As I have understood, this lecture is to outline two aspects of the many pain syndromes in the head and neck region, viz. to what extent the ANS is involved in those pain syndromes whether the ANS symptoms noted in such syndromes are a mere accompaniment or are of pathogenetic significance. In the latter case one might consider whether the ANS symptoms are of central or of peripheral nature.

The second of these aspects is, of course, directly related to the fundamental whether somatic or visceral autonomic afferents can be considered as nociceptive elements (which skeptics deny), and has immediate bearing on the rationale of anaesthesiologic intervention.

A multitude of types and subtypes of cephalalgias and nuchalgias have been clinically defined over the past century. Only hemicrania or migraine has been a fairly defined clinical entity since the ancient Greeks. In fact, anaesthetic drug treatment with opioid was practised as early as the late 12th century. Between the 16th century and late 19th century the terminus technicus ``dolor capitis" covered almost every condition manifesting with headache. Today, after a ±60 year period of more intensive diagnostic activity beginning in the early twenties, there are about 30 different types discerned. In migraine alone 1015 subtypes are distinguished, and in cluster headache some 3 or 4. The wealth of types and labels stands in stark contrast to the poverty of pathogenetic or causal understanding.

Starting with a survey of the occipitonuchalgias or cervicalgias, they are deceptively simple, not as rare as most physicians would think, and, in general, devoid of ANS symptoms.

The generation of older neurologists had only a limited list of differential diagnoses to consider in a case with chronic occipital or cervical pains.

Occipital neuralgia with its characteristic unilateral and shortlasting painattacks in the distribution area of Arnold's greater occipital nerve was erroneosly thought to be caused by trapezoid muscle spasm, pinching the nerve as it pierces the trapezoid muscle or aponeurotic tendon, It was rather easily cured by local anaesthetics, only, the nerve does not pierce the trapezoid, as Bogduk's anatomical work revaeled; it might be pinched between the atlantooccipital joint and the inferior oblique or semispinalis capitis muscle but that remains unclarified up to now. The same obtains for muscle contraction headache (0), assumed to be generated by a tonic contraction of the trapezius and splenius capitis muscles, induced by anxiety or frustration. Again, nobody has succeeded in convincingly documenting the chronic hypertonic neck muscles in that disorder. The typical occipitonuchal or occipitofrontal headaches of arterial hypertension and cervical arthrosis (which quite distinctly differ from psychogenic headache) usually are manifest upon awakening, like sleepapnoea headache, and seems to be entitities that rather rest upon clinical associative thinking than upon a proven pathogenesis. Some workers assume a hypertrophic lateral atlantoaxial joint (C1/C2) or its subluxation, or a zygoapophysial hypertrophy (C3/4/5) or consequent intervertebral joint synovitis, or ligamentum flavum hypertrophy, to produce either compression or ``irritation" of the C2 or C3 roots, which would generate pains in the distribution of Arnolds nerve or the third occipital nerve. If this would be correct (and the frequent occipito cervicalgias in rheumatoid arthritis would plead in favour of such a pathomechanism) facetdenervation might constitute the treatment of choice in wellselected, i.e. accurately diagnosed patients. Bogduk's concept on third occipital nerve neuralgia, however, turned out to be rather tenuous, as pains recurred in 5 of his 7 patients despite neurectomy or coagulation.

At this point, I should like to emphasize the careful examination of the patient, including the effect of cranial and neck movement as well as of pressure points upon the pains, and the obtention of Xrays of the neck in cranial retro and anteflexion. The pains might, at that, be of myofascial origin (another somewhat nebulous concept) or derive from arterial jeopardy.

In addition, I should like to indicate another, largely neglected factor in cervicooccipital nociception, viz. Luschka's sinuvertebral nerve and Franck's vertebral nerve. The sinuvertebral nerve is known as the ramus meingeus of the ventral branch of the spinal nerve root. It innervates the spinal meninges overlying the longitudinal ligaments. FrancoisFranck's vertebral nerve basically is a sympathetic ramus communicans griseus of the stellar ganglion (ggl. cervicale caudale) and the ggl. cervicale medius. That is, it has 2 origins (bipartite), a first one dorsally following the vertebral artery as a plexus up into the posterior fossa and accompanying the artery as far as the labyrinthe arteries and epidural venous plexus, and also sending twigs to the C6/7 roots, and a second minor one with twigs caudally to the Th2 roots. It is not unreasonable to entertain the idea that cervical integumental/vascular derangement via the nerves just mentioned, promote quite a few of the fairly diffuse pains that are the topics of this conference. If reasonable true, stellate ganglion blockade might be more efficient than facetdenervation. For a more precise anatomical argument one should need Dr. Groen from Utrecht to be present here. He has specialised on the topic. One item should be added to this list of occipitocervicalgias, the much en vogue ``whiplash syndrome", a fuzzy set of imprecise complaints never manifesting directly upon head/neck trauma (such as one would expert), but days to weeks later, and which, in addition, does not pathomechanically rest upon the deceleration cum vectorinversion of the whip's lash but on distal acceleration cum hyperextension (cum elongation?) of the cervical column.

This syndrome was outlined as posttraumatic by Barré and Lieou from Strassbourg (1924/5) and enjoyed prolonged popularity under the title ``syndrome sympathique cervical postérieur", reflecting the presumed causative lesion of the vertebral nerve. Subsequently, BärtschiRochaix from Bern revived it under the terminus technicus ``migraine cerviale", lecturing on it in Leiden and Utrecht in 1946. BärtschiRochaix attributed the posttraumatic ``migraine cervicale" to entrapment of the vertebral nerve by uncovertebral spondylarthrosis which compresses the vertebral artery and its adventital sympathetic plexus; the sympathetic plexus irritation in its turn might conceivably produce vertebral artey spasms.

Old terms, such as ``chronic posttraumatic headache" and new terms, such as ``cervicogenic headache (Sjaastad)" do not appear to clarify the issue. Still newer terms , such as Bogduk's ``third occipital nerve headache" do not seem to help either. Bogduk proposed this new entity, when his anatomical dissections revealed that his original supposition, viz. lesion of the isilateral C2 spinal root dorsa ramus (caused by extension and rotation of the head) turned out to be erroneous. Hyperextension does not compromise the C2 ganglion nor the C2 dorsal/ ventral rami, not even on combined rotation/ extension. These movements also leave Arnold's greater occipital nerve hors concours. He inferred only the third occipital nerve can be entrapped by (arthritic) C2/3 zygopophysial joint osteophytes or fracture fragments or ligament rupture. This joint is innervated by the third occipital nerve.

On this basis, it seems attractive to propose, grosso modo, two pathogenetic types in this diagnostic jungle:

a) an uncovertebral type, mostly spondylarthrotic by age or arthritis, involving the vertebral nerve (plexus). In this category stellate ganglion blocks might be useful.

b) a C23 zygapophysial type, mostly posttraumatic, involving the C3 root rami, in which facet denervation or C3 block might be beneficial.

Proof of this would require a wellplanned trial. Whatever the case, NS symptoms in this group of neckpains are to all practial intents and perposes absent.

Proceedings to an upper floor, only a few headaches that do include ANS features among their symptomatology qualify for the present discussion. At that, some are infrequent and, in addition, are of doubtful tenure.

Throughout the years, Sluder's pterygopalatine neuralgia has remained a rather nebulous concept. Precisley because the pterygopalatine ganglion is the second largest extracranial ganglion with numerous afferent and efferent connexions between facial structures and the nn V, VII, and IX, it confronts the clinician with a confusing array of symptoms. Sluder's neuralgia should be categorised as a facialgia rather than a headache. It usually follows a fronto/ ethmoid sinusitis and rarely (what one should expert) a maxillar sinusitis. The ANS symptoms rather seem to be produced by parasympatetic overactivity than sympathetic paralysis (no Horner syndrome). Treatment is no sinecure.

The term ``paratrigeminal syndrome" was so called by its auctor intellectualis, the Norwegian neurologist George Raeder (on advive of MonradKrohn), to distinguish it from Horner's syndrome. The symptomes essentially include Horner's syndrome together with pain and trigeminal sensory deficit with palsies of the IIIVII nerve due to a parasellar lesion, and intact facial sweating. Subsequently, cases were reported with persistent prominent periorbital pains and Horner's postganglionic sympathetic palsy signs, but no involvement of the nn III, VI, and slight forehead anhidrosis. This second category with absent parasellar pathology and unequivocal involvement of the sympathetic plexus of the internal carotid, cavernous sinus and or ophthalmic artery should of course properly be named pericarotid syndrome (VijajanWatson). It may be seen in carotid dissecting aneurysm or other carotid disease. The difference between the two syndromes, as far as the sympathetic symptoms are concerned is explainable by the fact that visceral efferents follow the external carotid for the lower facial sweat glands and the internal carotid for the forehead, which greatly helps in localising the lesion.

Cluster headache (BingHorton) is about 80 times less frequent than migraine. The marked ANS symptoms are not easliy explained as they are contradictory if one would infer to sympathetic 3rd neuron paralysis on the basis of the ptosis and miosis. Careful examination often reveals the symptoms to be bilateral, one side showing only minimal symptoms. Probably there is a central (hypothalamic) sympathetic dysfunction with denervation hypersensitivity. Hypothalamic blood flow changes have recently been identified in cluster headache (unpublished ). The effect of verapamil would suggest the disorder to be ranged with the calciumcanalopathies. In view of the afficacious drug therapy one would not expect anaesthesiologic intervention to be proposed. Yet, this has recently been advocated in the form of pterygopalatine blockade (Sanders/ Zuurmond 1997).

Sjaastad's CPH, is an even rarer disorder, only some 80 or 90 patients having been repoted mondially over the last 10 years. Whether its marked ANS symptoms are based on an ionchannel diorder is doubtful, given the fact that the most effective drug is a prostaglandin synthetaseblocker. Its standing remains unclear: at least 1 patient is known, in whom followup ultimately revealed a prolactinsecreting pituitary microadenoma.

The SUNCT syndrome (Shortlasting Unilateral Neuralgic attacks with Conjunctival injection and Tearing) is another acronymic of Sjaastad's discoveries to join the cluster club.

Its cardiac changes would indicate parasympathetic imbalance. As there are less than 15 patients (all male) reported worldwide we may consider ourselves blessed to run less chance of seeing a patient than winning the national lottery. However, more patients might be around walking misdiagnosed as cases of ``cluster headache".

Migraine, finally, is the headache that shows the most unequivocal ANS symptoms. Though it manifests in many types and forms, it cannot be denied a certain stereotype. The ANS symptoms, notably those of the patient feeling chilly and showing facial pallor or the inverse, feeling hot and showing a facial flush, led 19th century authors on the topic to dstinguish ``white" and ``red" migraine, a distinction that modern examination with the aid of infrared thermography proved incapable to substantiate this unequivocally.

Over the past decades a number of studies and reviews have appeared of ANS involvement in the migraine pathogenesis (Herberg 1975, Johnson 1978) but most studies remain fragmentary and uncorroborated. Hypothalamic endocrine function either in or outside attacks seems to be normal.

Only clinical evidence indicates ANS involvement and quite eloquently at that. In the prodromal stage and during the attack many patients report to be either euphoric and hyperactive, or depressed, irritable, with stiff neck muscles, to crave for food and baverages (polydipsia/ polyphagia) or to be anorexic, to feel feverish and hot or to shiver with feeling chilly, to yawn, then to become apathic, to withdraw and shut out sensory stimuli being hypersensitive to them, to become nauseated and vomit. The resolution of the attack features sleep, polyuria and often obstipation or the reverse: diarrhoea.

This set of ANS dysfunction covers homeostasis of bodytemperature, gastrointestinal activity, renal function, wakefulness, etc. One may infer the NA, 5HT and DAergic receptors or circuits to underlie the dysregulation, the more so, because prodromal serum NAreduction has been documented. One might be inclined to attribute the changes in appetite to oscillations in the hypothalamic (adrenegic) ventromedial nucleus, but modern research has not yet progressed the linkage of certain function and anterior hypothalamic nuclei. For istance the suprachiasmatic nucleus controls circadian rhythms and to a lesser extent bloodpressure (vasopressin) and metabolism (VIP), while the supraoptic and paraventricular nuclei control bloodpressure (vasopressin), water metabolism (ADH), basal metabolic rate (TRH) and activity (ACTH). Cajal's hypothalamic ventromedial nucleus is innervated by somatostatinergic fibers (Swaab 1997). Most of the hypothalamic nuclei, if not all, turn out to produce, or respond to, more than one neurotransmitter and, moreover, their complex hodology is insuficiently known. Accordingly, it is too early yet to make firm statements about a central ANS origin (however likely that mey be) to produce the marked vegetative symptoms in migraine.

A few remarks remain to be made

First, if the marked ANS symptomatology in migraine is of central origin, anaesthesiological intervention would be illusory, and stellar ganglion block, such as occasionally practised in the past with viable success, would lack rational basis.

Second, the pendular changes in migrainous ANS symptoms, both per attack and per patient, appear explainable in terms of either of two pathomechanisms:

a)a canalopathy, involving a receptor  rather than a voltage  gated channel.

b)an electronegative DC potential wavefront traversing the hypothalamus. Such a front, known as Leao's spreading depression made furore in migraine research between the 80's and early 90's. Notably in classic migraine the X¹³³cerebral blood flow studies by Lauritzen and Oleson revealed cortical ``oligaemia" during the attack, starting occipitally and spreading rostrally at a rate of ± 3 mm. p.min., a value computed for the scintillary scotoma.

The first possibility, a canalopathy appears to hold promise for further research because the Leyden migraine group last year defined the hereditary familial migraine gene on chr. 19p.13.1, which codes for the a₁subunit of the calciumchannel. Recently, a second mutation, on 1q.2131, was made known. In addition, flunarizine (a calciumentry blocker has been used with fair therapeutic success for many years. Finally, the therapeutic efficacy of 5HT1Breceptor agonists (such as sumatriptan) would indicate a close tie between this 5HTreceptor type and the Cachannel constituent protein, such as is known, e.g. between the C1channel and the benzodiazepine receptor. The gene mutation produces changed proteinconfiguration entailing deranged ionpassage through the channel.

A single consideration should warn us to exercise some reserves, however: Familial hemiplegic migraine, in my opinion, does not belong to the proper class of migraine, but to the variant of ``symptomatic migraines". Accordingly, hereditary migrainous recurrent hemiplegia would be a more appropriate term for it. Only ± 50% of the transient hemiplegic attacks are accompanied by migraine The same happens in MELAS, with ± 60% of the attacks being migrainous; yet, the mitochondrial disease MELAS is regarded as a disease sui generis and not as a migrainetype.

The ``spreading depression" hypothesis has come to be upset since a few years, since Diener et al. examined patients within 6 hours of onset in a common migraineattack by means of PETscanning. Instead of finding a cerebral cortical oligaemia, he discovered to his surprise a hyperaemia in 3 to 4 circumscribed areas:

a) the pontomesencephalic tegmentum (ncl. V?) conralateral to the pain,

b) bilateral anterior cingulate (Brodmann area (25) controlateral dorsal cingulate (BA 2H,31),

c) auditory and visual asociation areas (BA 19,21,22,39).

After Sumatriptan, b) and c) normalised, a) persisted.

Evidence that somatic and visceral pains other than headache are associated with hyperaemia in anterior or dorsal cinbualte, thalamus, hypothalamus, PAG and various cortical areas had already been available since 1991 (Talbot et al. 1991, Jones et al. 1991, Rosen et al. 1994, Casey et al. 1995). In addition experimental electrostimulation of the anterior PAG (activating serotonergic raphe dorsalis et magnus fibres to inhibit nociceptive neurons in Rexed laminae I, II, IV and V) had also pointed out to the crucial role of mesencephalic grey in painmediation (Behboni and Fields 1979, Jordan 1979, Oliveras et al. 1979), Jensen and Yaksh 1989, Baskin et al. 1985, Strassman et al. 1985). Chronic pain treatment in man by means of permanent electrodes in PAG may produce typical migraine attacks.

In short, the center of gravity of migraine research now shifts away from the (occipital, hypoperfused cortex) to the brain stem and rostral (deep) grey matter. The question remains of course whether the pain produces the hyperaemia in these areas or, vice versa, the activation of the latter are causative in producing pains. In any case, the conveergence area for nociception seems to be underlined by these blood flow changes in the brainstem, but other (cortical) areas are clearly participating in the process.

Accordingly, future research will decide what role anaesthesiology will assume in the treatment of migraine.

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