious heat stimuli. 4. The dorsal horn contains excitatory and inhibitory interneurons. The latter contain GABA, glycine, enkephalins, and other peptides. Many of these interneurons are located in the substantia gelatinosa of the dorsal horn. 5. One segmental mechanism for modulating incoming pain signals involves the inhibition of pain transmission by stimulation of large myelinated mechanoreceptor afferents that also enter this segment. This is the basis for the gate control theory of pain modulation. 6. Another segmental mechanism for modulating incoming pain signals involves increased pain transmission after repetitive activation of nociceptive fibers that enter this segment. This is called the windup phenomenon. 7. Descending supraspinal input also modulates incoming pain signals. This input comes from the descending pain modulation or endogenous analgesia system. The periaqueductal gray matter, which surrounds the cerebral aqueduct in the midbrain, the rostral ventromedial medulla especially the raphe nuclei that produce serotonin, and the locus ceruleus and adjacent pontomedullary nuclei all of which produce norepinephrine are important parts of this system. These CNS structures contain endogenous opioid neurons and receptors, are stimulated by opioids and mediate the analgesic effect of morphine-like drugs, receive input from the ascending nociceptive pathways, and when stimulated produce selective analgesia. Opioids activate the periaqueductal gray, which in turn leads to activation of the pontine and medullary serotonergic and noradrenergic nuclei, which project to the dorsal horn and directly or indirectly inhibit pain transmission. 8. Endogenous antinociceptive mechanisms are activated by stress, exercise, sexual activity, and previous physiological nociceptive stimulation.

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II.

Analgesics (See the drug list!) A. The NSAIDs (ibuprofen and acetaminophen) inhibit COX and lead to decreased prostaglandin synthesis. Prostaglandins are located at the afferent and efferent terminals of the first order pain neuron, where they serve as a pain amplification system. Thus, NSAIDs lead to decreased prostaglandins, decreased pain amplification, and decreased activation of the second order pain neuron for a given pain stimulus. They treat mild-to-moderate pain, as well as fever and (except for acetaminophen) inflammation. Important adverse effects include gastrointestinal side effects and decreased platelet aggregation that can lead to bleeding. B. Opioid analgesics include morphine (a full mu agonist) and buprenorphine (a partial mu agonist). Stimulation of mu receptors in the periaqueductal gray matter of the midbrain and in the spinal cord dorsal horn each strongly activates the descending pain modulation system. Opioids also act in the dorsal horn. Opioids are indicated for moderate-to-severe pain. Important side effects include sedation, respiratory depression, constipation, nausea/ vomiting, and the potential of abuse. C. Miscellaneous analgesics include the drug tramadol, which weakly stimulates mu receptors, and weakly inhibits SERT and NET. It is indicated for moderate pain. Adverse effects include dizziness, constipation, and nausea/ vomiting. Tramadol is one of the small number of commonly employed drugs that sometimes causes a seizure in an otherwise normal person. Drugs for neuropathic pain (See drug list!) A. Anticonvulsants. Note that facilitation of gabaergic (GABAA) transmission and prolongation of the inactivation stage of the voltage gated sodium channel each might treat neuropathic pain and seizures! So we are not surprised to find at least some antiepileptic drugs on this list. 1. Gabapentin probably enhances gabaergic transmission and is commonly used for the treatment of neuropathic pain. Dose related CNS depression is a common side effect at higher doses with sedation and ataxia. Weight gain may occur. Remember that gabapentin is excreted unchanged in the kidneys there is no hepatic metabolism. 2. Carbamazepine prolongs the inactivation stage of the voltage gated sodium channel. This presumably prevents the transmission of high frequency but not lower frequency action potentials. Sedation and ataxia occur at higher doses. Double vision can occur at otherwise non-toxic doses. Leucopenia always occurs to a small degree and may occur to a significant degree. There may be hyponatremia. Carbamazepine is particularly effective at treating sharp shooting neuropathic pains such as the pain of trigeminal neuralgia. Phenytoin has a similar mechanism of action and mostly similar dose related adverse effects. Gingival hyperplasia, coarsening of facial features acne and hirsutism are additional side effects. 3. Topiramate blocks Na+ channels and enhances gabaergic transmission. It also has some carbonic anhydrase activity (relevant to side effect profile).

III.

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B.

Adverse effects include cognitive problems and weight loss. Metabolic acidosis and kidney stones may occur. Antidepressants. Note that increasing norepinephrine and perhaps serotonin may activate the descending pain control system, and certainly treats depression. So we are not surprised that some antidepressant drugs effectively treat neuropathic pain. 1. Amitriptyline is a tricyclic antidepressant that inhibits NET and SERT. (Tricyclics are dirty SNRIs they inhibit NET, most also inhibit SERT, and most have some degree of antimuscarinic, anti-1, and anti-H1 activity.) Adverse effects often are due to its anti-mAChR effect and include dry mouth, blurred vision, urinary retention, and delirium (particularly in the elderly or cognitively impaired). Its 1 antagonist effect may lead to postural hypotension. Its H1 antagonist effect might lead to sedation, increased appetite and weight gain. It has a low therapeutic index. Cardiac arrhythmias can occur and can be difficult to treat. 2. Duloxetine is an SNRI that inhibits SERT and NET. Adverse effects can include gastrointestinal disturbances, sedation, and sexual dysfunction.

IV.

Mechanisms of headache A. There are no pain receptors in the brain. Nearby pain sensitive structures include the cerebral arteries and venous sinuses, much of the dura at the skull base, and periosteum of the skull. B. Trigeminal neuralgia is an uncommon head pain disorder that serves as our prototype of a sharp, shooting neuralgic pain. The pain is in the territory on one division of the trigeminal nerve, is always severe, is very brief (lancinating) each time that it occurs, and may occur spontaneously or be triggered by a normal touch stimulus in the territory of the trigeminal division. The pain appears to arise from cross talk between axons in a small region of demyelination near the root entry zone of the nerve. C. Cluster headache is an uncommon disorder of unknown pathophysiology in which there is severe boring pain in the orbital or periorbital region that lasts an average of 45 minutes. D. Tension headache is a common disorder in which there are band like steady headaches that last many hours and may be of any severity. The pathophysiology is not known and there is no relation to emotional stress or muscle tension. E. Migraine is a very common disorder in which there are unilateral throbbing headaches that last an average of about 4 to 6 hours and may be associated with nausea/ vomiting and excess sensitivity to external stimuli. Each headache can be mild, moderate, or severe. The headache sometimes is preceded by an aura which may include negative and positive neurological symptoms such as a visual aura, or even cognitive changes such as aphasia. The pathophysiology of migraine is thought to be related to neurovascular mechanisms.

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V.

Drugs for headache (See drug list!) A. Drugs for tension headaches include NSAIDs and amitriptyline, which already have been discussed. B. Drugs that abort an acute migraine make it go away, or at least decrease in intensity and duration. 1. NSAIDs have been discussed. 2. Triptans (sumatriptan) are 5-HT1B/1D agonists. Presumably they stimulate 5-HT1B/1D receptors on nerve terminals of the trigeminal sensory axons, which leads to decreased release of substance P and CGRP. Also, stimulation of 5-HT1B/1D receptors on vascular smooth muscle in the meninges leads to vasoconstriction. Side effects include paresthesias, flushing, dizziness; a tightness or pressure in the chest; and vasospasm. Triptans are contraindicated in patients with coronary artery disease, stroke, peripheral vascular disease, and uncontrolled hypertension. They should not be taken with MAO inhibitors. C. Drugs for the prevention of migraine. Note that the mechanism of the antimigraine action is not known for any of these drugs! 1. Propranolol is a beta antagonist - it blocks beta receptors. It has the expected beta antagonist side effects including depression, hypotension, exacerbation of asthma, and sexual dysfunction. 2. Verapamil is a calcium channel blocker that inhibits L-type Ca++ channels. Adverse effects include decreased heart rate, AV block, and constipation. 3. Amitriptyline is a tricyclic antidepressant that inhibits NET. (See discussion of side effects in drug list above.) 4. Divalproex is an antiepileptic drug that blocks Na+ channels and T-type Ca++ channels. Adverse effects include weight gain, alopecia (hair loss), and tremor. 5. Topiramate is an antiepileptic drug that has been discussed. 6. Ibuprofen is a NSAID, a COX inhibitor. It may have some utility as a migraine preventive agent. NSAIDs have been discussed. 7. Botulinum toxin appears to have some utility as an anti-migraine agent. It was discussed above. D. Drugs for treatment of cluster headache include the following. 1. Inhaled oxygen is highly effective in aborting individual cluster headaches in many patients. The mechanism of action is not known. It should not be used in patients with severe COPD, who may develop severe hypercapnia. 2. Sumatriptan is one of the triptans, which are 5-HT1B/1D agonists. The mechanism of action for aborting cluster headache is not known but is presumed to be the serotonergic activity. Triptans were discussed above. 3. Verapamil, the calcium channel blocker discussed above, has some utility in the prevention of cluster headaches. Integrated sensorimotor systems A. Lesions of the PNS often lead to combinations of somatosensory, motor and sometimes visceral dysfunction in the territory of the PNS structure(s) affected. 1. A focal lesion of a peripheral nerve is a mononeuropathy.

VI.

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2.

B.

A diffuse lesion of peripheral nerves is a polyneuropathy. Most are symmetrical and predominantly distal. 3. A lesion of a dorsal root, ventral root, or spinal nerve is called a radiculopathy. Lesions of the spinal cord also often lead to combinations of somatosensory, motor and sometimes visceral dysfunction. Myelopathy refers to spinal cord dysfunction and most often is either focal or diffuse.

1.

2.

Complete focal myelopathy of one spinal cord segment. (A) As expected, lose all somatosensation at and below the level of the lesion, have UMN syndrome below the level, have LMN syndrome at the level. a. With an acute lesion, there often is spinal shock with the spinal cord caudal to the lesion losing all function for days, weeks, or a few months after the injury. b. Episodes of autonomic dysreflexia occur in up to 85% of individuals with a focal spinal cord injury located at or above the T6 level and are brought on by a noxious stimulus (most frequently bladder distention) below the level of the lesion. Because of the loss of supraspinal inhibition, the normal local reflex and generalized sympathetic responses of tachycardia and vasoconstriction to the stimulus may be greatly exaggerated. Vasoconstriction leads to hypertension, which may trigger carotid bulb and atrial baroreceptors. This in turn leads to vagal discharges and slowing of the pulse (sometimes to a significantly bradycardic level) and to decreased sympathetic activity above the level of the lesion. However vasoconstriction and resulting hypertension persist. Spinal cord hemisection, focal at one spinal cord segment. (B) As expected but surprising for patients, lose all somatosensation and LMN ipsilateral at the level of the lesion, ipsilateral UMN syndrome below the level of the lesion, ipsilateral loss of proprioception and discriminative touch below the level of the lesion, contralateral loss of pain and temperature below the level of the lesion.
Syndrome of the anterior white commissure due to an uncommon focal lesion that is confined to the anterior white commissure and extends over many levels. As expected,

3.

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4.

loss of pain and temperature sensation in the dermatomes corresponding to the levels of the lesion. Central cord syndrome due to a focal lesion at one segment of the cord that causes dysfunction of bilateral spinothalamic tracts but spares the most peripheral axons that convey somatosensation from the sacral dermatomes. (C) As expected, loss of pain and temperature below the level of the lesion with sacral sparing. Also, bilateral LMN syndrome at this level, and perhaps additional deficits depending on other structures involved.

5.

C.

Syndrome of midline external compression. (D) This is focal segmental lesion is the most common spinal cord syndrome outside of acute traumatic spinal cord injuries, and it does not present as expected. UMN syndrome below the level of the lesion, with lower extremities affected first and worst regardless of the level; loss of proprioception and discriminative touch in a similar distribution; midline ataxia and sometimes lower extremity ataxia, neurogenic bladder. Remember that these same tracts share a number of selective vulnerabilities. In MBB2 we will learn about a number of diffuse disorders that present with dysfunction in this distribution in these tracts 6. Anterior spinal artery syndrome (E). A stroke of the anterior spinal artery can lead to a multi-segmental lesion of the anterior two-thirds of the spinal cord. As expected, there is an UMN syndrome and loss of pain and temperature sensation below the level of the lesion. The dorsal column sensations are spared. This can be the presentation of an aortic dissection. 7. Dorsal column syndrome. A focal lesion of the dorsal columns leads to the expected loss of proprioception and discriminative touch below the level of the lesion. Cranial neuropathies. Remember that for all clinical purposes the cranial nerves (except the optic nerve) are ipsilateral for example, the right brainstem connects to the right cranial nerve connects to peripheral structures on the right. We discuss complete lesions with total loss of function. In practice, you often will see patients with partial lesions of cranial nerves. 1. Lesion of oculomotor nerve complete ptosis, fixed and dilated pupil, lens that cannot accommodate for near vision, eye that appears to be fixed in the fully abducted position; and because the eyes do not line up with each other, the patient reports double vision (diplopia)

2. 3.

Lesion of the trochlear nerve eye that cannot move down when it is fully adducted; again the patient reports diplopia Lesion of the abducens nerve eye that cannot abduct beyond the midline; again the patient reports diplopia

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4.

Lesion of the sympathetics to the eye (not a cranial nerve, but we learn this syndrome here) mild ptosis, miosis, anhidrosis if all branches are involved (remember that the sympathetics to the eye travel rostrally along the carotid artery, then divide with the branches to the eye going with the internal carotid and the branches to the sweat glands of the face going with the external carotid)

5. 6.

Lesion of the trigeminal nerve complete loss of somatosensation in the trigeminal dermatomes, LMN syndrome of the muscles of mastication, hyperacusis in the ear Lesion of the facial nerve paralysis of all (as expected!) muscles of facial expression (including frontalis), loss of tearing, loss of taste on the anterior 2/3 of the tongue, hyperacusis; do not confuse with facial weakness that occurs with a contralateral UMN lesion that spares the frontalis muscles (depicted on the right)!

7.

D.

Lesion of glossopharyngeal nerve loss of gag reflex with stimulation of posterolateral pharynx on this side; gag reflex is gentle pressure with tongue blade to posterolateral pharynx on one side and bilateral elevation of the soft palate 8. Lesion of vagus nerve LMN syndrome of soft palate and larynx 9. Lesion of spinal accessory nerve LMN syndrome of sternocleidomastoid (rotate head to opposite side) and trapezius (shrug shoulder) 10. Lesion of hypoglossal nerve LMN syndrome of tongue, including when asked to protrude tongue into the midline it will go to the side of the lesion 11. Cerebellopontine angle syndrome facial nerve and vestibulocochlear nerve exit the brain stem together in the cerebellopontine angle and travel together to enter the internal acoustic meatus; bad things sometimes happen in the cerebellopontine angle Upper motor neuron innervation of the brain stem nuclei that give rise to the cranial nerves (this is mostly new) 1. We understand that the LMNs in the facial motor nucleus that supply the frontalis muscle are supplied by UMNs that have nerve cell bodies in contralateral primary motor cortex and by UMNs that have nerve cell

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E.

F.

G.

bodies in ipsilateral primary motor cortex. And we know that the LMNs in the facial motor nucleus that supply the rest of the muscles of facial expression are innervated only by UMNs with nerve cell body in the contralateral primary motor cortex. What about the UMN innervation of the LMNs located in the other brain stem nuclei? 2. The following are like the frontalis, with bilateral innervation. a. The nucleus ambiguus (large font even if this is the first you have heard about it) is hard to see but desperately important. It is in the lateral rostral medulla and contains the nerve cell bodies that are the LMNs for the glossopharyngeal nerve and especially the vagus nerve. The nucleus ambiguus is innervated by bilateral UMNs. 3. The following are like or nearly like the other muscles of facial expression with strictly or predominantly contralateral innervation. a. The motor nucleus of the trigeminal nerve is predominantly innervated by contralateral UMNs, but there is some innervation by ipsilateral UMNs. b. The motor nucleus to the trapezius is innervated by contralateral UMNs. c. The motor nucleus to the sternocleidomastoid is problematic. Anatomists tell us that it is innervated by contralateral UMNs, though this often does not appear to be the case clinically. d. The hypoglossal nucleus is innervated predominantly by contralateral UMNs. 4. We could summarize this as follows. The frontalis muscle and the muscles of the pharynx and larynx are supplied by bilateral UMNs. The rest of the muscles innervated by corticobulbar axons are entirely or predominantly supplied by contralateral UMNs. The muscles of the body are under strict contralateral control. Some brain stem reflexes (this is partly new) 1. Pupillary light reflex: shine a light in one pupil and both pupils get smaller; ipsilateral optic nerve in, bilateral oculomotor nerve out 2. Jaw jerk: the muscle stretch reflex for the masseter and temporalis muscles, tap the partly open jaw and these muscles contract; V3 in and Vmotor out 3. Corneal reflex: gently touch a cornea and both eyes blink; ipsilateral V1 in, bilateral facial motor nerve out 4. Gag reflex: gently touch the posterior pharynx on one side and bilateral soft palate goes up (forget the uvula!) and bilateral posterior pharynx comes in; ipsilateral glossopharyngeal in, bilateral vagus out Respiratory insufficiency may be due to a neurological lesion that leads to weakness of one or both diaphragms. This includes bilateral UMN lesions above the diaphragmatic nuclei that are located in the C3-C5 spinal cord segments, LMN lesions in the phrenic nerves or their nerve cell bodies, neuromuscular junction lesions, or myopathies that affect the diaphragm. Speech is a complex neuromuscular process that can be disrupted by lesions at many levels of the nervous system. A disorder of speech is called dysarthria.

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H. I.

J.

Swallowing is simpler and more stereotyped than speech. A disorder of swallowing is called dysphagia, which may be due to difficulty with the initiation, nasal regurgitation, or aspiration. Ataxic hemiparesis most often is caused by a partial unilateral focal lesion of the basis pontis. The patient has a mild contralateral hemiparesis because of the involvement of the pyramidal tract. They also have a mild contralateral hemiataxia because of the involvement of the descending corticopontine axons, the pontine nuclei, and the axons projecting from the pontine nuclei. Disorders of posture and gait 1. A waddling gait is due to bilateral weakness (of any localization) of the hip girdle muscles. It most often is seen in patients with diffuse proximal myopathy. 2. A steppage gait is due to weakness of foot and toe dorsiflexors. It most often is bilateral and due to a diffuse polyneuropathy that affects motor fibers in the distal lower extremities. 3. A spastic hemiparetic gait is due to an UMN syndrome of the extremities on one side. 4. A spastic paraparetic gait is due to bilateral UMN dysfunction of the lower extremities. 5. An ataxic gait is due to a lesion of the vermis or the spinocerebellar tracts. 6. A parkinsonian gait is due to bilateral lesions of substantia nigra (pars compacta), putamen (neurons that give rise to excitatory pathway), or (parts of the) globus pallidus.

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VII.

Bladder system

A.

B.

The urinary bladder is a bag for efficient urine storage. It is a big smooth muscle called the detrusor muscle. Parasympathetic axons from the detrusor nucleus in the conus medullaris lead to contraction of the detrusor muscle and bladder emptying. Sympathetics lead to bladder filling by relaxing the detrusor and contracting the internal sphincter at the bladder neck, but do not seen to be critical for bladder function. Somatic motor fibers from the conus supply the external urethral sphincter, which is the only striated muscle in the system. There are somatic and visceral afferents that project to reflex centers and consciousness. The parasympathetic and sympathetic centers are visceral, and so they are under reflex rather than conscious or voluntary control. 1. The parasympathetic center receives afferents from the bladder wall. When the bladder is emptying, the parasympathetic center keeps emptying the bladder until it is empty or until the reflex is consciously turned off. This center sometimes can be involved in the initiation of the reflex if there is a lesion in the brain stem centers.

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2. C.

D. E.

The sympathetic center receives afferents from the bladder wall. When the bladder is filling, the sympathetics lead to detrusor relaxation, which facilitates further filling. Patients do surprisingly well without this center. The pontine micturition center receives afferents from the bladder. When the bladder is full, the pontine micturition center initiates the void by activating the detrusor nucleus. The center simultaneously leads to relaxation of the external urethral sphincter so that the void is properly coordinated. This leads to a fully functional, but socially inappropriate bladder. The cerebral cortex tonically inhibits the pontine micturition center. When the time and place are right, the cortical inhibition is released consciously, and the pontine micturition center initiates the coordinated void. The cystometrogram is a pressure volume curve that depicts the function of the urinary bladder. The range of normal bladder function is shown in the upper left.

F.

A neurogenic bladder is a urinary bladder that is dysfunctioning due to a neurological lesion. Typically bilateral lesions are required to cause a neurogenic bladder. Know urge (usually feel the urge, cannot get to the toilet in time, and wet self partially or completely), overflow (usually constant low level leaking), and stress (wet self with increased abdominal pressure typically not neurological) incontinence. Know urinary frequency (too often), hesitancy (difficulty starting and maintaining the stream), and retention (incomplete emptying that may be partial or total). Know detrusor-sphincter dyssynergia (bladder contraction and external urethral sphincter relaxation are not well

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G. H. I.

synchronized; esoteric name, but makes sense, common, and clinically relevant because of predisposition to urinary tract infection). Uninhibited neurogenic bladder lesions above the pontine micturition center, as expected urges, frequency, and physically healthy voids that come at the wrong time (lower right) Automatic neurogenic bladder lesion between the pontine micturition center and the conus medullaris, as expected like uninhibited except some degree of urinary retention due to detrusor-sphincter dyssynergia (lower left) Lower motor neuron neurogenic bladders lesion of the reflex arc that maintains the void, as expected overflow incontinence, hesitancy, retention, and significant post void residual (the final three curves)

VIII.

Drugs for neurogenic bladder simple drugs with simple mechanisms of action that make sense and predict most of their adverse effects (See the drug list!) A. For the uninhibited and automatic neurogenic bladders we block parasympathetic overactivity with antimuscarinics such as oxybutynin. Sometimes we use local botulinum toxin. B. For detrusor-sphincter dyssynergia, local botulinum toxin injections into the external urethral sphincter are sometimes helpful. C. For the lower motor neuron neurogenic bladders we sometimes try to add to the remaining parasympathetic activity with a cholinomimetic drug such as bethanechol. More often we recommend catheterization. Sexual system A. The sexual systems are equally important, but are more complex, less well studied (particularly in women) not as well understood, and have many fewer clean localizations. We discuss the male, and note that it is reasonable to suppose that the equivalents apply to the female. B. Penile erection occurs by means of increased activity in the parasympathetic segmental reflexogenic erection pathway, increased activity in the sympathetic psychogenic erection pathway, and decreased activity in the sympathetic inhibitory pathway. Erection is terminated by activation of the sympathetic inhibitory pathway. C. Ejaculation involves emission of seminal fluid into the urethra and then ejaculation proper in which the seminal fluid is propelled out of the urethra with orgasm. Orgasmic sensations and rhythmic contractions of the pelvic floor are part of the process. D. Neurogenic sexual dysfunction can include lack of conscious pleasurable sensations, erectile impotence, anorgasmy, and retrograde ejaculation. It typically takes bilateral lesions to cause neurogenic sexual dysfunction. These disorders and their treatment will be discussed in other courses. Olfactory system A. Olfactory nerves detect odiferous molecules that are dissolved in the mucous in the roof of the nasal cavity. They project through the cribriform plate of the ethmoid bone and synapse in the olfactory bulbs. Those neurons project back

IX.

X.

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B. C. D. XI.

through the olfactory tracts to the primary olfactory cortex mostly in the region of the anterior parahippocampal gyrus and uncus. The olfactory system is ipsilateral. The neurosensory cells are constantly turning over. Anosmia is a loss of the sense of smell. The patient most often reports that food has lost much of its taste.

Gustatory system A. The taste receptors are in the taste buds, which are primarily on the tongue. The receptors detect salt, sweet, sour, bitter, and umami. B. Taste information mostly is projected on the facial nerve to the brain stem nucleus of the solitary tract, which in turn project via other nuclei to the primary gustatory area of the cerebral cortex located posteriorly to the somatosensory area for the mouth. C. The gustatory system probably is ipsilateral. D. The psychological experience of taste probably is mostly derived from olfactory inputs, secondly from true gustatory inputs, and somewhat from texture and pain inputs. Auditory system A. Sound waves are composed of pure tones that have frequency (Hz) and intensity (dB). Perceived pitch is related to frequency. Perceived loudness is related to intensity. Normal hearing is in the frequency range 20 to 20,000 Hz. Normal speech is in the range 250 to 4,000 Hz. B. The auditory pathway 1. Sound is collected by the external ear, which also boosts by resonance speech frequencies, and leads to vibration of the tympanic membrane. 2. The middle ear transmits the vibration from the tympanic membrane to the oval window of the labyrinth by means of three bones; and contains two muscles innervated by two different cranial nerves that each dampens vibration due to loud sound to protect the cochlear hair cells from acoustic trauma. The facial nerve innervates the stapedius muscle. The trigeminal nerve innervates the tensor tympani muscle. The middle ear is located in the petrous portion of the temporal bone. 3. The inner ear (also called labyrinth) is located in the petrous portion of the temporal bone. The holes in the temporal bone are called the bony labyrinth and are filled with a CSF-like fluid called perilymph. Within the bony labyrinth is a structure called the membranous labyrinth. It is filled with a potassium rich fluid called endolymph that is made in the stria vascularis. a. The hearing portion of the bony labyrinth is called the cochlea. It is about 3.5 cm in extent, and has the shape of a snail shell with 2 and turns. b. The hearing portion of the membranous labyrinth is called the cochlear duct.

XII.

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c.

The auditory sensory organ, called the organ of Corti, is located within the cochlear duct.

A. unroll the cochlea (sound in)

oval window round window

B. look at a cross section

to brain stem Spiral ganglion perilymph corti VIIIa perilymph bony wall endolymph stria vascularis (makes endolymph) bas ilar membrane (moves up & down in res ponse to sound waves )

perilymph endolymph perilymph

(pressure relief valve)

cross section

C. look at the Organ of Corti tectorial membrane (stays fixed when bas . memb.
moves up and down) outer hair cells (efferent!) inner hair cell (afferent) bas ilar membrane

C.

D.

E. F.

The cochlear portion of the vestibulocochlear nerve projects from the organ of Corti through the internal auditory meatus and enters the brain stem at the cerebellopontine angle. The nerve cell bodies for this bipolar neuron are located in the spiral ganglion within the cochlea. Just inside the brain stem the cochlear portion of the nerve synapses on the cochlear nuclei. The cochlear nuclei then project rostrally bilaterally by means of the lateral lemnisci. Some fibers synapse in the superior olivary nuclei (important for sound localization). Many proceed to synapse in the bilateral inferior colliculi. Each inferior colliculus projects to the medial geniculate (MG) nucleus of the thalamus. Each medial geniculate has reciprocal projections with the primary auditory cortex that is located on in the transverse temporal gyri on the superior temporal gyrus within the lateral fissure. Neural coding in the auditory system the map for the labeled lines is tonotopic, intensity of sound is coded by increased firing rate and increased number of neurons firing Deafness syndromes 1. Hearing loss in one ear is due to a lesion in the external ear, the middle ear, the cochlear portion of the inner ear, the cochlear portion of the vestibulocochlear nerve, or the cochlear nuclei in the lateral medulla. Unilateral lesions rostral to the cochlear nuclei typically do not produce hearing loss because of the bilateral nature of the projections from the cochlear nuclei. 2. If the lesion is in the conduction system external ear or middle ear then the hearing loss is called conductive.

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3. 4.

5.

If the lesion is in the sensory or neural system cochlea, nerve or nucleus then the hearing loss is called sensorineural. If the patient has hearing loss in one ear, then the Weber test (vibrating tuning fork to forehead, heard in each cochlea due to direct vibrations of the bones that lead to vibrations of the sensory organ) will localize the hearing loss as conductive or sensorineural. If the sound is louder in the good ear, then the hearing loss is sensorineural. This makes good sense. If the sound is louder in the bad ear, then the hearing loss is conductive. This is unexpected, and may be due to increased resonance in closed off portions of the ear. The pure tone audiogram also is different in patients with conduction deafness and patients with the most common types of sensorineural hearing loss.
Normal x x x x x conduction deafness x x x mos t common x x sensorineural deafness , esp "acous tic trauma" (loud nois es )

Audiogram
dB of loss

250 Hz

4000Hz

6.

Presbycusis is high frequency hearing loss with age. It's common, but not due to normal aging. It is partly related to a lifetime of acoustic trauma.

G.

Auditory evoked potentials provide an objective, electrophysiological measure of the well being of the auditory pathways. They most commonly are used to screen for otherwise undetectable hearing loss in patients who are difficult to examine (like neonates).

XIII.

Vestibular system A. The membranous labyrinth lies within the bony labyrinth. utricle
superior semi circular canal d u c t (a l s o c a l l e d a n t e r i o r ) posterior sem icircular canal duct horizontal sem icircular canal duct (also called saccule l a t e r a l) w i t h a m p u l l a drawn but not labeled anterolateral view of L m em branous labyrinth

cochlear duct ductus reuniens

MBB1 review of week 3, page 16

B. C.

Vestibular hair cells are "directional": increase rate of firing when bend toward the kinocilium, decrease rate of firing when bend away from kinocilium. Macula. A vestibular sensory organ designed to detect tilt to any side relative to gravity, and linear accelerations. One in saccule, one in utricle. posterior view of R utric.

macula:
A. u tricle
o to co n ia = o to lith s = ro ck s stick y membran e h air cells VIIIv en d o ly mp h x x xx x x x x x

B.

x x x x xx

C.

gravity

xx

gravity
x

nothing happens
Th e u tricu lar macula

* (similarly, there is firing of L utric. macular branch)

tilt h ead to , h air cells b en d b ecau se o f weig h t o f o to lith s s o tilt firin g rate o fb ran cho f v es tib u lar nerv e fro m u tricu lar macu la* an d co n tin u es to fire as h ead s tay s tilted

D. (small font concept)

x x x xx x gravity
linear acceleration to left produces same effect as head tilt to

E. The saccular macula detects linear accelerations in upright person.

D.

Crista ampullaris. A vestibular sensory organ designed to detect angular acceleration, it resides in the ampulla of each semi-circular canal duct.

A. horizontal semicircular
canal duct from the top a = ampulla a medial lateral

B. the ampulla

cupula blocking canal

VIIIv cris ta ampullaris (includes hair cells) hair cells with "hairs stuck into cupula

C.

R horizontal SCC duct. Rotate/turn head to the right: Head turns, petrous bone turns, bony & membranous labyrinths turn, cupula and crista ampullaris turn but endolymph stays put (at least for 15-20 sec.). So, effectively, it is as if endolymph pushes on cupula as shown to the left. Hair cells bend. Head turn to R causes "stimulation" of R horizontal SCC duct hair cells and firing of branch of R vestibular nerve from this duct. Similarly, there is firing of L horizontal SCC duct branch.

MBB1 review of week 3, page 17

D.

E.

This system shuts off after 15-20 of rotation but this rarely if ever occurs in normal life. E. L horizontal SCC duct designed to "detect" head rotation to L F. Anterior and posterior SCC ducts are designed to detect head rotations in other directions. G. Any head rotation (angular acceleration) can be detected by its net effect on each of the three pairs of SCC duct systems. Central Pathways vestibular nerve ipsilateral vestibular nuclei ascending and descending projections 1. Vestibulo-spinal Function Tilt head to R, stimulate R utricular macular, leads to activation of ipsilateral vestibulo-spinal tract, which generally increases extensor tone on this side of the body, which leads to maintenance of the upright posture. This is a major component of the descending extrapyramidal motor pathways. 2. Vestibulo-ocular Reflex (VOR) Rotate/turn head R, stimulate R horizontal semicircular canal duct vestibular organ, leads to lateral movement of eyes to the L to maintain gaze fixed in space. Leads to activation of L VI nerve, R III nerve. Projections in the medial longitudinal fasciculus (MLF).

MR III MLF VI VIIIv LR

The VOR keeps eyes fixed in space despite head movements. There is a more complex VOR for head movements in other directions. VOR works in dark, can be voluntarily suppressed or overridden. 3. 4.
5. 6.

Turn head Ey es move L

Vestibulo-cortical (conscious awareness) Vestibulo-autonomic (nausea, vomiting, vasomotor changes)

Vestibulo-cerebellar (important but complex & beyond the scope of this course) Descending MLF (another pathway of descending extrapyramidal system)

F.

Functional considerations 1. Eyes don't stick to L; there is a fast "corrective" eye movement to the & then this process of slow eye movement to L, fast movement to continues as long as this stimulation continues. This is called " beating" (after the fast component) vestibular nystagmus. Vestibular nystagmus is one of many different types of nystagmus. 2. Stimulation of labyrinth ~ vestibular nerve ~ vestibular nuclear is complex but often (certainly not always) looks like stimulation of (1) utricular macula and (2) horizontal semicircular canal organ. This leads to body tilting to L and tonic slow deviation of eyes to the L. 3. "Destructive" lesion of L labyrinth, nerve, nuclear complex looks like stimulation of labyrinth (because the vestibular system works by tonic output from each side at rest), which leads to tilt to L and slow eye MBB1 review of week 3, page 18

4.

5.

6.

deviation to L, fast movements to . "Fall to side of lesion" "Nystagmus with slow component toward lesion". Destructive lesions often are followed by significant compensation. This compensation is driven by the imbalance between the normal and the abnormal sides. So, the principle of using vestibulosuppressant drugs (H1 receptor antagonists, antimuscarinics, benzodiazepines) is to give the patient enough so they are not miserable, but do not try to completely suppress the symptoms of vestibular imbalance. And educate them to this effect! Understand the ice water caloric test. Standard position (supine, head up 30 to make the horizontal canals vertical) ice water irrigation of L ear acts like temporary destructive lesion of L vestibular apparatus stand up and tilt to L, nystagmus with slow phase to the L ("eyes to the ice"). (A reflex with VIII vestibular in; ipsilateral VI and contralateral III out.) Understand the Romberg test. Stand with feet together, feel steady, close eyes. Need proprioception and vestibular system to stay upright. If either one is sufficiently out, the patient will start to fall, but you will anticipate and catch them.

XIV. Eye movement control systems A. Each eye is moved by 6 extraocular muscles that are innervated by ipsilateral cranial nerves III, IV, and VI B.
MR III VI L LR

Know (LRVI SOIV) III

LR

SR

IO

MR

MR

IO

SR

LR

IR SO RE

SO IR LE

VOR eye movements are effected by neurons in the vestibular nuclei and serve to hold an image fixed on the fovea and retina during head movements. VORs do not require a target and may be suppressed voluntarily.

Vestibular nuclei

MBB1 review of week 3, page 19

C.

Smooth pursuit eye movements maintain a target fixed on the fovea. The pathway is complex and not easily understood. Horizontal smooth pursuit to the left would include
L cerebral cortex L cerebellum

vestibular nuclei

D.

Then, the right vestibular nucleus would effect the smooth pursuit eye movement as if it were executing a VOR to the left. Saccadic eye movements move the eyes to look at a conceived or perceived location in space. The speed of the saccade is hard wired into the brain stem and is much faster than the fastest possible VOR or smooth pursuit eye movement. Vision is temporarily suppressed during the saccade. The simple clinical model for a horizontal saccade to the left is the following (but remember that the caudate also is involved).

E. F.

A better term for the left abducens nucleus would be the nucleus for conjugate horizontal eye movements to the left because it is the final common pathway by which all eye movement control systems move the eyes conjugately to the left. The simple clinical model for a vertical saccade is the following (but remember that the caudate also is involved). Simultaneous activation of bilateral frontal eye fields midbrain reticular formation nuclei bilateral III, IV nuclei

MBB1 review of week 3, page 20

G.

Know the syndromes of internuclear ophthalmoplegia and involuntary eye deviation (eyes left!).

Know horizontal conjugate gaze is achieved by the MLF. A lesion of L MLF yields abnl mvt. of L eye called L internuclear ophthalmoplegia (INO).
RE LE

Acute L frontal eye field "destructive" lesion

. L "look straight ahead!"

The eyes are normally straight ahead because of symmetrical tonic input from the frontal eye fields and from the abducens nuclei. If only the frontal eye field is intact, the eyes go to L. Ice water in ear will cause tonic deviation to , then fast phase to L. Acute pontine tegmentum "destructive" lesion includes abducens nucleus, which includes VI cell bodies and interneurons to L III
L "look straight ahead!"

Tonic input from L abducens nucleus moves eyes to L. Ice water in ear produces no tonic deviation to because abducens nucleus on is not working. H. Know that individual eye movement control systems can dysfunction independently of each other. It depends on where the lesion is.

MBB1 review of week 3, page 21