Seminars in Arthritis and Rheumatism 43 (2013) 335–347

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Seminars in Arthritis and Rheumatism

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Neurologic involvement in scleroderma: A systematic review

Tiago Nardi Amarala,b, Fernando Augusto Peresb, Aline Tamires Lapab, João Francisco Marques-Netoa,
Simone Appenzellera,b,n
a
Rheumatology Division, Faculty of Medical Science, State University of Campinas, Campinas, Brazil
b
Rheumatology Lab, Faculty of Medical Science, State University of Campinas, Campinas, Brazil

A B STR AC T

Objectives: To perform a systematic review of neurologic involvement in Systemic sclerosis (SSc) and
Localized Scleroderma (LS), describing clinical features, neuroimaging, and treatment.
Methods: We performed a literature search in PubMed using the following MeSH terms, scleroderma,
systemic sclerosis, localized scleroderma, localized scleroderma “en coup de sabre”, Parry–Romberg
syndrome, cognitive impairment, memory, seizures, epilepsy, headache, depression, anxiety, mood
disorders, Center for Epidemiologic Studies Depression (CES-D), SF-36, Beck Depression Inventory (BDI),
Beck Anxiety Inventory (BAI), Patient Health Questionnaire-9 (PHQ-9), neuropsychiatric, psychosis,
neurologic involvement, neuropathy, peripheral nerves, cranial nerves, carpal tunnel syndrome, ulnar
entrapment, tarsal tunnel syndrome, mononeuropathy, polyneuropathy, radiculopathy, myelopathy,
autonomic nervous system, nervous system, electroencephalography (EEG), electromyography (EMG),
magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA). Patients with other
connective tissue disease knowingly responsible for nervous system involvement were excluded from
the analyses.
Results: A total of 182 case reports/studies addressing SSc and 50 referring to LS were identified. SSc
patients totalized 9506, while data on 224 LS patients were available. In LS, seizures (41.58%) and
headache (18.81%) predominated. Nonetheless, descriptions of varied cranial nerve involvement and
hemiparesis were made. Central nervous system involvement in SSc was characterized by headache
(23.73%), seizures (13.56%) and cognitive impairment (8.47%). Depression and anxiety were frequently
observed (73.15% and 23.95%, respectively). Myopathy (51.8%), trigeminal neuropathy (16.52%), periph-
eral sensorimotor polyneuropathy (14.25%), and carpal tunnel syndrome (6.56%) were the most frequent
peripheral nervous system involvement in SSc. Autonomic neuropathy involving cardiovascular and
gastrointestinal systems was regularly described. Treatment of nervous system involvement, on the other
hand, varied in a case-to-case basis. However, corticosteroids and cyclophosphamide were usually
prescribed in severe cases.
Conclusions: Previously considered a rare event, nervous system involvement in scleroderma has been
increasingly recognized. Seizures and headache are the most reported features in LS en coup de sabre,
while peripheral and autonomic nervous systems involvement predominate in SSc. Moreover, recently,
reports have frequently documented white matter lesions in asymptomatic SSc patients, suggesting
smaller branches and perforating arteries involvement.
& 2013 Elsevier Inc. All rights reserved.

Introduction The importance and frequency of neurologic involvement in

Scleroderma is a rare, autoimmune disorder, characterized by
inflammation, vascular injury, and fibrosis. The term includes a
variety of diseases, from localized scleroderma (LS) to systemic
sclerosis (SSc). The pattern of cutaneous involvement defines
diseases' subtypes [1,2]. In SSc, internal organ fibrosis is present,
while in LS it is a rare complication [3,4].
n
Corresponding author at: Rheumatology Division, Faculty of Medical Science,
State University of Campinas, Campinas, Brazil.
E-mail address: appenzellersimone@yahoo.com (S. Appenzeller).
scleroderma has been debated. Initial studies had reported central
nervous system (CNS) involvement in SSc as unusual and related
to SSc complications. Renal crises, cardiovascular and pulmonary
involvement, and also therapy had been pointed out as relevant
predictors of neurological damage [5,6]. On the other hand, recent
studies based on magnetic resonance imaging (MRI) have often
described asymptomatic CNS alterations, regardless of severity,
complications, or duration of disease [7,8].
Despite uncertainties concerning CNS and peripheral nervous
system (PNS) involvement in SSc, autonomic nervous system
(ANS) alterations and neurological involvement in scleroderma

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Table 1
LS studies/case reports presenting nervous system involvement

Classification Studies (total) Case reports Patients Male (%)/Female (%)

LScs/PRS 41 [9,168,190–224,226,229–232] 37 92 26 (44.83)/32 (55.17) a

Other LS subtypes 10 [168,187,189,225,227–235] 6 132 10 (34.48)/19 (65.52)b

Total 50c 43 224 36 (41.38)/51 (58.62)

a
34 Subjects without gender specifications.
b
103 Subjects without gender specifications.
c
Studies containing combined data of LScs and other LS subtypes were counted only once.

en coup de sabre have been well recognized and better charac-
terized throughout the last decades [5,9].
Objectives
The aim of this article is to perform a systematic review of
neurologic involvement in LScs and SSc, describing clinical fea-
tures, neuroimaging findings, and treatment.
Methods
We performed a literature search in PubMed using the follow-
ing MeSH entry terms: scleroderma, systemic sclerosis, localized
scleroderma “en coup de sabre”, Parry–Romberg syndrome, cog-
nitive impairment, memory, seizures, epilepsy, headache, depres-
sion, anxiety, mood disorders, Center for Epidemiologic Studies
Depression (CES-D), SF-36, Beck Depression Inventory (BDI), Beck
Anxiety Inventory (BAI), Patient Health Questionnaire-9 (PHQ-9),
neuropsychiatric, psychosis, neurologic involvement, neuropathy,
peripheral nerves, cranial nerves, carpal tunnel syndrome, ulnar
entrapment, tarsal tunnel syndrome, mononeuropathy, polyneur-
opathy, radiculopathy, myelopathy, autonomic nervous system,
nervous system, electroencephalography (EEG), electromyography
(EMG), magnetic resonance imaging (MRI), and magnetic reso-
nance angiography (MRA).
Bibliographies of articles were reviewed for additional litera-
ture not identified through the PubMed search, and patients with
other connective tissue disease knowingly responsible for nervous
system involvement were excluded from the analyses. We limited
our search to articles published in the English literature from 1954
to June 2012.
summing up 9506 SSc and 224 LS patients. Neurologic involve-
ment in SSc was further differentiated into central nervous system
(CNS), peripheral nervous system (PNS), and autonomic nervous
system (ANS) involvements (Tables 1 and 2).
Among LS patients, only 87 (38.84%) had gender discrimination,
51 (58.62%) female and 36 (41.38%) male (Table 1). In SSc group,
most patients were female, totalizing 6557 (84.05%), and 1244
(15.95%) patients were male. Nonetheless, information was found
lacking in 1705 (17.94%) subjects (Table 2).
Asymptomatic patients totalized 39 in LS and 11 in LScs
subgroup, and in the SSc group there were 236 in PNS and 276
in CNS; however, many studies did not report the exact number of
asymptomatic subjects, and more than one neurologic involve-
ment often took place in the same patient, making analysis
difficult.
Neurologic involvement in LS
General neurological involvement in LS
A total of 50 studies/case reports addressed neurologic involve-
ment in LS. Even though the majority of the reports referred to
LScs and PRS, central and peripheral nervous system pathologies
were also described in morphea and non-LScs linear scleroderma
subtypes [168,187,189,225,227–235] (Table 1). Among those
patients, myopathy was the most prevalent alteration (90.69%)
[168,187,225,227,228,231,233–235], but one case of multifocal
leukoencephalopathy has also been described [227]. Sixty-two
patients with LS did not have the disease-specific subtype speci-
fied, [168,187,189,229,230] and their neurologic presentation was
mainly characterized by electroencephalographic changes (56.25%)
[189]. However, a case of “dropped head” [187] and one other of
cerebral ischemic stroke [229] were also reported (Table 3).

Neurologic involvement in LScs

Results Epilepsy was the most frequent reported neurologic alteration,
present in 37 LScs patients with a total of 42 events (41.58%)
We identified a total of 232 case reports/studies, 182 addressing [9,190–214]. Complex partial seizures were described in 14
SSc [7,8,10–189] and 50 referring to LS [9,168,187,189–235], patients (37.84%) [196,198,203,206–210], followed by generalized

Table 2
SSc studies/case reports presenting nervous system involvement

Classification Studies (total) Case reports Patients Male (%)/Female (%)

SScd
CNS 90 [7,8,10–77,164–167,170–177,179–184,188,189] 47 6028 925 (15.49)/5046 (84.51)a
PNS 61 [14,34,35,47,53,56,78–120,159–164,168,169,178,185–187] 34 1628 207 (19.64)/847 (80.36)b
ANS 37 [121–158] 5 801 112 (14.43)/664 (85.57)c

Total 186e 86 8457f 1244 (15.95)/6557 (84.05)

a
57 Subjects without gender specifications.
b
574 Subjects without gender specifications.
c
25 Subjects with unknown gender.
d
1049 Subjects without gender specifications in unspecified nervous system involvement studies.
e
Studies containing CNS and PNS involvement were counted only once.
f
One subject presented both CNS and PNS involvement and was counted once.

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Table 3 Table 4
Non-LScs localized scleroderma: neurologic involvement and complementary exams Neurologic involvement in LScs and LScs/PRS

Clinical presentation and Patients and References Neurologic involvement Events (%) References
exams (%) findings (%)
Epilepsy
Signs and symptoms Total 42 (41.58)
Muscular weakness/pain 20 (80%) [168,225,233,234] Undetermined 8 [190–194,201]
Hemiparesis 1 (4%) [229] GTCS 13 [9,195–200,202–206]
“Dropped head” 1 (4%) [187] CPS 14 [196,198,203,206–210]
Ataxia 1 (4%) [227] SPS 4 [211,212,214]
Dysarthria 1 (4%) [227] EPC 1 [213]
Facial weakness 1 (4%) [227] Absence 1 [203]
Status epilepticus 1 [203]
MRI
Multifocal leukoencephalitis 1 (11.11%) [227] Headache
Cerebral stroke 1 (11.11%) [229] Total 19 (18.81) [190,193,195,198,201,205,214–219]
Myositis 6 (66.67%) [233] Migraine 3 [9,218,219]
Muscle atrophy 1 (11.11%) [235]
Vision involvement
Angiography Hemianopsia 1 (0.99) [208]
Irregular intracranial vessels 2 [227,229] Diplopia 2 (1.98) [220,226]
Posterior uveitis 1 (0.99) [195]
CSF normal 2 [227,229]
Ptosis 2 (1.98) [9,220]
EMG/ENG Papillitis 1 (0.99) [202]
Decreased muscular potential 23 (37.70%) [187,228,234,235]
Cranial nerve involvement
amplitude
III nerve palsy 2 (1.98) [194,197]
Decreased muscular potential 35 (57.38%) [168,187,228,234,235]
Trigeminal neuropathy 2 (1.98) [194,221]
duration
VI nerve palsy 1 (0.99) [194]
Neuropathic changes 1 (1.64%) [225]
VII nerve palsy 3 (2.97) [190,194,198]
Normal 2 (3.28%) [229,232]
Expressive aphasia 1 (0.99) [215]
EEG
Dysarthria 1 (0.99) [204]
Slight non-specific changes 18 (60%) [189]
Normal 12 (40%) [189] Hemiparesis/pyramidal signs 10 (9.9) [192,196,200,204,215,222,231,232]
Peripheral nerve palsy 1 (0.99) [197]
MRI ¼ magnetic resonance imaging; CSF ¼ cerebral spinal fluid; EMG/ENG ¼ Dysesthesia 1 (0.99) [215]
electroneuromyography; EEG ¼ electroencephalography. Paresthesia 2 (1.98) [196,231]

Cognitive impairment 3 (2.97) [192,210,214]

tonic-clonic seizures (GTCS) in 13 (35.14%) [9,195–200,202–206].
Further epileptic events were characterized as simple partial
seizures in 4 patients [211,212,214] and epilepsia partialis continua
[213] and absence seizure [203] in 1 patient each (Table 4).
Although not uncommon, headache features were poorly
pictured most of the time. A total of 19 patients were identified
with headache (18.81%) [9,190,193,195,198,201,205,214–219], and
only three cases were distinguished as migraine [9,218,219].
Descriptions of ophthalmologic symptoms and signs were infre-
quent; however, 2 cases of diplopia [220,226] and 1 case each of
papillitis [202], hemianopsia [208], and posterior uveitis [195] has
been reported.
Cranial nerve involvement, on the other hand, occurred more
frequently with a total of 8 events (9.63%) [190,194,197,198,221].
Seventh [190,194,198], 3rd [194,197], and 6th [194] nerve palsies
have been described as well as trigeminal neuropathy [194,221].
Among others neurologic involvement, pyramidal signs (including
hemiparesis) [192,196,200,204,215,222,231,232], cognitive impair-
ment [192,210,214], and behavior disorder [210] were present in 7
(8.43%), 3 (3.61%), and 1 (1.20%), respectively. Furthermore, one
report of dysarthria [204] and two reports of paresthesia [196,231]
as well as one case each of peripheral nerve palsy [197] and
dysesthesia [215] have been produced (Table 4).
Computed tomography (CT) and magnetic resonance imaging
(MRI) were the most frequently used neuroimaging methods, with
normal tests results being reported in 16.28% and 15.30%, respec-
tively. Cerebral calcification (25.58%) [191,195,198,199,212,214,215,
222,230], extracranial atrophy (18.60%) [191,207,220,222], and
cortical depression (13.95%) [207] were described among CT
evaluations. Of the 37 articles that mentioned MRI results, white
matter lesions (25.51%) [9,192,196,198,200,204,206–208,210,211,
215–217,219,222,224,230,232], almost exclusively hyperintensity
lesions, and abnormal gyral pattern (13.27%) [192,194,196,207,211]
were the most prevalent identified alterations, followed by
Behavioral disorders 1 (0.99) [210]
Diziness 5 (4.95) [190,216]
CPS ¼ complex partial seizures; EPC ¼ epilepsia partialis continua; GTCS ¼
generalized tonic-clonic seizures; LScs ¼ localized scleroderma en coup de sabre;
PRS ¼ Parry–Romberg syndrome; SPS ¼ simple partial seizures.
blurring of gray–white matter (10.20%) [207,211], cerebral atrophy
(including hippocampal atrophy) (10.20%) [192,194,204,205,207–
210,213,214], and cortical hyperintense lesions (6.12%) [200,203,
204,206,207,216] (Table 5).
Apart from electroencephalography (EEG), most frequently
abnormal (67.74%) [190,192,194,198–201,205,208–210,212–215,
218,219,232], other complementary exams were seldom utilized.
Hypometabolic areas [190,192,198,208,210,214], oligoclonal IgG
[9,194,200,204,222], and vasculitis [217] have been identified
through cerebral SPECT, cerebral spinal fluid analyses, and angiog-
raphy. Cerebral biopsy reports were depicted in 9 articles
[192,193,198,202,204,207,209,213,217], and gliosis and perivascu-
lar infiltrates were the most commonly reported abnormalities
(Table 6).
Neurologic involvement in SSc
Central nervous system involvement in SSc
A total of 90 studies/case reports addressed CNS involvement in
SSc, totalizing 6028 patients with 925 males (15.49%) and 5046
females (84.51%) [7,8,10–77,164–167,170–177,179–184,188,189]
(Table 2).
Psychiatric manifestations were assessed in 2712 patients [10–
33,180–184], including 6 case reports (11 subjects) [10–13,15,181,
184]. A total of 1090 cases of depression [10–12,14–33,180–184]
and 357 of anxiety [14–16,18–24] were documented. Estimated
prevalence varied from 6% to 77.4% for depression, with the
majority being around 30–40%, and 25–64% for anxiety.

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Table 5 Table 6
Complementary investigation in LScs and LScs/PRS: CT and MRI Other complementary exams in LScs and LScs/PRS

Complementary exam No of Reference Exam (number of Frequency of

(number of studies) alterations studies) findings (%) Reference
(%)
Angio / Angio MRI (8)
CT (23) Normal 5 (27.78) [9,192,195,209,219,223]
Normal 7 (16.28) [206–208,210,231,232] Vasculitis 4 (22.22) [217]
Skin/skull atrophy 8 (18.60) [191,207,220,222] Irregular intracranial 7 (38.89) [190,205,210,224]
Cortical depression 6 (13.95) [207] vessels
Brain calcification 11 (25.58) [191,195,198,199,212,214,215,222,230] Carotid abnormality 2 (11.11) [205,210]
WM hypodensity 2 (4.65) [206,224]
SPECT (5)
Encephalomalacia 2 (4.65) [198]
Hypometabolic areas 10 [190,192,198,208,210,214]
Porencephaly 2 (4.65) [205,212]
Flattened sulci 1 (2.33) [211] EEG (22)
Cerebral atrophy 1 (2.33) [205] Normal 10 (32.26) [9,190,191,196,198,211,231,232]
Hemorrhage 1 (2.33) [196] [190,192,194,198–201,205,208–
Tumor 1 (2.33) [223] Abnormal 21 (67.74)
210,212–215,218,219,232]
Cerebral infarction 1 (2.33) [232]
CSF (5)
MRI (37) Normal 1 (16.67) [214,217]
Normal 15 (15.30) [190,191,197,199,206,218,221,226] Oligoclonal IgG 5 (83.33) [9,194,200,204,222]
[9,192,196,198,200,204,206–
Biopsy (9)
WM lesions 25 (25.51) 208,210,211,215–
Gliosis 6 (19.35) [192,193,202,207,209,213]
217,219,222,224,230,232]
Perivascular infiltrate 7 (22.58) [193,198,202,204,207,213,217]
Blurring G/W matter 10 (10.20) [207,211]
Thickened 1 (3.23) [209]
Abnormal gyral 13 (13.27) [192,194,196,207,211]
leptomeninges
pattern
Calcifications 1 (3.23) [198]
Cortical hyperintense 6 (6.12) [200,203,204,206,207,216]
Cortical infiltrate 1 (3.23) [213]
lesions
Vessel thickening 3 (9.68) [198,209,217]
Cerebral atrophy 10 (10.20) [192,194,204,205,207–210,213,214]
Vessel ectasia 1 (3.23) [217]
Calcification 4 (4.08) [196,207,209,230]
Vessel wall 2 (6.45) [202,204]
Thalamic 1 (1.02) [204]
inflammation
hyperintense lesions
Fibrinoid vessel 1 (3.23) [202]
Cerebellar 1 (1.02) [204]
occlusion
hyperintense lesions
Thrombi 2 (6.45) [198,217]
Cerebellar infarction 1 (1.02) [193]
Vasculitis 1 (3.23) [204]
Cerebral infarction 2 (2.04) [192,232]
Focal parenchymal 2 (6.45) [204,213]
Cavernoma 2 (2.04) [196]
necrosis
Cystic-gliotic lesion 1 (1.02) [202]
Parenchymal atrophy 1 (3.23) [213]
Blood–brain barrier 1 (1.02) [202]
Neuronophagia 1 (3.23) [213]
dysfunction
Improper vascular 1 (3.23) [192]
Tumor 1 (1.02) [223]
network
Asymmetry of
hippocampal 1 (1.02) [194] EMG/ENG (5)
structures Normal 3 (60) [211,221,232]
Ventricular dilatation 1 (1.02) [211] Abnormal levator 1 (20) [220]
Porencephaly 1 (1.02) [205] palpebrae muscle
Encephalomalacia 1 (1.02) [215] Myopathy 1 (20) [231]
Leptomeningeal 1 (1.02) [215]
enhancement Angio ¼ angiography; CSF ¼ corticospinal fluid; EEG ¼ electroencephalography.

CT ¼ computerized tomography; G/W ¼ gray–white; MRI ¼ magnetic resonance

imaging; N ¼ number; WM ¼ white matter.
Considering a total of 1490 psychiatric events, 73.15% referred to
depressive disorders and 23.95% to anxiety. For others, psychiatric
evaluations disclosed dysthymia in 33 patients [19,21], suicidal
ideation in 6 patients [23], psychoticism in 2 patients [16,18], and
paranoid ideation in 2 patients [18,30]. Analysis of two sclero-
derma databases, encompassing 2780 subjects, has implied a
relative risk of 1.5 for both depression and anxiety [16] (Table 7).
A total of 177 events of neurologic involvement were described,
besides psychiatric syndromes. Headache was the most frequently
reported neurologic symptoms summing up 23.73% (15 migraine
and 6 tension-type cephalalgia) [7,8,14,17,34–42,170–173,175,177].
Cognitive impairment was documented in 15 subjects (8.47%)
[10,12,15,16,37,38,43–49,181] and 2 cases of transient global
amnesia have been reported [36,50]. Seizures were not as frequent
as in LScs, with a total of 24 descriptions (13.56%) [7,8,11,12,
35,37,38,40,41,51–55,172,174], 12 GTCS and 1 focal seizure.
Spinal and cerebral involvement, although uncommon, usually
draw in severe consequences. Eleven patients with organic brain
syndrome (6.21%) [13,16,35,44,70], 11 patients with cerebrovascular
disease (6.21%) [12,17,37–39,48,56,57], 10 manifesting radiculopathy
(5.65%) , seven with transverse myelitis (3.95%) [56,58–60], and
7 with spinal cord compression (3.95%) [64–67,164,188] have been
reported. Other involvements were fairly rare and comprised
cerebellar ataxia [68,173], cerebellar degeneration [69], reversible
posterior leukoencephalopathy syndrome [172,174,177], and hemi-
paresis [11,36,71,171] among others (Table 7).
Neuroimaging studies focused on MRI and CT evaluations. Sixty
studies/case reports reported MRI results [7,8,11,13–15,17,39,
41–43,47,48,50,59,60,63,69,71–77,164–167,171–177,179,188]; 152
events of white matter hyperintensities (WMH) were reported [7,8,
13–15,17,41,43,47,48,59,73–75,166,171], including brain stem [7,8]
and cerebellar [43,48] involvements. Some studies focused on MRI
documented WMH and reported a prevalence up to 70% [7,8]. Signs
of vasculopathy occurred in 14.34%, [17,170] and 8 patients had
cerebral atrophy [14]. CT evaluations were reported in 31 studies/
case reports [10,12,17,36,73,165,172,177,179,188].Vasculopathy (22
cases) [17], cerebral calcifications (22 cases) [10,12,17,36,73], cerebral
atrophy (7 cases) [10,12,38,44] and paraspinal and intraspinal
calcifications (13 cases) [62,63,67,76,77,179,188] were the more
frequent changes. Calcifications were described in both white and
gray matter, including 1 case of gyral [73] and 4 cases of deep gray
matter calcifications [10,12,36] (Table 8).

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Table 7
Neurologic involvement in SSc: PNS and CNS

Neurologic involvement Events (%) Reference

PNS
Total events 442
Peripheral sensorimotor polyneuropathy 63 (14.25) [35,47,53,56,79,84,86,88,93–103,159,185,186,231]
Sensory neuropathy 1 (0.22) [96]
Carpal tunnel syndrome 29 (6.56) [14,56,79,86,88,100,103,104,106,107,109,110]
Ulnar nerve 15 (3.39) [56,84,100,105–108,110,111,164]
Multiple mononeuropathy 8 (1.81) [86,96,114]
Other mononeuropathy 6 (1.36) [14,56,113,115,116]
Brachial plexopathy 3 (0.68) [84,117,118]
Lumbar plexopathy 2 (0.44) [84,119]
CPAN 1 (0.22) [120]
Trigeminal neuropathy 73 (16.52) [14,34,56,78–92,162]
Facial nerve 7 (1.58) [91]
6th 1 (0.22) [106]
8th 2 (0.44) [91]
9th 1 (0.22) [91]
12th 1 (0.22) [91]
Myopathy 224 (50.67) [34,35,53,56,78,80,84,94,96,159–161,163,168,169,185,186]
Paraspinal and scapular myopathy 5 (1.13) [178,187]
CNS
Total events 177
Headache 42 (23.73) [7,8,14,17,34–42,170–173,175,177]
Cognitive impairment 15 (8.47) [10,12,15,16,37,38,43–49,181]
Seizures 24 (13.56) [7,8,11,12,35,37,38,40,41,51–55,172,174]
Stroke/TIA 11 (6.21) [12,17,37–39,48,56,57]
Organic brain syndrome 11 (6.21) [13,16,35,44,70]
Transverse myelitis 7 (3.95) [56,58–60]
Radiculopathy 10 (5.65) [61–63,167,179,188]
Hemiparesis 4 (2.26) [11,36,71,171]
Spinal cord compression 7 (3.95) [64–67,164,188]
Visual disturbance 5 (2.82) [35,72,73,172,177]
Subarachnoid hemorrhage 3 (1.69) [173]
RPLS 3 (1.69) [172,174,177]
Optic atrophy 1 (0.57) [11]
Aphasia 4 (2.26) [11,40,71,73]
Cerebellar ataxia 2 (1.13) [68,173]
Cerebellar degeneration 1 (0.57) [69]
Auditory neuropathy 2 (1.13) [68]
Transient global amnesia 2 (1.13) [36,50]
Spontaneuos intracranial hypotension 1 (0.57) [175]
Unspecified pyramidal signs 5 (2.82) [35,68,176]
Unspecified neurologic signs and symptoms 17 (9.60) [7,8,10,12,35,38,40,72,73,165,170,172,176,177]
Psychiatric
Total events 1490
Anxiety 357 (23.95) [14,16,18–24]
Depression 1090 (73.15) [10–12,14–33,180–184]
Dysthymia 33 (2.21) [19,21]
Suicidal ideation 6 (0.40) [23]
Psychoticism 2 (0.13) [16,18]
Paranoid ideation 2 (0.13) [18,30]

ANS ¼ autonomic nervous system; CNS ¼ central nervous system; CPAN ¼ chronic progressive ataxic neuropathy; PNS ¼ peripheral nervous system; RPLS ¼ reversible
posterior leukoencephalopathy syndrome;SMP ¼ sensorimotor neuripathy; TIA ¼ transient ischemic attack.

As seen in LScs, cerebral SPECT evaluations disclosed focal or
diffuse hypoperfusion [43,47,48], sometimes involving basal ganglia
[43]. Angiography, on the other hand, rarely reported signs of
vasculitis (2 cases) [40,52], vascular stenosis (5 cases) [11,39], or
atherosclerosis (1 case) [40]. In 7 case reports, CSF analysis was
documented. Similarly to LScs, it pointed out oligoclonal bands of IgG
(1 cases) [68], but also showed elevated protein levels in 3 cases
[12,40,68] and gamma globulin paraproteinemia in 1 case [39]. CSF
was normal in 2 patients [70,171]. Finally, 9 case reports
[13,15,36,50,52,54,58,165,171] and 3 studies [14,38,189] analyzed
EEG in SSc patients. Among 75 EEG evaluations, 32 (42.67%) presented
slight general unspecific changes [13,15,36,38,50,52,54,70,165,189].
Peripheral nervous system involvement in SSc
A total of 61 studies/case reports addressed PNS involvement in
SSc, totalizing 1628 patients and 442 PNS events [14,34,35,
47,53,56,78–120,159–164,168,169,178,185–187] (Table 2). Of the
1054 (64.74%) subjects who had gender classification, 207 (19.64%)
were males and 847 (80.36%) females. A total of 279 (17.14%)
subjects were asymptomatic, although 5 studies (1049 subjects)
did not report on this issue.
Seventy-three trigeminal neuropathies (TN) (16.52% of total
events) were documented [14,34,56,78–92,162], and in association
with peripheral sensorimotor (14.25%) [35,47,53,56,79,84,86,88,
93–103] and entrapment neuropathies (9.25%) [14,56,79,84,
86,88,100,103–111,164], were the most often reported PNS involve-
ment. Sensory involvement predominated in trigeminal neuropathy,
but neuralgia was unusual. Twenty-nine cases of symptomatic carpal
tunnel syndrome (CTS) were recognized, as well as 15 cases of ulnar
nerve disorder. Nonetheless, an ultrasonography study for CTS in SSc
patients disclosed up to 67% of asymptomatic carpal tunnel abnor-
malities suggestive of CTS [112] (Table 7).

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Table 8
Complementary investigation in SSc: CT, MRI, and SPECT

Imaging study (number of studies) Events (%) Reference

CT (31)
Total events 102
Normal 16 (15.69) [38,44,51,52,54,58,72]
Vasculopathy 22 (21.57) [17]
Calcification 22 (21.57) [10,12,17,36,73]
Cerebral atrophy 7 (6.86) [10,12,38,44]
Cerebellar atrophy 2 (1.96) [10,69]
Cerebral aneurysm 2 (1.96) [42,246]
Cerebral vein thrombosis 1 (0.98) [53]
Subarachnoid hemorrhage 2 (1.96) [40,165]
Parenchymal hemorrhage 2 (1.96) [71,165]
Vertebral involvement 11 (10.78) [61,62,66,167,179,188]
Paraspinal and intraspinal calcification 13 (12.75) [62,63,67,76,77,179,188]
White matter low-attenuation areas 2 (1.96) [172,177]

MRI (60)a
Total events 272
Normal 38 (13,97) [14,43,47,48,50,72]
Cerebral WMH 152 (55.88) [7,8,13–15,17,41,43,47,48,59,73–75,166,171]
Cerebellar WMH 2 (0.74) [43,48]
Vasculopathy 39 (14.34) [17,170]
Cerebral atrophy 8 (2.94) [14]
Cerebellar atrophy 1 (0.37) [69]
Cerebral infarction 3 (1.10) [11,13,39]
Cerebral aneurysm 7 (2.57) [42,173,176]
Parenchymal hemorrhage 2 (0.74) [71,165]
Calcific masses in spinal canal 8 (2.94) [63,76,77,164,179,188]
Increased sign in medulla 2 (0.74) [59,60]
Vasogenic edema 3 (1.10) [172,174,177]
Subdural hygroma 1 (0.37) [175]
Thickened meninges 1 (0.37) [175]
Vertebral involvement 1 (0.37) [167]
Subarachnoid hemorrhage 4 (1.47) [166,173]

SPECT (4)
Total events 114
Normal 53 (46.49) [43,44,47,48]
Diffuse hypoperfusion 10 (8.77) [43,47,48]
Focal or multifocal hypoperfusion 48 (42.11) [43,47,48]
Basal ganglia and thalamus hypoperfusion 3 (2.63) [43]

CT ¼ computed tomography; MRI ¼ magnetic resonance imaging; WMH ¼ white matter hyperintensity.
a
Two studies [7,8] focusing on MRI results are not considered because they do not mention number of patients affected.

Other mononeuropathies have also been documented, totaliz-
ing 14 cases (3.17%) [14,56,86,96,113–116], as well as brachial
(0.68%) [84,117,118] and lumbar (0.44%) [84,119] plexopathies.
Apart from TN, other cranial neuropathies were unusually
reported. Sixth, 7th, 8th, 9th, and 12th cranial nerves involvement
have been observed in 1, 7, 2, 1, and 1 events, respectively [91,106].
On the other hand, myopathy was frequently present, involving
229 subjects (51.8%) [34,35,53,56,78,80,84,94,96,159–161,163,168,
169,178,185–187]. Muscular involvement was more often proxi-
mal, and 5 cases (1.13%) of paraspinal and scapular myopathy were
documented [178,187].
Eletroneuromyography was analyzed in 37 studies/case reports,
and mirrored the clinical data [34,35,53,78–80,84,86,88,89,92,94–
97,99–101,103,104,107–110,113,117–120,159–
161,168,169,178,185–187,236]. Myopathy was the prevailing find-
ing (56.55%), followed by sensory abnormalities (14.83%) and
motor abnormalities (13.45%). Electroneuromyographic alterations
associated with CTS and ulnar nerve impingement were present in
10 and 7 subjects, respectively [79,103,104,107,109,110]. Blink
reflex analysis, on the other hand, was more frequently normal
[89,90,237], except in 11 subjects with trigeminal neuropathy
(26.19%) [79,89,90,92,237]. Among those with overt trigeminal
symptoms, R1 and R2 abnormalities were more often described,
whereas studies involving asymptomatic patients reported an
exclusive R2 abnormality [237].
Evoked potentials were performed in only four subjects
[83,97,116,119] and demonstrated reduced sensory and motor
response amplitudes in two cases [97,119], and auditory brain
stem abnormality in another [116]. CT and MRI were rarely
performed and almost exclusively normal [34,83,85,87,89,110,
117–119]. However, mandible reabsorption [82], white matter
(WM) hyperintense lesions [83], and 5th nerve [85] enlargement
were described among trigeminal neuropathy patients, and
medullar involvement was described in a subject with CPAN [120].
Autonomic nervous system involvement in SSc
A total of 37 studies/case reports describing ANS involvement
were found [121–158] (Table 2). A total of 10 (1.24%) subjects were
mentioned in 5 case reports, and the remaining 791 patients were
evaluated in series of patients and therapeutic interventions
studies. Methods used to investigate ANS dysfunction consisted
of non-invasive cardiovascular reflex tests [121,122,124,125,127,
128,130,131,133,136–139,142–144,146,148–154,156], gastrointesti-
nal evaluation (including esophageal and rectal motility)
[129,134,135,139,140,146,147,149,157], skin [145,155] and pupil-
lary responses [126,139,151], and bladder activity [141]. Cardio-
vascular analyses were most frequently used (74.28%), focusing on
heart rate and blood pressure variability under sympathetic or
parasympathetic stimulations or during 24 h documentation.

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All studies/case reports described any degree of ANS involve- Table 9

ment. Autonomic dysfunction, consisting of parasympathetic under Treatment of neurologic involvement in LScs
activity and sympathetic overdrive were usually observed, and could
Neurologic involvement Treatment N I S D U
precede organ fibrosis. Increased heart rate, diminished heart rate,
and blood pressure variability were the most reported alteration (26 GTCS MP þ AZA 1 1
studies). Decreased pupil basal diameter and abnormal puppillary CE þ MTX 2 1
latency and maximal area were reported (3 studies) [126,139,151] as CE þ MMF 1 1
DXS þ PHE 1 1
well as abnormal sympathetic skin response (2 studies) [145,155]. MTX þ CBZ 1 1
Eight studies analyzed gastrointestinal involvement and correlated CE þ CTX 1 1
ANS involvement with gastrointestinal symptoms [146], anorectal
Second generalized seizures CE þ AZA þ IFNϒ 1 1
motility disorders [140,147], gastric compliance [129,137], and MP þ CTX þ AZA
esophageal dysfunctions [129,134,135,139,149].
Partial seizures Anticonvulsants 9 7 1 1
Prevalence of ANS involvement varied from 14.28% to 79%. MP þ MTX 1
Parasympathetic dysfunction occurred in 56–79%, sympathetic Surgery 1 1
involvement in 39.13–55%, and both dysfunctions were reported
Epilepsia partialis continua Hemyspherectomy 2 2
in 14.28%–75%. Altered sympathetic skin response was described
Intractable epilepsy IVIG þ MP 1 1
in 68.8% and 76.9% [145,155] and puppillary abnormalities in 10.5
IVIG þ CTX 1 1
and 13.7% [151]. One study utilized sweat-spot test and described
79 and 55 % of parasympathetic and sympathetic dysfunction, Status epilepticus Rituximab 1 1
CE þ MTX þ CLB þ OCBZ 1 1
respectively [129].
Hemiparesis IVIG þ MP 1 1
MP þ CE 1 1

Treatment Cranial nerves palsies IVIG þ CTX 1 1

Up to this moment, there are no randomized controlled trials MP þ MTX 1 1

evaluating treatment of any neurologic involvement in sclero-
derma. Epilepsy was the most common neurologic symptom in
LScs, and antiepileptic drugs were frequently used to control
seizures [9,196,198,201–204,208,210,212,214]. Carbamazepine,
oxcarbazepine, phenobarbital, sodium valproate, topiramate, clo-
bazam, pregabalin, nitrazepam, vigabatrin, sulthiame, and lamo-
trigine have all been used to manage seizures. In mild cases,
anticonvulsant therapy was prescribed alone and was efficient in
controlling seizures (77.77%).
On the other hand, GTCS and refractory epilepsy demanded
immunosuppressant therapy. Corticosteroid (CE) was the most
frequent (80%) drug administered to treat GTCS and recurrent or
intractable seizures [192,195,196,198,199,202–204] with observed
improvement in 90% of the time. However, in only one case report,
CE was the only immunosuppressive therapy applied. Methotrex-
ate (MTX) [196,198,199,203] and azathioprine (AZA) [9,195,
202,204] were the most frequently CE-associated therapy, three
cases each, followed by cyclophosphamide (CTX) (2 cases) [204],
mycophenolate mofetil (1 case) [196], interferon gamma (1 case)
[202], and intravenous immunoglobulin (IVIG) (1 case) [192].
Symptoms improvement was observed with all medications
except intravenous immunoglobulin [192,194] (Table 9). Occasion-
ally, seizures control demanded surgery; functional hemispherec-
tomy was applied in one case of EPC [213] and localized cortical
resections were performed in 2 cases of refractory seizures
[192,209], with symptoms improvement or recovery.
Case reports describing additional neurological involvement
rarely mention treatment. Progressive multifocal leukoencephal-
opathy, cerebral stroke, and peripheral neuropathic events were
adequately managed with CE [225,227,229]. Nonetheless, 2 case
reports of hemiparesis in LScs described conflicting results of
intravenous methylprednisolone (MP) [192,222], with failure
being observed in association with IVIG. Recurring headaches
and cranial nerve involvement showed adequate response to CE
as well as MTX and MMF [196,198,217,219], and anticonvulsant
and antidepressant therapy were effective at reducing symptoms
[201,216,218]; however, in one description of papillitis, CE and AZA
have failed to improve symptoms [202]. Cerebral vasculitis was
identified in 1 case and improvement was observed following
MMF treatment [217].
Among SSc patients, management of neurological manifestations
depended on severity and areas involved. Although, asymptomatic
Trigeminal neuropathy GON blockade 1 1
CBZ 1 1
Headache MMF 2 1 1
Anticonvulsants 3 2 1
Migraine AMT 1 1
iv DXS 1 1
AMI ¼ amitriptyline; AZA ¼ azathioprine; CBZ ¼ carbamazepine; CE ¼ corticos-
teroids; CLB ¼ clobazam; CPS ¼ complex partial seizures; CTX ¼ cyclopho-
sphamide; D ¼ deterioration; DXS ¼ dexamethasone; EPC ¼ epilepsia partialis
continua; GON ¼ great occipital nerve; GTCS ¼ generalized tonic-clonic seizures;
I ¼ improvement; IVIG ¼ intravenous immunoglobulin; MP ¼ methylpredniso-
lone; MTX ¼ methotrexate; MMF ¼ mycophenolate mofetil; N ¼ number of
subjects; OCBZ ¼ oxcarbazepine; PHB ¼ phenobarbital; PHE ¼ phenytoin; S ¼
stable; U ¼ undetermined.
cerebral hyperintensity lesions and subclinical peripheral neuro-
pathy were identified in several studies, treatment was reported in
few cases. On the other hand, patients with severe neurological
manifestations usually received CE and other immunosuppressive
medications (Table 10).
Patient with severe peripheral nervous system involvement,
such as brachial and lumbar plexopathy, and chronic progressive
ataxic neuropathy initially received oral or intravenous CE (83.33%)
[117–120]. Varied responses were observed, ranging from com-
plete improvement (75%) to clinical deterioration (1 case). In those
with persistent clinical activity, additions of pulse cyclophospha-
mide (2 cases) [117,118] or intravenous immunoglobulin (1 case)
[120] were described and clinical and laboratorial improvement
was observed with both drug regimens.
Entrapment neuropathies were basically managed with sur-
gery, local CE infiltration, and systemic CE with good responses
[79,103,104,106,108,111,115]. CE was also the main stem in myo-
pathy [178,185–187], multiple mononeuropathy [96,113,114], sen-
sorimotor polyneuropathy, [94,96,98,99,103] and trigeminal
neuropathy [34,89], although frequently associated with other
immunosuppressant, such as MTX and AZA. Cyclosporine, MTX,
AZA, and MMF were used in myopathy maintenance treatment
[185], while refractory cases were successfully managed with IVIG
[185]. In spite of increased effectiveness in myopathy (73.61%) and
mononeuritis (83.3%), trigeminal neuropathy and sensorimotor
polyneuropathy rarely improved with immunosuppressant ther-
apy. However, one case of sensory polyneuropathy improvement

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Table 10 cyclophosphamide [11,39–41,52,53,58–60,69,71]. Seizures [11,40,

Treatment of CNS and PNS involvement in SSc 41,52,53], transverse myelitis [58–60], central nervous system
vasculitis [11,39,53,71], and subacute cerebellar degeneration
Neurologic involvement Treatment N R I S D U
[69] often improved after high-dose CE, but recurrences were
PNS observed, especially during abrupt CE tapering. Aneurysms, radi-
Trigeminal neuropathy DP 4 1 3 culopathy, and cervical cord compression were managed with
CE 3 1 2 surgery, with recovery in almost all cases [61–63,66,173,176,
CE þ MTX 1 1
Anticonvulsants 7 4 3
179,188] (Table 10), and reversible posterior leukoencephalopathy
CBZ 2 1 1 syndrome (RPLS) always improved with blood pressure control
Gabapentin 2 2 [172,174,177].
Nortryptiline 1 1 Among ANS involvement, few studies focused on treatment to
Amitryptiline 2 2
address pathophysiologic process; however, iloprost and cyclo-
MVD 1 1
CTS Surgery 7 3 4 phosphamide were reported to decrease sympathetic overdrive in
CE 1 1 2 case reports [123,133], as well as transcutaneous electrical nerve
Ulnar nerve entrapment CE 1 1 stimulation was effective in normalizing sympathovagal balance
Surgery 2 1 1 and reducing gastrointestinal symptoms in one study [146].
Perineural calcifications Surgery 1 1
Multiple Mononeuropathy CE 4 3 1
Similarly, studies on psychiatric manifestations did not cover
CE þ MTX 2 2 specific treatment options, and conventional treatment for depres-
AZA þ CE 1 1 sion and anxiety should be adopted for now [15].
Peripheral SMP CE 3 3 Finally, although CNS and PNS studies have reported CE use in
CE þ PGE 1 1
severe manifestations, caution must be taken because of possible
IVIG 1 1
CTX 1 1 association with scleroderma renal crises.
DP 1 1
Amytriptiline 1 1
Lumbar plexopathy CE 2 1 1
Brachial plexopathy CTX þ CE 1 1
MP þ CTX 1 1
Discussion
IVIG 1 1
Auditory neuropathy Cochlear implantation 1 1 Previously considered a rare event or consequence of SSc
CSAN MP þ CE 1 1 complications, such as hypertension, cardiopathy, pneumopathy,
Myopathy CE 56 53 3
renal disease, and atherosclerosis, neurological involvement is
IVIG 9 9
currently considered a primary event in scleroderma. Overall,
CNS neurological complications are reported to occur between 1% and
Radiculopathy Surgery 4 3 1
CT-guided aspiration 1 1
40% of SSc patients [6,35,55,56,86,238], and patients with anti-
Cervical cord compression Surgery 5 3 1 1 U1RNP antibodies and possibly those with anti-Scl70 antibodies
OBS CE 1 1 seem to be at higher risk of developing neurological complications
Seizures MP 1 1 [239].
MP þ CTX 1 1
LScs and SSc pathogenesis are not fully understood. Most of the
CE þ CTX 2 1 1
CE þ plasma exchange 1 1 proposed pathophysiological mechanisms are similar to both
Plasmapheresis 1 1 entities, and clinical and laboratory data support the hypothesis
Tranverse myelitis CE þ CTX 1 1 that vasculature is a primary target [198,240,241]. Increased
MP þ CTX 1 1 vascular permeability due to damaged endothelial cells is associ-
MP 1 1
Hemianalgesia MP þ CTX 1 1
ated with mononuclear cell infiltration, leading to perivascular
Aphasia MP þ CTX 1 1 inflammatory cell infiltrates, vascular intimal thickening, and
SCD MP 1 1 vessel narrowing [240]. Gradually, small arteries lose their elas-
cc demyelination CE 1 1 ticity and media and adventitia become fibrotic and more prone to
Cerebral aneurysm Surgery 7 7
occlusion [240,242,243]. This process is further exacerbated by
TIA / Stroke MP þ ASA 1 1
Hemiparesis MP þ CTX 1 1 thrombotic events driven by platelets activation [240].
CE þ CTX 1 1 Loss of arteries and capillaries is observed in many organs, and
Optic atrophy CE þ CTX 1 1 overexpression of proangiogenic and antiangiogenic factors have
been documented. Although proangiogenic factors, such as VEGF,
CBZ ¼ carbamazepine; cc ¼ corpus callosum; CE ¼ corticosteroids; CSAN ¼
chronic progressive ataxic neuropathy; CTX ¼ cyclophosphamide; D ¼ deteriora-
interleukin-8, and basic fibroblast growth factor, prevail, angio-
tion; DP ¼ D-penicillamine; I ¼ improvement; IVIG ¼ intravenous immunoglo- genesis is dysregulated and aberrant [241,243,244]. The exact
bulin; MP ¼ methylprednisolone; MVD ¼ microvascular decompression; N ¼ mechanism of how dysregulated angiogenesis occurs is still being
number of patients; OBS ¼ organic brain syndrome; R ¼ recovery; S ¼ stable; characterized. Recruitment and differentiation of bone marrow-
SCD ¼ subacute cerebellar degeneration; SMP ¼ sensorimotor polyneuropathy;
derived endothelial progenitor cells (EPCs) are necessary to vascu-
U ¼ undetermined.
logenesis. In SSc, monocytic EPC seems to have an impaired ability
to incorporate into vasculature and EPC-mediated vasculogenesis
is diminished [242,245]. Therefore, a hypoxic state occurs and,
after prednisone and another due to IVIG have been described later, avascular areas [240,241,243].
[98,99]. D-penicillamine was also tried in some trigeminal neuro- Recent studies using MRI have identified an increased number
pathy cases, but no improvement was observed [34,83,85]. of white matter hyperintensities in areas of interface [7,8], and
Furthermore, amitriptyline, nortryptiline, carbamazepine, oxcar- SPECT studies have observed focal and diffuse cerebral hypoperfu-
bazepine, and gabapentin were successfully used to ameliorate sion in more than 50% of asymptomatic SSc patients [43,48],
peripheral neurologic symptoms [82,85,89,92,97] (Table 10). supporting pathophysiology theory. Furthermore, association
Severe CNS involvement was frequently treated with oral or between SPECT hypoperfusions and an active pattern in nailfold
intravenous CE, in association or not with intravenous pulse videocapillaroscopy has been observed [43].

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 T.N. Amaral et al. / Seminars in Arthritis and Rheumatism 43 (2013) 335–347
Neurologic manifestations in scleroderma are protean and
treatment approach varied. Seizures predominate in LScs and
varied in nature. Mild cases were usually managed with antiepi-
leptic drugs with unpredictable response. On the other hand,
uncontrolled seizures usually required immunosuppressive med-
ications, with positive results. Biopsies specimen when available
showed chronic perivascular lymphocytic inflammation, scattered
inflammatory cells within vessel walls, and microglial activation,
supporting the immunosuppressive therapy.
Mononeuritis multiplex and sensorimotor polyneuropathy
responses to immunosuppresants are also indicative of a causative
inflammatory process. Nonetheless, entrapment neuropathies and
trigeminal neuropathy seem to be related to edematous phase of
SSc, improving with inflammatory amelioration due to treatment
or disease evolution.
In CNS involvement, although an inflammatory process is
clearly involved in some manifestations, as transverse myelitis
and seizures, an undetermined cerebral and cerebellar small vessel
process could be evidenced. Recent studies demonstrated white
matter hyperintensity lesions in areas of interface, and a causative
vascular process was pointed out. As far as the authors know, no
specific study addresses metabolic risks and atherosclerotic proc-
ess accounting for cerebral involvement; however, accelerated
process of atherosclerosis has been identified in SSc patients and
could be responsible for CNS involvement as well.
Psychiatric manifestations in SSc have received attention lately.
An increased prevalence of depression and anxiety has been repor-
ted, even in comparison to other chronic and disfiguring diseases.
However, some frequently used questionnaires include organic
symptomatology that can cause increased scores in SSc patients
[32]. CES-D and PHQ-9, already validated to SSc, seem to be more
adequate at this scenario, minimizing confounding factors [32,33].
Finally, this study has some limitations. First of all, studies with
different methodology were analyzed simultaneously, and the
large number of case reports might have increased the prevalence
of certain neurological involvement. Secondly, studies/case reports
have been conducted/reported in different periods of time and
neurological involvement might have been unrecognized due to
unavailable methods of complementary evaluation. Furthermore,
disease classification and diagnostic criteria have been modified
throughout time, and possible patient classification mismatch
could occur. In order to minimize this possibility, no discrimina-
tion in limited and systemic forms of SSc was performed. Lastly, as
the treatment of neurological involvement in scleroderma was
approached only by case reports, no definitive conclusions regard-
ing effectiveness should be taken.
Conclusion
Evidence of primary neurologic involvement in SSc increased in
recent years. Inflammatory process was demonstrated in central
and peripheral lesions, and entrapment process was associated to
disease activity. Increased prevalence of white matter hyperinte-
sity lesions is suggestive of small vessel involvement and further
clarification is fundamental. Depressive and anxiety symptoms are
highly prevalent and psychiatric evaluation must be part of SSc
patient's assessment.
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