Headache Medicine 2021, 12(4):317-322 p-ISSN 2178-7468, e-ISSN 2763-6178

317

ASAA

DOI: 10.48208/HeadacheMed.2021.52

Headache Medicine

Original

Benign paroxysmal torticollis is a sensorimotor trigeminocervical

convergence mechanism? Experimental evidence

Elcio Juliato Piovesan , Pedro Andre Kowacs

Universidade Federal do Paraná, Curitiba, Parana, Brazil

Abstract

Introduction

Benign paroxysmal torticollis (BPT) is likely an age-sensitive, childhood periodic syndrome

that is commonly precursor of migraine, with atypical postural behavior (torticollis) to start

early and self-limited, of unknown etiology.

Objective

To prove the existence of forms of sensorimotor convergence between the trigeminal nerve

and upper cervical roots.

Methods

Ninety-ve Norvegicus rats were submitted to infraorbital nerve blockade using botulinum

neurotoxin type A (BoNT/A) (n=48) controlled by isotonic saline solution animals (ISS)

(n=47). After 84 days, the animals were evaluated on their motor functions using open

eld test and postural behavior.

Results

Of the 48 animals in the BoNT/A group, one animal showed the torticollis ipsilateral to

BoNT/A injection. The macroscopic analysis showed fasciculations on the clavotrapezius

muscle. The biopsy with optical and electronic microscopy of this muscle showed changes

suggestive of denervation secondary to BoNT/A.

Conclusion

We suggested the existence of a pathway sensorimotor probably in the brainstem involves

the trigeminal system and cervical motoneurons.

Elcio Juliato Piovesan

piovesan1@hotmail.com

Edited by:

Juliana Ramos de Andrade

Keywords:

Benign paroxysmal torticollis

Precursors of migraine

Sensorimotor

Trigeminocervical convergence

Received: March 20, 2021

Accepted: March 25, 2021

318

ASAA

Piovesan EJ, Kowacs PA

Benign paroxysmal torticollis is a sensorimotor trigeminocervical convergence mechanism? Experimental evidence

Introduction

enign paroxysmal torticollis (BPT) of infancy is considered

a migraine variant. Semiologic aspects include recurrent

episodes of an abnormal rotation and inclination of the

head to one side.

The torticollis lasted from a few hours to a

few days; the frequency of the episodes initially ranged from

once every two days to once every 45 days.

Associated

symptoms include: pallor, sweating and vomiting, hypotonia

of the homolateral lower limb and upward-diverted gaze,

photophobia, sleepiness, asthenia, and headache.

The International Headache Society included the BPT as one

of the childhood periodic syndromes that are commonly

precursors of migraine. Several factors can justify this statament:

migraine familial history, associated symptoms during the BPT,

recurrence and duration of the episodes, and the outcome of

these patients who progress to a typical migraine.

The trigemino-cervical convergence mechanisms have

been widely identied in human experiments

, in

pharmacological

and no pharmacological treatments

for migraine patients. Recently, patients with chronic

migraine have been handled with greater occipital nerve

neurostimulation with good results.

Besides, pain in the

neck is common during migraine attacks.

The trigeminal

and cervical systems are interrelated to other excitatory

and/or inhibitory according to the stimulus´s intensity,

duration and location.

To support the hypothesis that BPT occurs as a result of

trigeminal nociceptive activation on cervical motoneurons

(trigeminocervical convergence motor sensory mechanisms),

we carried out a preclinical study where we tried to

determine the modulatory nociceptive inuence on cervical

motoneurons through nociceptive and motor inhibition using

botulinum neurotoxin type A.

Methods

Subjects: Male rats (

Rattus-norvegicus

) (n=95), weight from

240-340 grams, were housed in standard plastic cages

(4 per cage) with sawdust bedding in a temperature-

controlled room (23+10C) and maintained on a 12 hours

light-dark cycle. Animals were allowed to have free access

to food pellets and water. The trial was conducted at

the Neurology Research Laboratory of the Universidade

Federal do Parana, Brazil. Animals were randomized

double-blind to receive either isotonic 0.9% saline solution

(ISS) as a control group or neurotoxin botulinum type-A

(BoNT/A) as an active drug.

Phases of the study: All animals were submitted two

treatments (day 0 and day 42), one open eld test, and

one posture behavior (84 days after the beginning of the

treatment, “day 0”).

Drugs and treatment: The animals were divided into two

groups: one group used ISS, and the other used BoNT/A.

For the experimental group, BoNT/A (Botox®, Allergan,

Inc, Irvine, CA) was reconstituted in 2 ml of ISS, and, for

the Control Group, only ISS was used. All the doses of

BoNT/A and ISS used were administered as a 40 µl bolus

into the right upper lip, just lateral to the nose using a 0.5

ml syringe with a 29-gauge needle. The dose of BoNT/A

was 12 units per kilogram.

Open Field Test (OFT): This test assesses motor skills,

including animals´ integrity and spontaneous exploratory

behavior. As described, the OFT is a behavioral test

that depends upon other cortical functions, such as the

integrity of the motor circuitry of the animal. During the

OFT, the animals were deprived of food and water. The

parameters evaluated were: 1- latency to movement onset;

2- rearing frequencies (number of times the animals stood

on their hind legs); 3- numbers of the square (numbers of

the time that the animal entered a new square with all four

paws); 4- immobility time (number of seconds of lack of

movement during testing), and 5- abnormal posture during

the test. After ve minutes of the test, the animals were

removed from the OFT arena and transferred to a second

room. The OFT apparatus was washed with 5% ethanol

before testing to eliminate possible bias due to odors left

by previous mice.

Posture Behavior: The test was performed during the

open eld test. The evaluation was purely semiological,

trying to identify anomalous cervical postures. Animals

that showed postural abnormalities underwent cervical

dissection of neck muscles and visualization of ectopic

cervical muscles. Anomalies such as muscle atrophy or

fasciculations and muscles changes were considered to

be investigated.

Muscle Biopsy: For this procedure, all animals were

anesthetized utilizing intraperitoneal ketamine 50 mg/

kg and 10 mg/kg xylazine. The muscle was undergoing

optical microscope analysis and electronic scanning.

Regulatory aspects: All the experiments adhered to the

guidelines of the Committee for Research and Ethical

Issues of IASP (Pain 1983). The experimental procedures

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Piovesan EJ, Kowacs PA

Benign paroxysmal torticollis is a sensorimotor trigeminocervical convergence mechanism? Experimental evidence

were reviewed and approved by the regulatory committee

of the Universidade Federal do Paraná, Health and Animal

Sciences Sector.

Statistical analysis: The t-test was used for comparisons

between paired subgroups. For comparisons between

unpaired subgroups, the Mann-Whitney test was used.

For all tests, only “p” values smaller than 0.05 were

considered signicant.

Results

In this study, 48 animals were subjected to treatment with

BoNT/A, and 47 animals used ISS.

Open field test: The results showed that there was no

difference between all the parameters studied between

the groups: 1- latency to movement onset; 2- rearing

frequencies; 3- numbers of the square; 4- immobility time;

and 5- abnormal posture during the test.

Posture behavior: Of the 48 animals subjected to

treatment with BoNT/A, only one animal showed postural

abnormalities behavior. The animal showed turning of the

head to left side “torticollis” (Figure 1). Animals treated

with ISS showed no changes in postural behavior.

Figure 1. Rat with left torcicollis after BoNT/A treatment.

Muscle biopsy: During the muscle biopsy, the anesthetized

animal was assessed macroscopically, which showed

the presence of fasciculations on clavotrapezius muscle

ipsilateral to the site of nerve block infraorbital with

BoNT/A. Motoneurons supplying the clavotrapezius

showed a rostrocaudal somatotopic distribution in the

spinal accessory nucleus and in column-5. Column-5

consists of the motoneurons passing through the central

nervous system extending longitudinally from C3 to C5.

This muscle was resected and underwent biopsy using

optical microscopy techniques and electronics. Optical

microscopy showed space between cells and formed

round or triangular suggested atrophy of the myobres

(Figure 2 panels A and B). Eletromicrography of the

muscle in scanning electron microscopy showed spacing

between the muscle bundles (Figure 2 panels C and D).

Eletromicrography of muscle in transmission electron

microscopy, showed the absence of mitochondrial cristae,

and there little glycogen scattered throughout the cytoplasm

also suggested muscle atrophy (Figure 2 panels E and F).

Discussion

The features of our study showed the existence of a

convergence mechanism between the trigeminal sensory

system and cervical motoneurons. The semiology of this

animal demonstrated a shift in posture characterized as

torticollis. The semiology features are similar to those

found in BPT.

First described by Snyder in 1969, benign paroxysmal

torticollis (BPT) is characterized by abnormal postural

head behavior, sometimes accompanied by vomiting,

pallor, agitation, vomiting, nystagmus, abnormal trunk

posture, apathetic, unsteadiness of gait, and ataxia which

duration is limited from one hour to 14 days.

9,10

The

frequency is most variable from one per month to several

times per month.

Symptoms begin very early, like within

two months, and the duration can reach up to eight years;

most patients have a family history of migraine (mother),

and many of these patients will develop migraine.

Additional tests, such as EEG and neuroimaging (CT or

MRI), are normal.

1,9,10

Having demonstrated that, Snyder reported that “ice water

applied to the ear canal failed to produce nystagmus” in

9 of his 12 patients, and Sanner and Bergstrom

“normal

vestibular responses with electronystagmography control

both between attacks and during the BPT”, many papers

have suggested that BPT probably was a compensatory

torticollis for a functional vestibular disturbance.

9,10

The

hypothesis is based on clinical manifestations during the

paroxysms, especially since these patients develop in the

evolution the benign paroxysmal vertigo of childhood, a

precursor form of migraine.

A vascular disruption in the brainstem territory, as in basilar

migraine, might be responsible for BPT.

11,13

Although,

torticollis has not been reported in cases of basilar

migraine in children.

Four new cases were described

with the unusual syndrome of BPT showed evidence that

it may be considered as a childhood migraine equivalent

and may be associated with a calcium channelopathy.

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Piovesan EJ, Kowacs PA

Benign paroxysmal torticollis is a sensorimotor trigeminocervical convergence mechanism? Experimental evidence

Figure 2. A- Atrophy of the myobras (Picrosírius 40x) (*) Presence of space between cells and form round or triangular

and of the same; B- Immersion (Picrosírius) round form clearer; C- Electromicrography of muscle in scanning electron

microscopy of the ISS rat, muscle tissue in longitudinal view of the ISS rat; D- Electromicrography of muscle in scanning

electron microscopy of the BoNT/A rat, muscle tissue in longitudinal view of the BoNT/A rat areas with a spacing between

the muscles bundles (arrows); E- Electromicrography of muscle in transmission electron microscopy, mitochondria dispersed

throughout the cell cytoplasm (arrow head) among the mitochondria to see if the material deposition electron rosettes of

glycogen (circle) animal of the ISS group; F BoNT/A group in this group did not observe the mitochondrial cristae, and there

is little glycogen scattered throughout the cytoplasm.

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Piovesan EJ, Kowacs PA

Benign paroxysmal torticollis is a sensorimotor trigeminocervical convergence mechanism? Experimental evidence

Recently was suggested that BPT is commonly accompanied

by delayed motor development; this study showed gross

motor delays in 50% of the children (5/10) with additional

ne motor delays in 3/5 children.

In this study we suggested a connection between the

trigeminal sensory and motor system (motoneurons) in the

neck. BoNT/A was administered in the second branch

of the trigeminal nerve trafc until the fth column of

the rats producing denervation of the motoneurons of

C3 through C5 paralyzing and atrophying the cervical

muscles (specically the clavotrapezius). The paralysis of

this muscle produced a very similar behavior semiological

(torticollis) in rats, similar to BPT in humans.

We can suggest that, in patients with BPT, stimulation of the

trigeminal nerve roots that converge to promote activation

of cervical motoneurons and induce contractions (dystonia)

can generate transient torticollis. This hypothesis can be

acceptable in patients with headaches associated with

BPT; however, we know that many patients do not show

this association. Many forms of periodic precursors of

migraine also do not present headaches at earlier ages,

presenting migraine many years later, during adult age.

As described above, the most recent studies suggest that

patients with BPT present delayed motor development

probably making these motoneurons more sensitive

to noxious stimulation during this phase of human

development. This would explain why the BPT does not

occur in adulthood in patients with migraine, and why

patients during migraine attacks can show symptoms in

the cervical spine.

Additionally, a semiological aspect of

migraine related to this hypothesis is that many pediatric

and adult patients can experience symptoms like neck

pain and stiff neck (2.91% of the patients) as premonitory

migraine symptoms.

Here we suggested the existence of a pathway

trigeminocervical sensory-motor type (Figure 3). The

relationship of this pathway with the BPT cannot be wholly

conrmed; new studies will be necessary to prove but is a

new hypothesis on the pathophysiology of the BPT.

Contributions of authors: The authors contributed equally.

Conflict of interest: The authors deny any conict of interest.

Funding: No support funding.

Figure 3. Convergence mechanism. CN, Caudalis nucleus; IN, Inerpolaris nucleus; ON, Oral nucleus; MTN, Mean trigeminal

nucleus; MN, Motor nucleus; C1-C5, Cervical roots.

322

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Piovesan EJ, Kowacs PA

Benign paroxysmal torticollis is a sensorimotor trigeminocervical convergence mechanism? Experimental evidence

Elcio Juliato Piovesan

https://orcid.org/0000-0002-0915-0430

Pedro André Kowacs

https://orcid.org/0000-0001-7770-7475

References

1. Drigo P, Carli G and Laverda AM. Benign paroxysmal

torticollis of infancy.

Brain Dev

2000;22(3):169-172

Doi:10.1016/s0387-7604(00)00099-1

2. Piovesan EJ, Kowacs PA, Tatsui CE, Lange MC, Ribas

LC and Werneck LC. Referred pain after painful

stimulation of the greater occipital nerve in humans:

evidence of convergence of cervical afferences on

trigeminal nuclei.

Cephalalgia

2001;21(2):107-109

Doi:10.1046/j.1468-2982.2001.00166.x

3. Piovesan EJ, Werneck LC, Kowacs PA, Tatsui CE,

Lange MC and Vincent M. Anesthetic blockade of the

greater occipital nerve in migraine prophylaxis.

Arq

Neuropsiquiatr

2001;59(3-a):545-551

4. Piovesan EJ, Di Stani F, Kowacs PA, Mulinari RA,

Radunz VH, Utiumi M, . . . Werneck LC. Massaging

over the greater occipital nerve reduces the intensity

of migraine attacks: evidence for inhibitory trigemino-

cervical convergence mechanisms.

Arq Neuropsiquiatr

2007;65(3a):599-604 Doi:10.1590/s0004-

282x2007000400010

5. Saper JR, Dodick DW, Silberstein SD, McCarville

S, Sun M and Goadsby PJ. Occipital nerve

stimulation for the treatment of intractable

chronic migraine headache: ONSTIM feasibility

study.

Cephalalgia

2011;31(3):271-285

Doi:10.1177/0333102410381142

6. Calhoun AH, Ford S, Millen C, Finkel AG, Truong Y

and Nie Y. The prevalence of neck pain in migraine.

Headache

2010;50(8):1273-1277 Doi:10.1111/

j.1526-4610.2009.01608.x

7. Piovesan EJ, Kowacs PA and Oshinsky ML.

Convergence of cervical and trigeminal sensory

afferents.

Curr Pain Headache Rep

2003;7(5):377-

383 Doi:10.1007/s11916-003-0037-x

8. Kitamura S and Sakai A. A study on the localization

of the sternocleidomastoid and trapezius

motoneurons in the rat by means of the HRP method.

Anat Rec

1982;202(4):527-536 Doi:10.1002/

ar.1092020412

9. Snyder CH. Paroxysmal torticollis in infancy.

A possible form of labyrinthitis.

Am J Dis

Child

1969;117(4):458-460 Doi:10.1001/

archpedi.1969.02100030460013

10. Deonna T and Martin D. Benign paroxysmal torticollis

in infancy.

Arch Dis Child

1981;56(12):956-959

Doi:10.1136/adc.56.12.956

11. Sanner G and Bergström B. Benign paroxysmal torticollis

in infancy.

Acta Paediatr Scand

1979;68(2):219-

223 Doi:10.1111/j.1651-2227.1979.tb04992.x

12. Dunn DW and Snyder CH. Benign paroxysmal vertigo of

childhood.

Am J Dis Child

1976;130(10):1099-1100

Doi:10.1001/archpedi.1976.02120110061008

13. Deonna T. Neurologic problems of abdominal

migraine in children. Clinical study of 15 cases and

review of the literature.

Pediatrie

1977;32(2):119-

127

14. Gifn NJ, Benton S and Goadsby PJ. Benign

paroxysmal torticollis of infancy: four new cases

and linkage to CACNA1A mutation.

Dev Med

Child Neurol

2002;44(7):490-493 Doi:10.1017/

s0012162201002407

15. Rosman NP, Douglass LM, Sharif UM and Paolini

J. The neurology of benign paroxysmal torticollis of

infancy: report of 10 new cases and review of the

literature.

J Child Neurol

2009;24(2):155-160

Doi:10.1177/0883073808322338

16. Cuvellier JC, Mars A and Vallée L. The prevalence

of premonitory symptoms in paediatric migraine:

a questionnaire study in 103 children and

adolescents.

Cephalalgia

2009;29(11):1197-1201

Doi:10.1111/j.1468-2982.2009.01854.x