Neurophysiological assessment of trigeminal nerve reﬂexes in ...Document Transcript
Clinical Neurophysiology 116 (2005) 2255–2265
Neurophysiological assessment of trigeminal nerve reﬂexes in disorders
of central and peripheral nervous system
EMG Unit, Neurology Department, Hospital Clinic, Villarroel, 170, Barcelona 08036, Spain
Accepted 28 April 2005
Available online 6 July 2005
The trigeminal nerve and nuclei (the trigeminal complex) are unique in the human body with regard to their anatomical and physiological
characteristics. They are also special regarding the lesions in which they are involved, both at the peripheral level because of the
susceptibility of some terminal branches, and at the nuclei because of their large size and the large amount of connections with other centers.
Conventional magnetic resonance imaging studies are often not sufﬁciently informative to demonstrate very tiny lesions that could be
responsible for an important damage in the brainstem. Therefore, clinical neurophysiology and speciﬁcally, the techniques used in the study
of the trigeminal functions, remain as convenient diagnostic and research tools to document clinically evident lesions or uncover subclinical
abnormalities. This review is focussed on the clinical applicability of the study of trigeminal reﬂexes, including methods employed in the
documentation of focal lesions of peripheral branches, trigeminal involvement of peripheral neuropathies, speciﬁc lesions of the trigeminal
ganglia, central nervous dysfunctions causing abnormalities in the excitability of trigeminal neurons, and the possible use of trigeminal nerve
reﬂexes in the study of facial pain syndromes and headache.
q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Trigeminal nerve; Blink reﬂex; Brainstem reﬂexes; Trigeminal sensory pathways
1. Background proprioceptive information are located inside the central
nervous system, in the mesencephalic nucleus (Lazorthes,
The trigeminal nerve is one of the largest cranial nerves, 1976; Ongerboer de Visser and Goor, 1976), when
sending ﬁbers to innervate all muscles controlling jaw comparable sensory neurons from other muscles in the
movements and the skin of virtually the whole face and skull. body are located in the dorsal root ganglia, half covered only
The trigeminal nerve and nuclei (the trigeminal complex) by the blood–brain barrier (Jacobs et al., 1976). Vibration,
have interesting anatomical and physiological peculiarities. which causes a decrease of the H reﬂex in limb muscles,
No Renshaw cells have been identiﬁed in the trigeminal induces potentiation in trigeminal motoneurons (Godaux and
motor nucleus and, therefore, trigeminal motoneurons have Desmedt, 1975). The size and connections of the bulbospinal
no recurrent inhibition (Lund et al., 1983). The trigeminal sensory nucleus testify of the importance of the trigeminal
sensory nucleus is a complex structure, divided into many neurons as a relay station for cutaneous somatosensory
subnuclei extending from the mesencephalon to the spinal inputs in their way to higher order structures and to the
cord. One of the most striking anatomical peculiarities of the integrative motor centers of the reticular formation.
trigeminal complex is that the ﬁrst order sensory neurons for As it is the case with other cranial nerve nuclei,
trigeminal motoneurons receive bilateral inputs from
cortical neurons. They also receive ipsilateral projections
* Address: Unitat d’EMG, Servei de Neurologia, Facultad de Medicina, from muscle spindle afferents, and bilateral projections from
IDIBAPS (Institut d’Investigacio Biomedica August Pi i Sunyer), Hospital cutaneous afferents (Cruccu et al., 1989). Sensory inputs to
Clınic, Villarroel, 170, Barcelona 08036, Spain. Tel.: C34 932275413; fax:
the neurons of the mesencephalic nucleus come from
E-mail address: email@example.com. muscle receptors of trigeminal muscles and, possibly, also
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
J. Valls-Sole / Clinical Neurophysiology 116 (2005) 2255–2265
from those of the extraocular muscles (Alvarado-Mallart et dysfunctions of the trigeminal nerve and nuclei. The
al., 1975). Those to sensory neurons of the bulbospinal following is a review of the clinical applicability of
trigeminal nucleus come from cutaneous receptors, with a brainstem reﬂexes mediated by the trigeminal nerve, such
relatively well-deﬁned somatotopic distribution. These as the blink reﬂex, the corneal reﬂex, the masseteric
neurons also receive modulatory inputs from the basal inhibitory reﬂex, the mandibular reﬂex, and other neuro-
ganglia through the superior colliculus and the nucleus physiological responses that may help in understanding the
raphe magnus (Basso and Evinger, 1996; Basso et al., 1996), pathophysiology of symptoms and signs of lesions
but the exact relationship between the nuclei of the reticular involving the trigeminal complex. The clinical utility of
formation and the neurons of the trigeminal sensory nucleus trigeminal nerve reﬂexes is not supported by data
is still unclear. originating on evidence-based medicine. However, this is
The trigeminal complex and their central projections are a common situation in neurophysiology, in which the tests
the site of a variety of lesions that may or may not be can be considered as a continuation of the clinical exam.
accompanied by clinical manifestations (Table 1). Clinical
assessment of motor and sensory dysfunction in the
trigeminal complex may be difﬁcult. Motor dysfunction is 2. Methods
only identiﬁable in severe lesions, there are no objective
means for the assessment of sensation in the face, and the This review is not intended to describe speciﬁc technical
mandibular reﬂex is not usually accompanied by a visible and methodological aspects of trigeminal reﬂexes. There-
movement of the chin. On the contrary, cutaneous reﬂexes fore, only a short summary of them is included here. The
are most helpful for clinical assessment. Typically, reader interested in these aspects can ﬁnd information in
previously published reviews (Aramideh and Ongerboer de
brainstem reﬂexes mediated by the trigeminal nerve are
Visser, 2002; Cruccu and Deuschl, 2000; Kimura et al.,
consensual, which means that unilateral stimulation leads to
responses in both sides. Because of that, a defect in the
afferent branch of the reﬂex gives rise to abnormalities in
2.1. Trigeminal nerve conduction studies
both sides while a defect in the efferent branch leads to
abnormalities in the affected side to stimulation of either
Despite the fact that branches of the trigeminal nerve are
side. Radiological neuroimaging techniques may also not
accessible in many sites, the possibilities for the study of
provide good resolution for topographical diagnosis within
motor and sensory nerve conduction are only limited, and
the brainstem (Marx et al., 2002).
most electrodiagnostic studies rely on the assessment of
For the reasons above, neurophysiological tests remain as reﬂex muscle responses. A few methods have been
most valuable methods to assess the functions and described to assess sensory nerve conduction in the
Table 1 mandibular branch of the trigeminal nerve (Deeb et al.,
Lesions involving the trigeminal complex 2000; Jaaskelainen, 1999a; Liguori et al., 1998), with
consistent results in healthy subjects and still scarce
Trigeminal nerve branches
Isolated idiopathic trigeminal neuropathy demonstration of abnormalities in patients with neuropathic
Vasculitis lesions. Recording requires needle electrodes inserted
Traumatisms. Mainly some dental procedures below the zygomatic arc at a depth sufﬁcient to reach the
Lymphoma and bone tumours or metastatis foramen ovale (4–4.5 cm). Electrical stimulation can be
Trigeminal nerve tumors
applied to the mentalis nerve at the mental foramen or to
Herpes zoster other terminal branches of the mandibular division.
Immunological aggressions to Gasserian ganglia neurons
Surgical interventions to treat trigeminal neuralgia 2.2. Trigemino-trigeminal reﬂexes
Trigeminal nerve roots
Meningioma, acoustic neurinoma, trigeminal neurinoma
The mandibular reﬂex, or jaw jerk, is the only
Aneurysms and other vascular malformations
Polyradiculoneuritis monosynaptic reﬂex available to electrophysiological
Vascular compression in trigeminal neuralgia testing in the cranial and facial muscles. It is ordinarily
Trigeminal nuclei elicited by a mechanical tap over the mandible with a reﬂex
Infarcts and other vascular lesions in the brainstem tendon hammer that electronically triggers the oscilloscopic
Encephalitis and intra-axial tumours
sweep. The reﬂex responses are recorded simultaneously
Demyelinating diseases of the central nervous system
Syringobulbia from the right and left masseter muscles using two pairs of
Changes in excitability in trigeminal nerve mediated reﬂexes surface electrodes, the active one placed over the muscle
Parkinson’s disease and other parkinsonisms belly at the angle of the mandible, and the reference one
Cranial and cervical dystonia placed over the mastoid process or the ear lobe. Since reﬂex
latencies vary with successive trials, comparison of
Various movement disorders (tics, head tremor; hemifacial spasm)
simultaneously recorded right-sided and left-sided
J. Valls-Sole / Clinical Neurophysiology 116 (2005) 2255–2265 2257
responses is more meaningful than absolute values, which two separate components: an early ipsilateral R1 response
are of the order of 6–8 ms in normal subjects (Hopf, 1994). that appears at a latency of 10–13 ms, and a later bilateral R2
Stimulation of the stretch receptors induces not only the response that appears at a latency of 38–45 ms. Because of
jaw jerk but also inhibitory effects that can be easily the differences in the circuitry of the R1 and R2 responses, an
observed as a silent period when the stretch is applied during interesting possibility emerges from the study of the onset
masseter contraction. The silent period to chin taps begins at latency of the responses: The latency of the R1 depends
about 10–12 ms and lasts for 20–40 ms, although latency more on the trigeminal and facial conduction times than on
and duration are both dependent partly on the strength of the the intra-axial synaptic connectivity, with only 1 or two
tap and the level of sustained activation of the masseter interneurons in the circuit (Aramideh and de Visser, 2002).
muscles. The masseter inhibitory reﬂex (MIR) can be The reverse occurs with regard to the R2, which latency is
obtained by applying electrical stimulation to the mentalis more dependent on interneuronal synapsis than on periph-
nerve, which is a more standardized technique to examine eral nerve conduction time. Therefore, a delay is observed
reﬂex inhibitory circuits on trigeminal motoneurons. The predominantly in the R1 response in lesions involving the
electrical stimulation of the mentalis nerve induces a two- peripheral nerve and in the R2 response in lesions involving
phase inhibition, MIR1 and MIR2. The latency of the MIR1 the trigeminal complex at the brainstem (Kimura, 1975,
is of about 10–14 ms and the latency of the MIR2 is of about
1982; Kimura and Lyon, 1972; Kimura et al., 1970).
40–50 ms (Cruccu and Ongerboer de Visser, 1999). If the
However, a delay in the R1 response can also be found in
MIR is to be used for electrodiagnostic purposes, the subject
clinical manifest or silent pontine lesions in multiple
must exert a stable background voluntary contraction, and
sclerosis (Kimura, 1975). The blink reﬂex can also be
the amount of inhibition should be quantiﬁed, which often
obtained by stimulation of infraorbital and mental nerves.
requires rectiﬁcation and averaging of EMG activity in a
sufﬁcient number of trials (Fig. 1(A) and (B)). The responses are less reliable and the R1 is not consistently
obtained. However, they can be of help for the assessment of
the site of the lesion in the trigeminal spinal nuclei in
2.3. Trigemino-facial reﬂexes ´
brainstem vascular lesions (Valls-Sole et al., 1996).
Mechanical or electrical stimulation of the lips can
The best known and most commonly used of all induce the perioral reﬂex (Larson et al., 1978). Responses to
brainstem reﬂexes is the blink reﬂex elicited by an electrical
mechanical stimuli, recorded with EMG surface electrodes
stimulus applied to the supraorbital nerve. This causes an
placed on the orbicularis oris, reveal that the reﬂex is
involuntary closure of the eyelids, and the reﬂex response
composed of a bilateral early response, at 11–18 ms,
can be recorded with EMG electrodes over the orbicularis
followed by a late response, at 24–45 ms (Topka and
oculi muscles in the lower eyelid (Kimura et al., 1969;
Hallett, 1992; Valls-Sole et al., 1994b). In adults, perioral
Shahani, 1970). Surface electrodes are used to apply single
responses are usually accompanied by responses in the
stimuli of an intensity 2–3 times the perception threshold to
the supraorbital nerve over the supraorbital notch. Careful orbicularis oculi at a similar latency. Although the reﬂex is
placement of the electrodes may help with reducing the of interest, interindividual variability and poor consistency
stimulus artifact that could interfere with the appropriate has probably prevented a wider use of the perioral reﬂex. In
assessment of response latencies. The response consists of infants, perioral reﬂexes can be used for the study of the
Fig. 1. The masseter inhibitory reﬂex (MIR) and the blink reﬂex to a supraorbital nerve electrical stimulus in a healthy volunteer (A and C) and in a patient with
a Guillain–Barre syndrome (B and D). For the MIR, the recordings are rectiﬁed and averaged to facilitate measuring the amount of inhibition at each phase. In
both reﬂexes, the electrical stimulus is marked with ‘s’. Note the delayed onset of MIR1 and of the R1 in the patient.
J. Valls-Sole / Clinical Neurophysiology 116 (2005) 2255–2265
physiological mechanisms underlying the sucking reﬂex 2.5.2. Prepulse inhibition of the blink reﬂex
(Barlow et al., 2001). The availability of interneurons of the blink reﬂex
pathway to inputs from the supraorbital nerve is also
transiently modiﬁed by the arrival at the brainstem of
2.4. Trigeminal evoked potentials
sensory inputs from different sources. The phenomenon of
prepulse inhibition, which was described initially in relation
Evoked potentials to electrical stimulation of branches of
to the startle reaction, consists in the inhibition of the
the trigeminal nerve are difﬁcult to obtain because of the
response to a stimulus when this is preceded by a weak
artifact usually induced by the electrical stimulus. This was
stimulus of the same or different modality at speciﬁc leading
a technical impediment in the exam of possible trigeminal ´
intervals (Valls-Sole et al., 1999). In the case of the blink
nerve conduction abnormalities in the posterior fossa.
reﬂex to supraorbital nerve electrical stimuli, the R1
Leandri et al. (1988) obtained reproducible responses with
response is enhanced or not modiﬁed, while the R2 is
needle stimulation of the infraorbital nerve. However, this ´
signiﬁcantly suppressed (Ison et al., 1990; Valls-Sole et al.,
invasive technique did not reach a widespread use. 1999) when the electrical stimulus is preceded by low
Nowadays, some of the methodological problems limiting intensity acoustic stimuli or peripheral nerve electrical
the recording of trigeminal nerve evoked potentials have stimuli with an interval of 100 ms. An abnormal blink reﬂex
been overcome with the introduction of laser stimulation. A inhibition by a prepulse may indicate an abnormal
laser CO2 stimulus induces the activation of epidermal skin processing of sensory inputs at brainstem level.
receptors of pain with no skin contact and little or no artifact
(Bromm and Treede, 1984). Laser-induced trigeminal nerve
evoked potentials have been studied in normal subjects and 3. Trigeminal reﬂexes in the assessment of focal lesions of
in patients with a variety of disorders (Cruccu et al., 1999; trigeminal nerve branches
Romaniello et al., 2003). The limitations of the technique lie
in the fact that it permits to assess conduction in small ﬁbers Selective lesions of the sensory branches of the trigeminal
but not in large ﬁbers and that the information comes from nerve are relatively infrequent. They may occur as a result of
brain centers activated after some elaboration of sensory nerve ischaemia (Lapresle and Lasjaunias, 1986) or
information. traumatic injuries. The ophthalmic branch of the trigeminal
nerve may be lesioned together with the oculomotor nerves
2.5. Other tests involving activation of trigeminal neurones in the wall of the cavernous sinus. Usually, transient
oculomotor paresis can occur together with the involvement
of the ophthalmic branch in the Tolosa–Hunt syndrome,
2.5.1. The blink reﬂex excitability recovery curve while sympathetic dysfunction and a painful Horner’s sign
While nerve conduction and synaptic connectivity occurs in the Raeder’s paratrigeminal syndrome (Mokri,
between the trigeminal nerve and the facial nuclei can be 1982). Trigeminal nerve dysfunction and hemicranial pain
assessed with the blink reﬂex, a single stimulus does not tell was observed in 3.7% of 190 patients with spontaneous
us much about the excitability of the whole circuit, which is dissection of the extracranial internal carotid artery (Mokri
regulated by inputs from various sources, including the et al., 1996). The infraorbital and mental branches of the
basal ganglia. To test the excitability of the brainstem trigeminal nerve can be damaged at the infraorbital foramen
interneurons in the blink reﬂex pathway, Kimura (1973) or at the mentonian foramen, when the nerves cross the skull,
devised the method of paired stimulation. Two stimuli of the in the so-called numb-cheek (Campbell, 1986) or numb-chin
same intensity are delivered. The ﬁrst stimulus (condition- (Lossos and Siegal, 1992) syndromes. These syndromes are
ing) leaves a trace of excitability changes in some brainstem typically associated with metastatic inﬁltration of bone in
interneurons and induces a reﬂex response, whose size patients with cancer of various types, but other causes are
reﬂects the number and density of inputs reaching the facial also possible. A numb chin could result from a lesion of the
motoneurons. The second stimulus (test), applied after a alveolar, dental or lingual nerves by dental procedures or
certain time period, goes through the same interneurons. bone infection (Liguori et al., 1998).
However, their availability to transmit the inputs would There are no formally standardized procedures for the
have changed because of the change in excitability induced assessment of nerve conduction in all trigeminal branches.
by the ﬁrst stimulus. The excitability recovery curves are The sole means to document the involvement of the
different for the early and late blink reﬂex responses ophthalmic branch is to use the blink reﬂex elicited by
probably because of the different number of synapses electrical conventional or nociceptive stimulation of the
involved in the two of them. Therefore, an abnormality in supraorbital nerve (Katsarava et al., 2002). In lesions
the excitability recovery of the R2 component with no affecting the maxilar and mandibular branches, bilateral
changes in that of the R1 component would indicate a absence or delay of either or both the blink reﬂex and the
disorder of the excitability of brainstem interneurons MIR brings the evidence for functional abnormalities of the
mediating the R2 component. afferent ﬁbers. Nerve conduction studies of the mentalis
J. Valls-Sole / Clinical Neurophysiology 116 (2005) 2255–2265 2259
nerve may be convenient in expert hands for the assessment involvement, including focal peripheral neuropathies,
of abnormalities in focal lesions of the mandibular branch trigeminal neuronopathies, and lesions compatible with
(Deeb et al., 2000; Jaaskelainen, 1999a; Liguori et al., central nervous system lesions at the level of the spinal
1998). However, further technical developments are needed nucleus of the trigeminal nerve. Casale et al. (2004) have
before mentalis nerve conduction studies can have a reliable reported selective abnormalities of the R2 component of the
and widespread use in the assessment of suspected lesions of blink reﬂex and suggested the possibility of lesions of the
the lingual, alveolar or mental nerves in clinical practice. medullary polysynaptic circuits or of the subcortical white
matter due to disseminated microvascular lesions. Patients
with systemic sclerosis may present with the so-called
4. Trigeminal reﬂexes in the assessment of systemic scleroderma en coup de sabre, or Parry–Romberg’s
polyneuropathies syndrome, featuring bone and skin linear abnormalities
and facial hemiatrophy (Stone, 2003). Some of these
The trigeminal nerve, together with other cranial nerves patients have abnormal morphogenesis affecting the brain
may be involved in toxic or metabolic polyneuropathies. and frequently leading to epilepsy (DeFelipe et al., 2001).
Usually, in these instances, the clinical and neurophysiolo- However, the exact relationship between scleroderma ‘en
gical ﬁndings are less prominent in cranial nerves than in coup de sabre’, the Parry–Romberg syndrome with
limb nerves, but their assessment may be of great utility in
dysmorphogenesis, and the central nervous system involve-
the study of severe polyneuropathies. Sensory nerve action
ment in these disorders is not at all clear (Blaszczyk et al.,
potentials may be not recordable in limb nerves and the only
2003; Lehman, 1992).
evidence for a response to cutaneous inputs could be found
The trigeminal nerve is also involved in hereditary
in the trigeminal nerve area. In patients with Guillain–Barre ´
peripheral neuropathies (Fig. 2). In the hereditary motor and
syndrome, bilateral facial nerve paralysis occurs in about
50% of patients, and involvement of bulbar cranial nerves in sensory neuropathy type I (HMSN-I), the blink reﬂex shows
10–30%. In these instances, the study of the blink reﬂex a marked delay of R1 and R2 (Kimura et al., 1969). This is
(Fig. 1(C) and (D)) demonstrates a delay in the R1 and R2 not the case in patients with the HMSN-II, which constitutes
responses that occurs relatively early in the course of the a clear electrophysiological difference between the two
disorder and may be of help to put on show subclinical main forms of Charcot–Marie–Tooth disease.
involvement of the trigeminal and facial nerves (Kimura,
1982; Montero, 1998; Vucic et al., 2004).
Isolated trigeminal nerve branches may be involved in
diseases of connective tissue (Lecky et al., 1987), being a
common target for granulocitic inﬁltrates of the vasa
nervorum. This leads to a syndrome of mononeuritis
multiplex, in which trigeminal neuropathy may be the
only neurological manifestation. Involvement of the
trigeminal nerve is relatively frequent in patients with
Sjogren’s syndrome. These patients could undergo a focal or
multifocal trigeminal nerve branch lesion due to an axonal
lesion in vasa nervorum, as well as an antigen-mediated
immunological attack to the neurons of the Gasserian
ganglia (Font et al., 2003). Even though both types of
lesions would present with clinical pictures of certain
similarities, the pathophysiology of the neuropathic damage
is completely different. In pure sensory neuronopathies, the
Gasserian ganglia (and the dorsal root ganglia as well) are
damaged by circulating antibodies because of their lack of
protection by the blood–brain barrier (Malinow et al., 1986).
Although systemic sclerosis was once believed to rarely
lead to peripheral neuropathy, recent reports prove that this
is not the case (Hietaharju et al., 1993). However, it is not
always clear where is the site of the lesion in these patients.
In a group of six patients with systemic sclerosis who
Fig. 2. The blink reﬂex to supraorbital nerve electrical stimuli in a control
complained of facial sensory disturbances, we system-
subject (A), a patient with an inherited motor and sensory neuropathy type I
atically examined brainstem reﬂexes, including blink reﬂex, (B), and in a patient with MSA, with degenerative brainstem and cerebellar
mandibular reﬂex and masseteric inhibitory reﬂex (Con- atrophy (C). Note the delay of R1 in the patient with peripheral neuropathy,
treras and Valls-Sole, 2002). We found different patterns of and the delay of R2 in the patient with brainstem atrophy.
J. Valls-Sole / Clinical Neurophysiology 116 (2005) 2255–2265
5. Trigeminal reﬂexes in the assessment of lesions of the sudomotor skin response of the palms after electrical
trigeminal nerve nuclei and tracts stimulation of the supraorbital nerve (Obach et al., 1998).
The correlation between magnetic resonance imaging and
Lesions may be induced in the Gasserian ganglion electrophysiological ﬁndings in these patients led to a better
following therapeutic thermocoagulation or compression delineation of the circuits of the trigemino-facial and
for trigeminal neuralgia (Cruccu et al., 1987). In accordance ´
trigemino-trigeminal reﬂexes (Valls-Sole et al., 1996). One
with the fact that thermocoagulation predominantly affects of such outcomes was the evidence for impairment of the
small ﬁbers while compression affects large ﬁbers, Cruccu masseteric inhibitory reﬂex in patients with infarcts located
et al. (1987) found that patients with thermocoagulation had in the upper or middle medulla, a ﬁnding indicating that the
predominant impairment of corneal reﬂexes while patients circuit for the masseteric inhibitory reﬂex reaches as far
who were treated with compression had predominantly down in the medulla as the middle part, and is not conﬁned to
abnormal jaw jerks. the pons as it had been previously suggested (Cruccu et al.,
As stated before, the Gasserian ganglion is subject to ´
2005; Valls-Sole et al., 1996).
autoimmune attack, similarly to the dorsal root ganglia The correlation between magnetic resonance imaging
because they are only half covered by the blood–brain ﬁndings and electrophysiological abnormalities has been the
barrier. Autoimmune-mediated ganglionic neuronal damage aim of more recent studies. In a study investigating the
may cause involvement of all sensory modalities in the abnormalities of R1 in 12 patients with conﬁrmed brainstem
limbs, with widespread loss of deep tendon reﬂexes. Also, vascular lesions, Marx et al. (2001) observed that in most
there is loss of cutaneous sensation in the face, with patients the lesions were located in the ipsilateral mid to
consistent abnormalities in trigemino-facial and trigemino- lower pons and, therefore, concluded that the pathway of the
trigeminal reﬂexes. However, a striking difference is the R1 descends more medially and ventrally with regard to the
preservation of the jaw jerk (Valls-Sole et al., 1990). The principal sensory nucleus. As the result of a joint effort
reason is that the jaw jerk is mediated by neurons of the between an italian and a german center, authors have
mesencephalic nucleus, lying within the brainstem where it developed an ingenious method to plot in a tridimensional
is not exposed to circulating antibodies. representation of the brainstem the lesions which are
Central nervous system demyelinating diseases may thought to be responsible for clinical and electrophysio-
affect cranial nerves in isolation or in combination (Thomke logical abnormalities. Marx et al. (2004) have reported the
et al., 1997). The study of brainstem reﬂexes may bring use of such method in the assessment of the lesions leading
further evidence of demyelination in circuits where no to a Horner’s sign, while Cruccu et al. (2005) have produced
clinical involvement can be recognized and provide a review of the brainstem reﬂex circuits in the light of such
quantitative measures (Hopf et al., 1991). The R1 was correlation.
found to be of prolonged latency on one or both sides in 49 of
63 patients who had clinical pontine signs (Kimura, 1975).
Although brainstem vascular lesions may cause injuries 6. Trigeminal reﬂexes in the study of dysfunctions lying
in many sites involving the nuclei and tracts of the trigeminal rostrally to the trigeminal complex
nerve (Hopf, 1994), the most frequent and also the most
studied of them all is Wallenberg’s syndrome. In this The blink reﬂex responses can be abnormal not only in
syndrome, an ischaemic lesion takes place in the arteries lesions affecting the reﬂex pathways directly, but also in
supplying the lateral medulla. The typical syndrome results lesions indirectly inﬂuencing the excitability of the circuit.
from the involvement of the nucleus ambiguous, the spino- Thus R2 is absent, or markedly diminished or delayed, in
thalamic tract, and the spinal trigeminal nucleus. However, comatose states regardless of the site of the responsible
other structures may also be involved, including nuclei of the lesion (Lyon et al., 1972). A signiﬁcant change in the
reticular formation and their input and output ﬁbers. The latency of R1 has also been described in acute hemispheric
exact location of the lesion depends on the vascular territory stroke by Fisher et al. (1979) who used mechanical rather
affected and on the possibilities for compensatory blood than electrical stimulation. These observations seem to
supply, aspects that may differ slightly among individuals. point out to a cortical control of the excitability of the
Therefore, patients with Wallenberg’s syndrome may neurons mediating the blink reﬂex. However, there is also
present with a slightly different picture regarding clinical, proof for direct basal ganglia connections to the trigeminal
magnetic resonance imaging, and electrophysiological neurons (Basso and Evinger, 1996; Basso et al., 1996).
abnormalities (Valls-Sole et al., 1996). The most character- In degenerative diseases of the basal ganglia, the latency
istic electrophysiological dysfunctions are the delay or and amplitude of the blink reﬂex responses is usually normal,
absence of trigeminal nerve mediated reﬂex responses to but their excitability is altered (Kimura, 1973). The study of
electrical stimulation of the trigeminal branches of the side the blink reﬂex excitability recovery curve to paired stimuli
of the Horner’s sign (Aramideh et al., 1997; Fitzek et al., has been used in the study of many disorders presenting with
1999; Valls-Sole et al., 1996). The abnormality of trigeminal basal ganglia dysfunction. Enhancement of excitability is
nerve afferents can be also shown by recording found not only in Parkinson’s disease (Kimura, 1973), but
J. Valls-Sole / Clinical Neurophysiology 116 (2005) 2255–2265 2261
also in blepharospasm (Berardelli et al., 1985), cervical al., 1997a); Huntington’s disease (Munoz et al., 2003) and
dystonia (Tolosa et al., 1988), tics (Smith and Lees, 1989), blepharospasm (Gomez-Wong et al., 1998). Prepulse
and other disorders (Eekhof et al., 1996). It is, therefore, of inhibition has been more largely studied using the startle
little use for differential diagnosis between degenerative reaction as a probe. A large amount of research in that ﬁeld
disorders. In clinical practice, the assessment of enhanced has been devoted to patients with schizophrenia, in whom
trigemino-facial reﬂex excitability may be of interest for the reduced prepulse inhibition is interpreted as reﬂecting
documenting the existence of an abnormal function of the attentional deﬁcit and information processing abnorm-
brainstem interneurons in patients in whom clinical alities of these patients (Perry and Braff, 1994; see Braff et
assessment is dubious or at early stages of their disease. al., 2001 for an update on abnormalities of prepulse
As with many other aspects of neurophysiology, the study inhibition of the startle reaction).
of the blink reﬂex excitability recovery is of interest for
improving our knowledge on the physiology of central
nervous system connectivity and pathophysiological mech- 7. Trigeminal reﬂexes in the study of pain syndromes
anisms underlying disorders of the basal ganglia. Being
opposite in many respects to Parkinson’s disease, the Trigeminal reﬂexes are useful in the study of the
excitability recovery curve in patients with Huntington’s conduction in large axons and, therefore, they are of little
disease is also of opposite behavior (Esteban and Gime- ´ utility in the assessment of pain syndromes. Nevertheless,
nez-Roldan, 1975). This is probably due to the different sign experts in orofacial pain syndromes have found abnormal-
in the abnormality of the basal ganglia output in the two ities in some of the reﬂexes, mainly those involving the
disorders (Agostino et al., 1988; Esteban and Gimenez- ´ masseter muscles.
Roldan, 1975; Valls-Sole et al., 2004). Fig. 3 depicts a
7.1. Trigeminal neuralgia
schematic representation of the circuits pressumably
mediating the control of the blink reﬂex by the basal ganglia.
No abnormalities are usually found on trigeminal
Prepulse inhibition of the blink reﬂex is also abnormal in
reﬂexes in patients with idiopathic trigeminal pain (Cruccu
patients with Parkinson’s disease (Nakashima et al., 1993;
et al., 1990), but the study of trigeminal nerve evoked
Schicatano et al., 2000) and in patients with Huntington’s
potentials to percutaneous stimulation of the infraorbital
disease (Swerdlow et al., 1995). However, the abnormal
nerve could document a dysfunction located at the posterior
prepulse inhibition in both disorders is of the same sign,
fossa in some patients (Leandri et al., 1988). However, these
pointing out to a different pathophysiological mechanisms
methods test the function in large ﬁbers and may not be
for the regulation of the blink reﬂex excitability and the appropriate for the study of dysfunctions in small ﬁbers.
control of prepulse inhibition (Valls-Sole et al., 2004). Using a laser CO2 stimulus, Cruccu et al. (2001) reported
Prepulse inhibition of the blink reﬂex induced by frequent abnormalities in the evoked potentials, suggesting
trigeminal nerve stimuli has been found abnormally reduced a dysfunction of small-myelinated afferents at the level of
in many disorders, including Parkinson’s disease (Lozza et the posterior fossa as an important pathophysiological
mechanism of neuralgic pain. Patients with trigeminal
neuralgia may have a severe dysfunction of the nociceptive
SC NRM afferent system in the painful side. Fig. 4 shows one
example of trigeminal laser evoked potentials in a healthy
volunteer and in a patient with trigeminal neuralgia.
Fig. 3. Schematic representation of the circuit connecting the basal ganglia
with the trigeminal neurons (modiﬁed from Basso and Evinger, 1996).
GPi/SNr, globus pallidus internum/substantia nigra pars reticulata; SC,
superior colliculus; NRM, nucleus of the raphe magnus; I, inhibitory
connections; E, excitatory connections. Thick lines represent the increase
activity of the connection. The ﬁnal effect of the initial enhancement of Fig. 4. Examples of trigeminal laser evoked potentials (LEPs) to
activity in pallidal connections to the superior colliculus that is typical of stimulation of the mentonian region in a healthy volunteer (A) and in a
Parkinson’s disease is a decrease of the inhibitory actions of the nucleus patient with trigeminal neuralgia (B). Each trace is the average of four trials,
raphe magnus on trigeminal neurons. Thin lines represent the decrease of and two traces are superimposed in each graph. Note the smaller amplitude
activity. The ﬁnal effect of the initial decrease of activity in pallidal and larger dispersion of the evoked potential in the patient. The peaks of the
connections to the superior colliculus that is typical of Huntington’s disease LEPs are only labelled in the healthy volunteer because of the imprecise
will cause an enhancement of the inhibition upon trigeminal neurons. latency of N2 in the patient.
J. Valls-Sole / Clinical Neurophysiology 116 (2005) 2255–2265
7.2. Atypical facial pain cortical responses and brainstem reﬂexes elicited by
nociceptive inputs, suggesting that patients with chronic
Some patients complain of orofacial pain that does not craniofacial pain due to temporomandibular joint dysfunc-
fulﬁl the criteria for trigeminal neuralgia and may be tion syndrome have an altered trigeminal nociceptive system.
diagnosed as atypical facial pain. The etiology of this
syndrome is unknown and proper diagnostic criteria are still 7.4. Headache
lacking. Nevertheless, Jaaskelainen et al. (1999b) studied
blink and jaw reﬂexes in 17 patients with atypical facial Among the complexities involving the pathophysiologi-
pain, in whom they identiﬁed trigeminal dysfunctions that cal mechanisms of the different forms of headache, some
did not correspond to any abnormality in the magnetic authors have hypothesized the possible role of dysfunctions
resonance image. Furthermore, combining different brain- of the trigeminal nerve or brainstem interneurons (Lozza et
stem reﬂexes, trigeminal nerve evoked potentials, mental al., 1997b; van Vliet et al., 2003). Leandri et al. (1999)
nerve conduction studies and quantitative sensory testing of reported a patient with multiple sclerosis who presented
the face, Jaaskelainen (2004) proposed a mechanism-based with a plaque of demyelination in the trigeminal root entry
classiﬁcation of orofacial pain. zone and a cluster headache, suggesting that there was a
trigeminal mediated mechanism for pain. Furthermore,
7.3. Temporomandibular joint dysfunction syndrome Ellrich et al. (1999) have proven that meningeal afferents
converge together with facial sensory afferents in trigeminal
There has been a large number of publications on whether neurons. The reﬂex responses to trigeminal nerve stimu-
the patients with temporomandibular joint dysfunction lation are larger during a migraine attack than in the same
syndrome have or have not abnormalities in jaw reﬂexes person in periods free of pain or in comparison to control
(De Laat et al., 1985; van Steenberghe and de Laat, 1989). In subjects (Kaube et al., 2002; Sandrini et al., 2002),
some studies, the second phase of the MIR was reduced or suggesting that the trigeminal neurons are sensitized during
absent (De Laat et al., 1985). It is possible that some of the an acute migraine attack. This ﬁnding may be of interest for
abnormalities are due to mechanical alterations rather than further understanding of the role of the trigeminal complex
neurological dysfunctions, since Cruccu et al. (1997) found in the pathophysiology of headache and for follow-up of
no abnormalities in the excitability of the MIR, nor in the patients during their attack or in response to treatment.
motor evoked potentials to transcranial magnetic stimu-
lation. However, experimental studies have shown that
chronic pain causes excitatory effects on the masseteric 8. Conclusions
stretch reﬂexes (Svensson et al., 2001), which may bring
support to neurologically based pathophysiological mech- The study of trigeminal nerve conduction, trigeminal
anisms for the abnormalities in the jaw reﬂexes. More nerve-mediated brainstem reﬂexes, and trigeminal centers-
recently, Romaniello et al. (2003) found abnormalities in related brainstem functions, provide a wealth of data of high
Map of the theoretical correlation between neurophysiological studies of the trigeminal nerve and lesions along the trigeminal pathway
Nerve Jaw Blink Blink Masseter Laser Reﬂex Prepulse
conduction jerk reﬂex R1 reﬂex R2 inhibitory evoked excitability inhibition
studies reﬂex potentials recovery
Ophthalmic branch lesions CC C Ca
Maxilar branch lesions Cb Ca
Mandibular branch lesions C CC Cb C Ca
Gasserian ganglia lesions CC CC CC C
Root lesions C CC C C C
Mesencephalic lesions C
Pontine lesions CC C
Medullary lesions CC C CC
Supranuclear lesions CC CC CC
Trigeminal neuralgia CC
TMJD syndrome C C C
Headache and facial pain C C
The crosses mark the tests in which abnormalities are most likely to be found (in response latency, response amplitude, or both) at each of the conditions listed
in the left column. One cross, possible; two crosses, probable. In most instances, the applicability of tests that are not marked has not been properly examined
and, therefore, absence of a cross does not necessarily mean that the result of applying that speciﬁc test will not be of interest. TMJD, temporo-mandibular joint
After selective stimulation of each branch.
Responses elicited after maxilar or mandibular electrical stimulation.
J. Valls-Sole / Clinical Neurophysiology 116 (2005) 2255–2265 2263
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