Neuroscience Letters 595 (2015) 4144

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Neuroscience Letters
journal homepage: www.elsevier.com/locate/neulet

Research article

Neurological soft signs in primary headache patients

L. Tremolizzo , S. Ferrario, A. Pellegrini, L. Fumagalli, C. Ferrarese, I. Appollonio
Neurology Unit, San Gerardo Hospital, Department of Surgery and Translational Medicine (DCMT) and Milan Center for Neuroscience (Neuro-MI),
University of MilanoBicocca, Monza, Italy

h i g h l i g h t s

Neurological soft signs (NSS) are clinical markers of minor brain alterations.
NSS are increased in primary headache outpatients (HP).
NSS are increased in HP expressing white matter hyperintensities at brain imaging.
Headache type and characteristics do not inuence NSS presentation.
NSS identify a subset of primary HP sharing brain anomalies and comorbidities.

a r t i c l e

i n f o

Article history:
Received 31 January 2015
Received in revised form 4 March 2015
Accepted 3 April 2015
Available online 4 April 2015
Keywords:
Comorbidity
Endophenotypes
Episodic frequent tension-type headache
Migraine
Neurological soft signs
White matter hyperintensities

a b s t r a c t
Neurological soft signs (NSS) are semeiotic anomalies not assessed by the standard neurological examination, primarily developed in psychiatric settings and recently proposed as potential markers of
minor brain circuit alterations, especially the cerebellarthalamicprefrontal network. Primary headache
patients present with normal neurological examination and frequent psychiatric comorbidity. Aim of this
exploratory study consisted in assessing NSS in 20 episodic frequent migraine (MH) and in 10 tensiontype headache (ETTH) outpatients compared to 30 matched healthy controls. NSS were assessed by the
Heidelberg scale; clinical characteristics and brain MRI were additionally obtained in all patients. NSS
were increased by 70 and 90% in ETTH and MH, respectively, with respect to controls (p < 0.001)
and the difference remained signicant even after controlling for age and education. Headache type and
characteristics did not inuence NSS presentation, while headache patients with white matter hyperintensities (WMH) at brain MRI had higher NSS scores compared both to normal controls and patients
without WMH. NSS identify a subset of primary headache patients sharing the same comorbidities or
minimal brain anomalies, suggesting that tailored prophylactic options might apply.
2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Neurological soft signs (NSS) are minor semeiotic anomalies
not assessed during the standard neurological examination and
for a long time postulated to indicate a diffuse dysfunction within
the nervous system [1]. A more recent concept assumes the presence of micro-anomalies within more specic brain networks [2,3].
In particular, studies suggest the NSS might predict abnormalities within the cerebellarthalamoprefrontal circuitry [4,5] and
be viewed as an index of cognitive dysmetria [5,6]. NSS assessment encompasses different domains, such as motor coordination

Corresponding author at: Neurology Unit, University of MilanoBicocca, Via

Cadore 48, 20900 Monza, Italy. Tel.: +39 2 6448 8128; fax: +39 2 6448 8108.
E-mail address: lucio.tremolizzo@unimib.it (L. Tremolizzo).
http://dx.doi.org/10.1016/j.neulet.2015.04.007
0304-3940/ 2015 Elsevier Ireland Ltd. All rights reserved.

(e.g., nger-to-nose test or diadochokinesis), up to complex motor

sequences (e.g., Ozeretzkis or Lurias tests), and often include also
sensory integration (e.g., stereognosis or graphesthesia). Furthermore some NSS scales include the assessment of primitive reexes
as well (e.g., snout or Myerson reexes).
NSS have been studied extensively in the eld of psychiatry, and
mainly of schizophrenia [7]; accordingly, several authors considered them as a potential marker for endophenotypes of psychotic
conditions, being already present before transition to psychosis in
at-risk individuals to the same extent as after transition [8] and
even among non psychotic relatives in affected pedigrees [9].
By contrast, NSS expression has been rarely addressed in the
eld of neurology, possibly because the concept of a neurological
semeiotics failing to localize lesions is in dramatic contrast with
its founding principles [10]; the only notable exceptions relate to
NSS correlations with specic cognitive functions and impairments,
mainly of the executive type [1113].

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L. Tremolizzo et al. / Neuroscience Letters 595 (2015) 4144

Table 1
Demographic and clinical data. CTRL, healthy controls; ETTH, frequent episodic tension-type headache; MH migraine; NP, not performed; PROF, prophylaxed primary
headache patients (including 3 MH and 2 ETTH). Data are reported as mean SD (range).

Sex, M/F
Age, years
Education,
years
HDI
Symptomatic drugs,
n/month
Frequency, n
attacks/month

CTRL
n = 30

MH
n = 20

ETTH
n = 10

PROF
n=5

7/23
39.7 12.1
(2272)
13.1 3.2
(518)
NP

4/16
40.3 9.3
(2557)
12.7 2.5
(818)
47.1 12.1
(2672)
9.4 5.9
(430)
8.9 3.5
(414)

3/7
39.1 16.6
(2374)
12.2 5.8
(523)
40.6 12.6
(2864)
8.6 3.5
(414)
8.8 3.3
(414)

2/3
40.6 13.7
(2662)
11.2 3.5
(513)
NP

NP
NP

Primary headaches are very prevalent conditions that imply

high social and personal costs with the constant need of developing effective therapeutic strategies [14]. Standard neurological
examination in these disorders is almost always not informative
and often brain imaging studies are requested in order to reach an
exclusion diagnosis. Often these conditions are co-morbid to mood
disorders [15], besides other psychiatric diseases, due to a mix of
psychological adaptation to frequent pain, genetic predisposition,
and neurotransmitter imbalance [1618].
The availability of endophenotypes for psychiatric conditions
in primary headache patients might be useful for further exploring boundaries between these conditions and testing drugs more
rationally. Therefore, the primary aim of this pilot work consisted in
assessing NSS in primary headache patients with respect to healthy
matched controls, assessing as secondary aims the relationship
between NSS scores and headache characteristics both clinical and
of brain imaging.
2. Methods
In this exploratory case-control study, 30 consecutive primary headache patients (HP) were recruited following informed
consent during the headache-free period from the outpatients
afferent to the Neurology Unit. Inclusion criteria were: (a) diagnosis of migraine (MH) with or without aura or frequent episodic
tension-type headache (ETTH) according to current criteria from
the International Headache Society [19]; (b) age >18 and <75 years
old; (c) history of at least 10 episodes and number of attacks 1
and <15/month; (d) no current prophylaxis or other psychoactive
medications; (e) no previous history of neurological or psychiatric
disorders other than headache; (f) a fully normal standard neurological examination.
For both MH patients (n = 20) and ETTH ones (n = 10) number of
attacks/month and number of over-the-counter medication/month
referring to the previous three months period were recorded;
patients were also asked to complete the headache disability inventory (HDI) [20]. Only one MH patient reported more than 15
symptomatic drugs/month (specically n = 30), raising the suspect
of a concomitant medication-overuse headache. Considering the
exploratory nature of this study and the impossibility of a formal a
priori power calculation, the recruited sample size was considered
sufcient for generating the reported preliminary data.
Furthermore, 5 primary headache patients (3 MH and 2
ETTH) taking amitriptyline 10 mg o.d. as prophylaxis (PROF) were
recruited post hoc in order to explore the potential contributory role
on the NSS score of the exposure to anticholinergic and sedative
medications.
Finally, healthy controls (CTRL) were age- (2 years) and sexmatched and education-comparable and they were recruited from
the spouses of other neurological outpatients. They had no previous

NP
NP

history of neurological or psychiatric disorder (including significant headache), nor were they under psychoactive medications.
Demographic and clinical data are included in Table 1.
Besides a complete neurological examination, all patients were
also evaluated for NSS. The examination was carried out in a
calm environment, without interruptions or additional observers.
Among the available tools [21], we choose the 16-items Heidelberg scale [22] since, unlike other batteries, it excludes primitive
reexes. These are, in fact, automatic responses marking, more
properly, cognitive and upper motor neuron dysfunctions [23].
As so, they are qualitatively different from the core NSS, mainly
addressing sensorimotor integration and coordination [22]. In the
Heidelberg scale, the examination procedure is so chosen that the
initial tests are carried out with the patient in a standing position.
The patients ability to perform a given exercise is scored on a 4point scale, from 0 (no difculties) up to 3 (marked difculties).
The Heidelberg scale explores ve different subdomains, as follows:
(1) motor coordination, including: Ozeretskis test, diadochokinesis, pronationsupination, nger-to-thumb opposition, speech and
articulation, (2) integrative functions, including: gait, tandem walking, two-point-discrimination, (3) complex motor tasks, including:
nger-to-nose test, st-edge-palm-test, (4) right/left and spatial
orientation, including: right/left orientation, graphesthesia, facehand test, stereognosis, (5) hard signs, including: arm holding test,
mirror movements. In the original report, this scale was found to
have a high internal reliability (Cronbachs alpha 0.83) and a high
inter-rater reliability (0.88) [22].
All patients also underwent a brain MR scan (1.5 T), including
axial FLAIR sequence (slice thickness 5 mm with a gap of 1 mm;
TR 6000 ms/TE 120 ms; eld of view: AP 230 mm/RL 183 mm/FH
155 mm), performed in order to provide whole brain coverage.
Images were assessed blindly and the Fazekas scale applied to
qualitatively score white matter hyperintensities (WMHs), dividing them in periventricular white matter, and deep white matter
(DWM) signal alterations [24].
Statistical analysis was performed by SPSS. NSS differences
among the recruited groups were assessed by ANCOVA followed
by Bonferroni post hoc test, controlling for age and education. Twotailed Students t-test, ANOVA followed by Bonferroni and Pearson
analysis of correlation were used as appropriate.
3. Results
The impact of age on the NSS score was initially determined in
the group of CTRL (n = 30). However, since the age of the recruited
subjects distributed unevenly in the older group, we recruited 8
more elderly controls. The whole group of CTRL subjects (n = 38)
displayed a very strong correlation with the NSS scores (r = 0.91
p < 0.0001). A similar albeit less strong correlation was present in
primary HP (r = 0.31 p = 0.01 n = 20 and r = 0.65 p < 0.005 n = 10, for

L. Tremolizzo et al. / Neuroscience Letters 595 (2015) 4144

43

Fig. 1. NSS scores. CTRL, healthy controls (n = 30); ETTH, frequent episodic tensiontype headache (n = 10); MH migraine (n = 20); PROF, prophylaxed primary headache
patients (n = 5). Average values are reported. ANCOVA p < 0.001 followed by Sidakcorrected post-hoc test (*p < 0.001 versus all the other groups).

MH and ETTH, respectively). Education years also correlated, negatively, with NSS scores both in CTRL (r = 0.69 p < 0.0001), and MH
(r = 0.52 p = 0.0003) patients, while did not reach signicance in
ETTH ones (r = 0.33 p = 0.082).
The NSS score was increased (70% and 90%, for ETTH and
MH, respectively) in primary HP with respect to CTRL, regardless
of the headache type; the same result was shown including PROF
patients (Fig. 1). Age and education were analyzed as covariates
without modifying this result. Estimated baseline characteristics
(frequency and symptomatic drug use) were not correlated to the
NSS score. On the other hand, HDI scores demonstrated a correlation with NSS (r = 0.54 p = 0.01) only in MH patients. The single
suspect medication-overuse headache did not show differences
with respect to the other MH recruited subjects. HDI correlated
with NSS in the whole HP group as well (r = 0.52 p < 0.003).
Analyzing each NSS separately, HP presented increased values
(p < 0.05) for items belonging to all subdomains: (1) motor coordination (Ozeretzkis test, diadochokinesis, speech and articulation;
3 out of 5 NSS belonging to this category), (2) integrative functions
(tandem walking; 1 out of 3), (3) complex motor tasks (st-edgepalm-test; 1 out of 2), (4) right/left and spatial orientation (right/left
orientation, stereognosis; 2 out of 4), and (5) hard signs (armholding test; 1 out of 2) (data not shown). Dichotomizing HP
according to the diagnostic category, each of these items resulted
signicant at ANOVA (p < 0.05) and MH patients were always different from CTRL at the post hoc test (p < 0.05). On the other hand,
ETTH patients presented a signicant increase versus CTRL only for
items: tandem walking, right/left orientation, st-edge-palm-test,
speech and articulation (data not shown).
WMHs were found in 8 out of 20 MH patients (40%) and 2 out of
10 ETTH patients (20%). At the Fazekas score none of the patients
displayed periventricular white matter signal alterations. Almost
all positive patients displayed a DWM score of 1, and only one
MH patients had a score of 2, while none had a score of 3. Diabetes and dyslipidemia were not represented among the recruited
patients. Three MH patients and one ETTH reported hypertension,
albeit this did not appear to be related to the presence of WMHs.
Dichotomizing patients according to the presence or absence of signal alterations, WMH+ subgroups showed signicantly increased
NSS scores when compared to WMH- for both MH (+40%, p = 0.003,
Fig. 2a) and ETTH (p = 0.05, Fig. 2b). Furthermore, after lumping
patients independently from headache type, a signicant overall
difference in NSS scores (p < 0.0001) emerged at ANOVA. At the subsequent analysis, even with Bonferroni correction, all three tests
were signicant; in particular, HP without WMHs (n = 20, 66%) displayed a signicantly increased NSS score (+58% p < 0.001) with
respect to CTRL (Fig. 2c).

Fig. 2. NSS scores in both (a) MH patients and (b) ETTH ones, dichotomized according to the presence (DWM > 0) or absence (DWM = 0) of WMHs at the Fazekas scale.
#p = 0.003 and p = 0.05 two-tailed Students t-test. (c) Headache patients (HP) with
WMHs (DWM > 0; n = 10) display increased NSS scores with respect to HP without
WMHs (DWM = 0; n = 20) and CTRL (n = 30). ANOVA p < 0.0001, followed by Bonferroni post hoc analysis (p < 0.001 for all the comparisons).

4. Discussion
We report here a clear increase of NSS expression in neurological
outpatients affected by frequent episodic MH or ETTH with respect
to matched controls. However, at least in our sample, NSS did
not differentiate MH from ETTH notwithstanding the impressive

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L. Tremolizzo et al. / Neuroscience Letters 595 (2015) 4144

differences, in terms of physiopathology, between them. Taken

together, these results seem to suggest the presence of a common
downstream phenotypic trait (or comorbidity) that leads to NSS
increase in both populations.
In addition, given the lack of correlation between NSS and
headache characteristics this hypothetic common factor appears
only minimally related, if at all, to headache severity. One potential
bias to this latter point consisted, however, in obtaining baseline data only from the history, without having a diary. Recruited
patients reported a quite signicant number of attacks/month
(average 9): this might be due to the fact that they have been
recruited as outpatients coming for a neurological consultation and
they might, therefore, display more aggressive diseases within the
denition of episodic frequent.
Moreover, we found increased NSS in headache patients with
WMHs at brain imaging. These data conrm that NSS expression is,
indeed, somehow related to minimal brain circuitry anomalies not
identied by the standard neurological examination and suggests
a minimal localization value for these semeiotic gestures. Indeed,
altered sensory integration and poor motor coordination have
already been previously reported in primary headache patients
[25,26], suggesting that the observed increase in NSS scores might
simply quantify and reect such anomalies.
However, WMHs do not fully explain the higher NSS scores in
HP; in fact, compared to controls, they were higher also in HP without WMHs. One additional intriguing possibility is that a further
common phenotypic trait might be looked for in the psychiatric
eld. Here we included only episodic frequent headaches, since the
relationship between chronic headaches and psychiatric conditions
might be much more complex to unravel [27]. However, mood and
anxiety dysfunctions were not addressed and deserve full consideration as possible links between MH and ETTH in future studies.
In partial contrast is the report that prophylaxis patients display
similar NSS values to untreated patients. These data should be probably replicated considering the reduced size and post hoc nature of
the prophylaxis group, but one issue might be that the amitriptyline dose was quite low for targeting depression. Nevertheless,
the search for this missing psychiatric link in headache might be
very complex to be accomplished, since NSS expression has been
reported unchanged in depressed patients with respect to controls
[28]. On the other hand, obsessivecompulsive disorder, another
relevant headache comorbidity [15], displays increased NSS motor
coordination scores with respect to healthy controls [29].
In conclusion, an overall pattern emerges, where NSS identify
a specic subset of primary headache patients presenting with
more pronounced minimal brain anomalies and, perhaps, psychiatric and/or psychological maladjustment traits. Further studies are
needed, since this subgroup might in principle benet from tailored
prophylactic options.
Conict of interest and sources of funding
None.
Acknowledgment
None.
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