Blackwell Publishing LtdOxford, UKCHACephalalgia0333-1024Blackwell Science, 2006266747751Clinical CorrespondenceCephalalgic alopecia areataFM Cutrer & MR Pittelkow

doi:10.1111/j.1468-2982.2006.01098.x

CLINICAL CORRESPONDENCE

Cephalalgic alopecia areata: a syndrome of neuralgiform head pain

and hair loss responsive to botulinum A toxin injection
FM Cutrer1 & MR Pittelkow2
1
Department of Neurology and 2Department of Dermatology, Mayo Clinic, Rochester, MN, USA

F. Michael Cutrer MD, Department of Neurology, 8WB Mayo Clinic, Rochester, MN

55905, USA. Tel. +1 507 538 1036, fax +1 507 266 4419, e-mail cutrer.michael@mayo.edu
Received 6 July 2004, accepted 15 October 2004

for a patient of her age but were otherwise

Case report
unremarkable. Biopsy of the affected scalp showed
A 34-year-old woman presented with a 30-month lymphocytic infiltration around the hair bulb
history of recurrent episodes of occipital and characteristic of alopecia areata (Fig. 2). Thyroid-
parietal-temporal jabbing, burning head pain which stimulating hormone, free T4, α-androstanediol
was preceded by a febrile illness associated with and glutamate levels were normal. Blood testing
localized pruritus on the neck, a low-grade diffuse for inflammatory markers including erythrocyte
headache and extreme fatigue. After a week, the sedimentation rate (ESR), rheumatoid factor (RF),
fever and headache resolved but malaise persisted. antinuclear antibody (ANA) and antibodies to
Two weeks later, the patient began to have a cramp- extractable nuclear antigens (ENA) was negative.
ing, squeezing pain in the muscles of her neck and Four months after presentation, the frequency of
upper back and a burning sensation that spread over attacks began to increase. From her local dermatolo-
the occipital region of her head. Superimposed upon gist, the patient received two series of triamcinolone
the burning pain were intermittent volleys of severe acetonide injections (4 and 6 mg) into the scalp
jabbing occipital and temporal pain that lasted sev- lesions combined with 40 mg intramuscularly, with-
eral minutes. Within several hours of the episode of out improvement. Over the course of 5 years, the
jabbing scalp pain, the patient began to experience patient had tried numerous treatments for her scalp
hair loss at the site of the pain. Even after resolution pain and hair loss, including the maximally tolerated
of the pain, the hair loss continued for days. At first, daily doses of buspirone (55 mg), propranolol
the episodes of pain and hair loss were separated by (180 mg), and tizanidine (16 mg), indomethacin
days to weeks and were infrequent enough to allow (225 mg), nortriptyline (50 mg), amitriptyline
hair regrowth. However, subsequent episodes of jab- (50 mg) and gabapentin (2700 mg), all without
bing pain resulted in more persistent loss of hair. sustained benefit. Oral opiates including pro-
Small patches of alopecia were observed. Increasing poxyphene, codeine and hydrocodone provided
frequency of attacks resulted in large areas of the only transient, incomplete relief. In an attempt to
scalp that were almost completely devoid of hair reverse hair loss, the patient also received midodrine
(Fig. 1). On presentation, the burning scalp dysaes- 5 mg three times per day in an attempt to decrease
thesia occurred daily; however, the jabbing pain was access to the hair follicles by circulating autoanti-
intermittent and not diurnal. Allodynia was present bodies. There was no response to this manoeuvre.
in area of affected scalp but no vasomotor changes She was refractory to all attempted therapies and
were apparent. The patient adamantly denied pull- was increasingly disabled by her jabbing pain which
ing or in any way manipulating her hair. There was became daily. In addition, the patient began to have
no family history or prior personal history of alope- worsening myalgias and fatigue.
cia areata. The patient had not observed loss of eye- Treatment with botulinum A toxin (BTXN A) was
brow, lash or any other body hair. then attempted. BTXN A was injected into procerus,
Investigations, including magnetic resonance corrugator, frontalis, temporalis, splenius capitus,
imaging/angiography of brain, showed that the lat- occipitalis and trapezius muscles (100 units total)
eral ventricles were near the upper limit of normal with special care taken to inject sites most frequently

© Blackwell Publishing Ltd Cephalalgia, 2006, 26, 747–751 747

748 FM Cutrer & MR Pittelkow
Figure 1 Intensive patchy hair thinning and loss
characteristic of alopecia areata.
Figure 2 Peribulbar and external root sheath infiltration by
autoreactive T lymphocytes with resultant hair shaft
diminution and loss (H&E, ×100).
involved by the neuralgiform pain. BTXN A treat-
ment resulted in a marked reduction in the fre-
quency and intensity of the jabbing head and neck
pain, which began approximately 10 days after injec-
tion and lasted 6 weeks. The patient reported partial
hair regrowth during this remission. However, no
improvement was seen in the myalgias and fatigue
and she began to experience muscle spasm in the
intrascapular and thoracic areas of her back. Three
months later, she received a second 100-unit BTXN
treatment to the head and neck, as well as 192.5 units
Figure 3 Marked hair regrowth following botulinum A toxin
injection (4 weeks after treatment).
of BTXN injected into the paraspinal muscles. This
second treatment resulted in complete remission of
the back pain for 45 days and the head pain for
60 days. During this period she had significant hair
regrowth (see Fig. 3). By the eighth week she began
to experience recurrence of the neck and head pain
and loss of hair. A third BTXN treatment has resulted
in a similar remission.
Discussion
With the exception of a single case briefly mentioned
in the Journal of Nervous and Mental Disease in 1894
(1), to our knowledge this is the only reported asso-
ciation between recurrent episodes of the head pain
and colocalized hair loss from scalp. Unlike our case,
facial flushing occurred with the head pain in the
1894 case. In addition, myalgias and muscle spasm
in the neck and back eventually developed in the
current case, while similar symptoms are not men-
tioned in the 1894 patient. In our patient, neuralgi-
form pain did not show a sustained response to
gabapentin, amitriptyline or nortriptyline, medica-
tions that are often effective in the treatment of
occipital and other scalp-based neuralgias. The close
association of alopecia areata with cephalalgia in our
case suggests that the pain involves the primary
afferent neuron, as it is difficult to explain direct
effects on the hair follicle by activation restricted to
the CNS. Once initiated, however, prolongation of
the pain and its evolution from intermittent to
chronic probably involves sensitization at second
and perhaps higher order neurons. It may be that
during the early weeks of evolution, the constant
© Blackwell Publishing Ltd Cephalalgia, 2006, 26, 747–751
 Cephalalgic alopecia areata 749

input from the primary afferent nociceptors
exceeded the modest central effects of tricyclic anti-
depressants and gabapentin. Lack of response to ste-
roidal and non-steroidal anti-inflammatory drugs
argues against focal peripheral inflammation as the
sole basis for the pain. Systemic markers of inflam-
mation (elevated ESR, RF, ANA and ENA) were also
conspicuously absent.
A biopsy of the affected scalp revealed lympho-
cytic peribulbar inflammation consistent with alope-
cia areata, raising the possibility that the case was
simply an atypical presentation of alopecia areata.
The biopsy showed no features of psychogenic hair
pulling (trichotillomania). Alopecia areata is not
accompanied by pain, although paraesthesias and
pruritus may occasionally be experienced. The dif-
fuse myalgias and muscle spasms in the back that
developed in the patient are also not suggestive of
alopecia areata. Even if one assumes that this patient
has a variant of alopecia areata, the relationship
between the pain and recurrent hair loss still war-
rants explanation and may provide important infor-
mation about neural regulation of hair follicles.
Alopecia areata is considered an autoimmune
disease mediated by a reversible, tissue-restricted
immune reaction involving T lymphocytes that infil-
trate and surround the hair bulb and root sheath (2).
Hair loss within the affected area can be fairly rapid
and profound because all hair bulb follicles are
affected (3).
In this particular case, it seems likely that hair loss
is initiated and sustained by the recurrent activations
of the trigeminal and upper cervical branches inner-
vating hair follicles (Fig. 4). Several factors support
this possibility: (i) the patient did not develop alope-
cia until after the appearance of the neuralgiform
pain; (ii) early in the evolution of the syndrome,
partial hair regrowth occurred during spontaneous
remissions, during which the patient was free of the
neuralgiform pain; (iii) treatment with BTXN that

SP promotes hair growth CGRP

1. Normal state regulates immune response 6. Primary afferent neuron begins slow recovery

Primary afferent Hair

neuron Pain suppression regrowth
Second-order persists 30-45 days
neuron Branch to
hair follicle

Release of SP & CGRP

2. Acute activation from activated 7. Primary & secondary neurons recover completely
terminal
40-45 days post
Neuralgiform pain botulinum toxin

3. Prolonged or frequent activation SP & CGRP depleted 8. Recurrent acute activation Release of SP & CGRP
from repeatedly from activated
activated terminal Hair loss terminal

Pain becomes chronic Loss of GCRP

supression of antigen
Langerhans presentation immune
cells attack on follicle

4. Botulinum toxin injected 9. Process repeats SP & CGRP depleted

first week after injection Primary afferent deactivated, from repeatedly
SP & CGRP in terminal activated terminal Hair loss
begins repletion
Pain continues
Langerhans
cells

5. Botox deactiviation of primary

& second-order neuron SP & CGRP resume
baseline regulation
of immune response
at follicle
Pain subsides after
7-10 days

CP1155979B-1

Figure 4 Neuron projections and innervation of hair follicle. Botulinum A toxin (BTXN) transport and localization in neurons.
Neural and hair follicle pathology remedied by BTXN injections.

© Blackwell Publishing Ltd Cephalalgia, 2006, 26, 747–751

750 FM Cutrer & MR Pittelkow
caused a remission of the neuralgiform pain resulted
in hair regrowth; (iv) at the end of remission, recur-
rence of the neuralgiform pain resulted in loss of
regrown hair.
The anatomy and physiological interactions
between nociceptive neurons and the hair follicle are
complex. Hair follicles are innervated by neuropep-
tide-containing, unmyelinated neural plexuses (4)
with varicosities located in close proximity to the
likely site of hair follicle stem cells (5). Nociceptive
unmyelinated C-fibres known to have terminals in
skin contain neuropeptides including substance P
(SP) and calcitonin gene-related peptide (CGRP),
which when released by capsaicin injection are asso-
ciated with a neurogenic inflammatory response (6).
SP release from C and A δ fibres is associated with
mast cell degranulation both in skin (7) and dural
vessels (8). In the skin, SP receptors have been iden-
tified in the walls of perifollicular vessels (9) and SP
is also involved in the induction and regulation
of hair growth (7). In addition to its vasodilatory
actions, CGRP inhibits antigen presentation by
Langerhans cells and other dendritic cells (10) and
regulates T cell proliferation (11) when released from
perifollicular nerves within the epidermis. Disrup-
tion of the physiological, tonic release of neuropep-
tides from perivascular neurons may therefore result
not only in derangement of trophic vasomotor regu-
lation but also in altered peribulbar antigen presen-
tation and inhibition of further hair growth.
Response to botulinum toxin
Perhaps most intriguing is the fact that injection of
BTXN caused both remission of neuralgiform pain
and subsequent hair regrowth. There is no known
direct effect of BTXN on the hair follicle; thus, it is
likely that the regrowth was related to abolition of
the recurrent activation of primary afferent nocicep-
tive neurons. There is evidence to suggest that BTXN
A is taken up into the primary afferent neurons
innervating the muscles into which it is injected and
undergoes retrograde transport within the neuron
(12) to exert its effects at the interface of the central
and the peripheral nervous systems. In animal stud-
ies, injection of BTXN (3 ng/kg) into abducens
muscle resulted in a marked decrease in synaptic
transmission within abducens nuclei from vestibular
afferent inputs to abducens motoneurons within
2 days (13). Between 7 and 15 days post injection,
both excitatory and inhibitory postsynaptic poten-
tials were abolished. This was followed by profound
ultrastructural changes which included synaptic
stripping with a decrease in the number of synaptic
boutons as well as widening of the subsynaptic
interspace (13). It remains to be determined if
transsynaptic effects on the postjunctional fibre are
exerted by BTXN A. However, there are preliminary
data to suggest that this might occur (14, 15).
Possible mechanism of BTXN
One possible scenario for the evolution of events
observed in this case is summarized as follows. The
asymptomatic patient harbours an immunogenetic
predisposition for alopecia areata and sustains an
insult to trigeminocervical C and A δ fibres related
to the febrile, possibly viral, illness which activates
recurrent episodes of aberrant firing of nociceptive
neurons innervating the scalp and neck. When
occurring infrequently, activation of these fibres
causes the release of neuropeptides (including SP
and CGRP) from perifollicular nerve terminals with
local activation of mast cells. Because the firing is
relatively infrequent, the peripheral terminals are
able to undergo repletion of the neuropeptides and
there is no effect on hair growth. As the frequency
and duration of the episodes of C and A δ fibre
activation increase, SP and CGRP are depleted in
the perifollicular terminals. The tonic suppression
of antigen presentation and immune reactivity by
CGRP and the induction of hair growth by SP are
lost as the perifollicular terminals are unable to
recover neuropeptide concentrations between depo-
larizations. Antigen presentation is de-repressed and
activated local immune cells recognize and target
the hair bulb and root sheath. Induction of new
hair growth also markedly decreases or ceases com-
pletely in the affected areas. Hair loss becomes clin-
ically apparent.
The patient receives BTXN injection into muscles
innervated by branches of the affected neurons.
BTXN is taken into the nerve terminal and trans-
ported proximally, where it disables the synapse
between the primary afferent and the second-order
neuron within the trigeminal nucleus caudalis and
the dorsal horn of upper cervical spine. Whether the
blockade of firing at this synapse is based on trans-
synaptic migration of BTXN A to affect directly the
second-order neuron or is solely a prejunctional
effect on the primary afferent neuron is unknown.
Aberrant neural activation is halted. The perifollicu-
lar peripheral terminals replete their neuropeptides
and the tonic release of SP and CGRP resumes. Hair
regrowth resumes and continues as long as C and A
δ fibre activations are suppressed. After a period of
weeks, disabled synapses recover and the injured
neurons resume frequent aberrant firing. The
© Blackwell Publishing Ltd Cephalalgia, 2006, 26, 747–751

perifollicular terminals are again depleted and pain-
associated hair loss recurs.
Though this is a rare presentation of alopecia
areata closely associated with neuralgiform pain, the
marked hair regrowth and pain relief observed fol-
lowing BTXN injections strongly implicate local neu-
ral factors in mediating immunological activity of
alopecia areata. BTXN may also improve alopecia
areata not overtly linked to cephalalgia by similar
mechanisms. These observations may also provide
a mechanism by which BTXN targets first- and
second-order neurons in cephalalgia and other
BTXN-responsive headaches.
Acknowledgements
We gratefully acknowledge the contributions of Drs Christo-
pher Boes and Paola Sandroni to this report.
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