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Neurologic manifestations in the systemic autoimmune rheumatic diseases (SARDs) are protean. They add to the disease burden and could contribute to mortality. Increasing awareness about the neuro-rheumatologic syndromes might help with early diagnosis and effective therapy. Our aim is to survey the clinical and imaging patterns of neurological involvement in Egyptian patients with SARDs.
Results
Neurological involvement is common in Behçet’s disease (BD) (12.7%) and systemic lupus erythematosus (SLE) (6.4%) patients compared with other SARDs. Compared with SLE, neurological involvement in BD tends to develop at an older age (31 ± 7.1 versus 28.3 ± 9.6 years = 0.022) with a greater progression risk (13.8% versus 2.6%, P = 0.003). A higher proportion of SLE patients had abnormal neuroimaging without neurological symptoms (15.7% versus 4.3%, P = 0.026, OR = 4.9, 95%CI 1.1–22.4). SLE patients had a higher frequency of seizures (31.3% versus 6.4%, P < 0.001, OR = 6.7, 95%CI 2.7–16.7) and benign intracranial hypertension (9.6% versus 1.1%, P = 0.009, OR = 9.8, 95%CI 1.2–77.7) but a lower prevalence of quadriplegia due to brain insult (1.7% versus 3.2%, P = 0.045, OR = 0.2, 95%CI 0.04–0.9), dural sinus thrombosis (13% versus 33%, P = 0.001, OR = 0.3, 95%CI 0.2–0.6), brainstem syndrome (0.9% versus 6.4%, P = 0.047, OR = 0.1, 95%CI 0–1.1) and cranial neuropathies (9.6% versus 31.9%, P < 0.001, OR = 0.2, 95%CI 0.1–0.5). Concerning neuroimaging, brain atrophic changes were more common (27.4% versus 9.5%, P = 0.002, OR = 3.6, 95%CI 1.6–8.3) while thrombosis was less prevalent (36.3% versus 53.6%, P = 0.016, OR 0.5, 95%CI = 0.3–0.9) in lupus patients. The cerebral cortex was more commonly affected (20.4 versus 4.8%, P = 0.002, OR = 5.1, 95%CI 1.7–15.4) while dural sinuses (14.2% versus 40.5%, P < 0.001, OR = 0.2, 95%CI 0.1–0.5), basal ganglia (1.8% versus 10.7%, P = 0.010, OR = 0.2, 95%CI 0–0.7), diencephalon (0% versus 13.1%, P < 0.001) and brainstem (1.8% versus 22.6%, P < 0.001, OR = 0.1, 95%CI 0–0.3) were less frequently involved in SLE patients. Concerning other SARDs, cranial neuropathies were the most common neurological presentations. Abnormalities in neuroimaging did not correlate with the patients’ clinical presentations.
Conclusions
Neurological presentations associated with SARDs are protean. Neuroimaging abnormalities should be interpreted within the context of the clinical picture and the results of other investigations.
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aPL
Antiphospholipid antibodies
APS
Antiphospholipid syndrome
BD
Behçet’s disease
CNS
Central nervous system
CS
Cogan syndrome
CT
Computerized tomography
CVA
Cerebrovascular accidents
GPA
Granulomatosis with polyangiitis
MCTD
Mixed connective tissue disease
MRI
Magnetic resonance imaging
n
Number
MS
Multiple sclerosis
NMOSD
Neuromyelitis optica spectrum disorders
NPS
Neuropsychiatric
PNS
Peripheral nervous system
PRES
Posterior reversible encephalopathy syndrome.
PSS
Progressive systemic sclerosis
RA
Rheumatoid arthritis
RPC
Relapsing polychondritis
SARD
Systemic autoimmune rheumatic diseases
SD
Standard deviation
SLE
Systemic lupus erythematosus
TA
Takayasu arteritis
TIAs
Transient ischemic attacks
VKH
Vogt–Koyanagi–Harada syndrome
Background
Unlike organ-specific autoimmunity, systemic autoimmune rheumatic diseases (SARDs) could affect any organ system. Neurological involvement has been described in almost all SARDs. It contributes significantly to the disease burden as well as disease-related morbidity and mortality. It could develop at any time point along the disease course; and it could, even, precede other disease manifestations. Underlying etiopathogenesis includes disease activity, disease-related damage and medication side effects. SARDs have variable neurological presentations that could differ in frequency, etiology, pathology and distribution. Certain presentations were reported as relatively unique to a specific SARD. Increasing awareness about these specific neuro-rheumatologic syndromes might help with early diagnosis and effective therapy [1‐7].
This study aimed to survey the clinical and imaging patterns of disease-related neurological involvement in the spectrum of SARDs in an Egyptian cohort.
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Methods
Medical records of 5279 adult patients available in the archive of the Rheumatology and Rehabilitation Outpatient Clinic and Inpatient Department were screened for clinical and/or neuroimaging evidence of neurological involvement attributed to SARDs. Among those patients, 267 cases were identified and included in the statistical analysis. Patients were classified according to the standard classification criteria (supplementary material).
Patients with neurological involvement were managed on a case-by-case basis, taking into consideration clinical manifestations, blood tests, and specific investigations including brain and spine imaging, vascular studies, electroencephalography, evoked potential and cerebrospinal fluid analysis as indicated. Patients with proven SARD-related CNS disease, including cranial neuropathy, were enrolled, while those with CNS involvement secondary to another etiology, such as infections or metabolic or degenerative diseases were excluded.
Patients with peripheral neuropathies, mononeuropathies, entrapment neuropathies and muscle diseases were excluded as well. Being a retrospective study, symptomatic patients were the target population. Since many patients with peripheral nervous system (PNS) involvement associating SARD have a subclinical disease [8], retrospective collection of those cases could underestimate the actual frequency of PNS involvement. Therefore, CNS involvement was specifically addressed in this study.
All patients were managed in collaboration with neurologists and psychiatrists experienced in SARDs. Neurologists and radiologists reviewed neuroimaging studies. Other investigations were done based on each patient’s case scenario (data not shown). Vascular pathology was determined based on arterial imaging and confirmed by identifying the embolization source, if indicated, using echocardiography and aortography.
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Demographic characteristics, comorbidities, and clinical and imaging features of neurological involvement were retrospectively collected. Symptomatic cognitive dysfunction was documented as a subjective patient’s complaint impairing the activities of daily living. When available, standard definitions for the neurological manifestations of a certain SARD were applied [9].
Statistical analysis
In this descriptive study, quantitative and qualitative data were described in terms of means ± standard deviations (± SD) and frequencies and percentages, respectively. Data were coded and entered using the statistical package for the Social Sciences (SPSS) version 28 (IBM Corp., Armonk, NY, USA).
Results
The frequency of neurological involvement among the different SARDs is shown in Fig. 1.
Fig. 1
Frequency of neurological involvement among the different systemic autoimmune rheumatic diseases. TA Takayasu arteritis, GPA granulomatosis with polyangiitis, APS antiphospholipid syndrome, BD Behçet’s disease, VKH Vogt–Koyanagi–Harada syndrome, SLE systemic lupus erythematosus, MCTD mixed connective tissue disease, PSS progressive systemic sclerosis, RA rheumatoid arthritis, n number. The number of patients with neurological involvement among the population with each SARD is shown in brackets
Among the screened cases, 267 patients were enrolled in the study. Table 1 shows the patients’ demographic characteristics for the different SARDs. Table 2 shows the patients’ comorbidities and special habits.
Table 1
The demographic characteristics of the study cohort
Characteristics
RA
n = 6
SLE
n = 115
Primary APS
n = 30
PSS
n = 1
MCTD
n = 4
BD
n = 94
TA
n = 5
CS
n = 2
RPC
n = 1
GPA
n = 3
VKH
n = 1
Sarcoidosis
n = 5
Total cohort
n = 267
Age at disease onset (years, mean ± SD)
44.67 ± 15.91
25.42 ± 8.3
25.33 ± 7.31
52
39.25 ± 11.47
26.84 ± 7.11
32.6 ± 10.29
18 ± 1.41
17
35 ± 12.12
30
46.3 ± 11.42
27.2 ± 9.3
Age at last visit (years, mean ± SD)
55.33 ± 15.87
33.52 ± 9.12
34.33 ± 8
53.5
49.38 ± 7.74
35.5 ± 7.85
39.8 ± 12.27
21.5 ± 3.54
24
39.67 ± 8.74
31
49.9 ± 12.74
35.5 ± 9.8
Disease duration (years, mean ± SD)
10.67 ± 5.28
8.02 ± 5.44
9 ± 6.02
1.5
10.13 ± 8.91
8.46 ± 6.05
7.2 ± 4.98
3.5 ± 2.12
7
4.77 ± 4.35
1
3.6 ± 3.15
8.2 ± 5.7
Follow-up duration (years, mean ± SD)
5.58 ± 5.98
4.9 ± 4.7
2.59 ± 2.94
0.5
6.44 ± 7.83
3.19 ± 4.79
3.62 ± 4.36
1.38 ± 1.59
3.5
4.37 ± 4
0.25
2.36 ± 3.1
3.9 ± 4.6
Age at NPS involvement (years, mean ± SD)
52.5 ± 14.29
28.29 ± 9.64
30.2 ± 8.24
53.5
42 ± 11.4
30.96 ± 7.12
34.6 ± 9.48
18 ± 1.41
17
36.67 ± 9.24
30
47.6 ± 12.34
30.7 ± 1
Duration to NPS involvement (years, mean ± SD)
6.54 ± 5.84
3.73 ± 5.38
5 ± 5.77
1.5
2.75 ± 2.63
3.77 ± 4.25
2 ± 1.58
0.13 ± 0.18
0
1.8 ± 2.77
0
1.3 ± 1.2
3.8 ± 4.9
Duration of NPS disease (years, mean ± SD)
3.99 ± 3.11
4.72 ± 4.7
4.03 ± 3.46
0.1
7.38 ± 7.25
4.73 ± 4.32
5.22 ± 5.77
3.38 ± 2.3
7
3.03 ± 2.59
1
2.36 ± 3.1
4.6 ± 4.4
Gender
Females, n (%)
6 (100)
105 (91.3)
28 (93.3)
1 (100)
4 (100)
10 (10.6)
3 (60)
1 (50)
1 (100)
2 (66.7)
1 (100)
5 (100)
167 (62.5)
Males, n (%)
0 (0)
10 (8.7)
2 (6.7)
0 (0)
0 (0)
84 (89.4)
2 (40)
1 (50)
0 (0)
1 (33.3)
0 (0)
0 (0)
100 (37.5)
APS antiphospholipid syndrome, BD Behçet’s disease, CS Cogan syndrome, GPA granulomatosis with polyangiitis, MCTD mixed connective tissue disease, n number, NPS neuropsychiatric, PSS progressive systemic sclerosis, RA rheumatoid arthritis, RPC relapsing polychondritis, SD standard deviation, SLE systemic lupus erythematosus, TA Takayasu arteritis, VKH Vogt–Koyanagi–Harada syndrome
Table 2
Special habits and comorbidities of the study cohort at the onset of neurological involvement
Comorbidity
n = 267
Smoking, n (%)
36 (13.5)
Drug abuse, n (%)
11 (4.1)
Alcohol consumption, n (%)
2 (0.7)*
Secondary antiphospholipid syndrome, n (%)†
37 (15.6)
Systemic hypertension, n (%)
49 (18.4)
Ischemic heart disease, n (%)
8 (3)
Rheumatic heart disease, n (%)
9 (3.4)
Diabetes mellitus, n (%)
7 (2.6)
Hypothyroidism, n (%)
1 (0.4)
Viral hepatitis C, n (%)
3 (1.1)
Chronic kidney disease, n (%)
18 (6.7)
*The two patients were occasional ethanol consumers: One patient with BD presented with encephalitis and altered signals in the cerebral white matter, while the other had TA with evidence of arterial stenosis on imaging. †Out of 237 patients after excluding 30 patients with primary antiphospholipid syndrome. n number
The clinical patterns of neuropsychiatric presentations of the different SARDs are shown in Table 3. Among 28 patients who were asymptomatic at onset, neurological involvement was detected during routine clinical assessment in 11 patients. 9 patients had grade 1 papilledema upon routine fundus examination, with a final diagnosis of dural sinus thrombosis in 5 patients and benign intracranial tension in 4 patients. Evidence of unilateral upper motor neuron lesion was detected upon examination in a patient without neurological symptoms. Unilateral partial thrombosis of the extracranial portion of the vertebral artery was accidentally detected during a routine angiographic assessment in one of Takayasu’s arteritis (TA) patients; this patient developed isolated vestibulocochlear neuropathy later. On the other side, imaging abnormalities, including atrophic changes, altered signal intensities, encephalomalacia and abnormal vascular imaging, were accidentally detected in the remaining 17 patients with neither neurological symptoms nor signs during imaging of the orbit/paranasal sinuses.
Table 3
The clinical presentation of the neuropsychiatric disease in the study cohort
Characteristics
RA
n = 6
SLE
n = 115
Primary APS
n = 30
PSS
n = 1
MCTD
n = 4
BD
n = 94
TA
n = 5
CS
n = 2
RPC
n = 1
GPA
n = 3
VKH
n = 1
Sarcoidosis
n = 5
Total cohort
n = 267
Onset of NPS involvement
Sudden, n (%)
0 (0)
27 (23.5)
5 (16.7)
0 (0)
0 (0)
1 (1.1)
1 (20)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
34 (12.7)
Acute, n (%)
1 (16.7)
64 (55.7)
22 (73.3)
1 (100)
3 (75)
80 (85.1)
0 (0)
0 (0)
0 (0)
3 (100)
0 (0)
3 (60)
177 (66.3)
Gradual, n (%)
0 (0)
4 (3.5)
0 (0)
0 (0)
0 (0)
7 (7.4)
0 (0)
2 (100)
0 (0)
0 (0)
0 (0)
1 (20)
14 (5.2)
Asymptomatic, n (%)
0 (0)
17 (14.8)
3 (10)
0 (0)
0 (0)
4 (4.3)
4 (80)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
28 (10.5)
Indeterminate, n (%)
5 (83.3)
3 (2.6)
0 (0)
0 (0)
1 (25)
2 (2.1)
0 (0)
0 (0)
1 (100)
0 (0)
1 (100)
1 (20)
14 (5.2)
Course of NPS involvement
Progressive, n (%)
1 (16.7)
3 (2.6)
0 (0)
0 (0)
0 (0)
13 (13.8)
0 (0)
2 (100)
0 (0)
0 (0)
0 (0)
0 (0)
19 (7.1)
Regressive, n (%)
0 (0)
47 (40.9)
12 (40)
0 (0)
0 (0)
28 (29.8)
1 (20)
0 (0)
0 (0)
1 (33.3)
1 (100)
1 (20)
91 (34.1)
Stationary, n (%)
1 (16.7)
12 (10.4)
8 (26.7)
0 (0)
1 (25)
21 (22.3)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
43 (16.1)
Relapsing, n (%)
0 (0)
38 (33)
7 (23.3)
0 (0)
2 (50)
23 (24.5)
1 (20)
0 (0)
1 (100)
2 (66.7)
0 (0)
1 (20)
75 (28.1)
Asymptomatic, n (%)
0 (0)
12 (10.4)
1 (3.3)
0 (0)
0 (0)
2 (2.1)
3 (60)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
18 (6.7)
No follow–up, n (%)
4 (66.7)
3 (2.6)
2 (6.7)
1 (100)
1 (25)
7 (7.4)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
3 (60)
21 (7.9)
Disturbed consciousness, n (%)
0 (0)
3 (2.6)
1 (3.3)
0 (0)
0 (0)
1 (1.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
5 (1.9)
Cognitive impairment, n (%)
0 (0)
3 (2.6)
1 (3.3)
0 (0)
0 (0)
3 (3.2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
7 (2.6)
Psychosis, n (%)
0 (0)
9 (7.8)
0 (0)
0 (0)
0 (0)
2 (2.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
11 (4.1)
Seizures, n (%)
0 (0)
31 (27)
5 (16.7)
0 (0)
0 (0)
3 (3.2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
39 (14.6)
Mono/hemiplegia, n (%)
0 (0)
14 (12.2)
10 (33.3)
0 (0)
1 (25)
15 (16)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
40 (15)
Hemihypoesthesia, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Paraplegia due to brain insult, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Tri/quadriplegia due to brain insult, n (%)
0 (0)
2 (1.7)
0 (0)
0 (0)
0 (0)
3 (3.2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
5 (1.9)
Ataxia, n (%)
0 (0)
2 (1.7)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (0.7)
Extrapyramidal syndromes, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Encephalitis*, n (%)
0 (0)
7 (6.1)
0 (0)
0 (0)
0 (0)
10 (10.6)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
17 (6.4)
Meningitis, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Brainstem syndrome, n (%)
0 (0)
1 (0.9)
0 (0)
0 (0)
0 (0)
6 (6.4)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
7 (2.6)
Benign increased intracranial tension, n (%)
0 (0)
10 (8.7)
0 (0)
0 (0)
0 (0)
1 (1.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (40)
13 (4.9)
Hydrocephalus, n (%)
0 (0)
1 (0.9)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (33.3)
0 (0)
0 (0)
2 (0.7)
PRES, n (%)
0 (0)
1 (0.9)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Transverse myelitis, n (%)
0 (0)
4 (3.5)
0 (0)
0 (0)
0 (0)
2 (2.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
6 (2.2)
Ever neurogenic bladder, n (%)
0 (0)
6 (5.2)
0 (0)
0 (0)
0 (0)
3 (3.2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
9 (3.4)
Isolated cranial neuropathy, n (%)†
5 (83.3)
4 (3.5)
1 (3.3)
1 (100)
2 (50)
17 (19.1)
0 (0)
1 (50)
1 (100)
2 (66.7)
1 (100)
3 (60)
38 (14.2)
Ever cranial neuropathy, n (%)††
5 (83.3)
8 (7.5)
3 (10)
1 (100)
3 (75)
20 (25.6)
0 (0)
2 (100)§
1 (100)
2 (66.7)
1 (100)
4 (80)
50 (18.7)
Involved cranial nerves ׀׀
Optic, n (%)
0 (0)
2 (25)
3 (100)
0 (0)
0 (0)
12 (60)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
3 (75)
20 (7.5)
Oculomotor, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (5)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Trigeminal, n (%)
0 (0)
0 (0)
0 (0)
1 (100)
2 (66.7)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
3 (1.1)
Abducent, n (%)
0 (0)
2 (25)
0 (0)
0 (0)
0 (0)
2 (10)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
4 (1.5)
Facial, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (50)
0 (0)
0 (0)
1 (0.4)
Vestibulocochlear, n (%)
5 (100)
4 (50)
0 (0)
0 (0)
1 (33.3)
5 (25)
0 (0)
2 (100)
1 (100)
2 (100)
1 (100)
1 (25)
22 (8.2)
Bulbar, n (%)
0 (0)
1 (12.5) ¶
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Acute inflammatory demyelinating polyradiculoneuropathy, n (%)
0 (0)
1 (0.9) ¶
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Intracranial hemorrhage, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (2.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (0.7)
Pulsating carotid aneurysm, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Transient ischemic attacks, n (%)
0 (0)
5 (4.3)
2 (6.7)
0 (0)
0 (0)
3 (3.2)
1 (20)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
11 (4.1)
Dural sinus thrombosis, n (%)
0 (0)
14 (12.2)
11 (36.7)
0 (0)
1 (25)
30 (30.6)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
56 (21)
Primary headache
1 (16.7)
6 (5.2)
1 (3.3)
0 (0)
1 (25)
1 (1.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
10 (3.7)
Mixed clinical presentation, n (%)**
0 (0)
14 (12.2)
4 (13.3)
0 (0)
1 (25)
3 (3.2)
0 (0)
1 (50)
0 (0)
0 (0)
0 (0)
1 (20)
24 (9)
Asymptomatic with normal clinical examination, n (%)
0 (0)
12 (10.4)
1 (3.3)
0 (0)
0 (0)
2 (2.1)
4 (80)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
18 (6.7)
APSantiphospholipid syndrome, BD Behçet’s disease, CS Cogan syndrome, GPA granulomatosis with polyangiitis, MCTD mixed connective tissue disease, n number, NPS neuropsychiatric, PRES posterior reversible encephalopathy syndrome, PSS progressive systemic sclerosis, RA rheumatoid arthritis, RPC relapsing polychondritis, SD standard deviation, SLE systemic lupus erythematosus, TA Takayasu arteritis, VKH Vogt–Koyanagi–Harada syndrome
*Encephalitis refers to the development of multiple clinical neurological deficits with the existence of diffusely distributed lesions of the same pattern and pathology on imaging. †Isolated cranial neuropathy denotes the development of cranial neuropathy without other clinical neurological deficits. ††Percentages were calculated from the total number of patients after exclusion of patients with encephalitis and brainstem syndrome. §One CS patient had cranial neuropathy with asymptomatic carotid artery thrombosis. ׀׀Percentages were calculated out of the total number of patients with cranial neuropathy after excluding cranial neuropathies secondary to encephalitis and brainstem syndrome. ¶A lupus patient had acute inflammatory demyelinating polyradiculoneuropathy with abducent and bulbar palsy. **Mixed clinical presentations mean the development of multiple clinical neurological deficits of the previously described ones with the presence of multiple lesions of different patterns and pathology on imaging
The neurological diagnoses in the 25 patients without neuroimaging studies were isolated bilateral sensorineural hearing loss (5 rheumatoid arthritis/RA patients, 1 patient with relapsing polychondritis/RPC, 1 patient with Cogan syndrome/CS, 1 patient with granulomatosis with polyangiitis/GPA); isolated optic neuritis (10 Behçet’s disease/BD patients, 3 sarcoid patients); trigeminal neuralgia (1 progressive systemic sclerosis/PSS patient); and primary headache (2 systemic lupus erythematosus/SLE patients, 1 patient with mixed connective tissue disease/MCTD).
Of the 242 patients with available neuroimaging studies, 218 had magnetic resonance imaging (MRI) with T1, T2 and FLAIR sequencing, and 24 had computerized tomography (CT). Of those patients, 190 (78.5%) had neurological manifestations with neuroimaging abnormalities, 34 (14%) had neurological manifestations with normal neuroimaging, and 18 (7.4%) had no neurological manifestations with accidentally discovered neuroimaging abnormalities.
Table 4 shows the patterns of lesions on neuroimaging. The anatomical locations of the neuroimaging abnormalities are shown in Table 5. Table 6 shows the etiological diagnosis of the neuroimaging findings. The relation between clinical presentations and the location of neuroimaging lesions is shown in Table 7.
Table 4
Neuroimaging findings of the study cohort
Characteristics
RA
n = 1
SLE
n = 113
Primary APS
n = 30
MCTD
n = 3
BD
n = 84
TA
n = 5
CS
n = 1
GPA
n = 2
VKH
n = 1
Sarcoidosis
n = 2
Total cohort
n = 242
Altered signals, n (%)
1 (100)
57 (50.4)
9 (30)
1 (33.3)
38 (45.2)
0 (0)
0 (0)
0 (0)
1 (100)
0 (0)
107 (44.2)
Infarct, n (%)
0 (0)
21 (18.6)
9 (30)
1 (33.3)
13 (15.5)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
44 (18.2)
Encephalomalacia, n (%)
0 (0)
9 (8)
3 (10)
0 (0)
3 (3.6)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
15 (6.2)
Atrophic changes, n (%)†
0 (0)
31 (27.4)
1 (3.3)
0 (0)
8 (9.5)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
40 (16.5)
Hydrocephalic changes, n (%)
0 (0)
1 (0.88)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (50)
0 (0)
0 (0)
2 (0.8)
Brain edema, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Mass effect, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
3 (3.6)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
3 (1.2)
Intracerebral hemorrhage, n (%)
0 (0)
3 (2.7)
0 (0)
0 (0)
5 (6)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
8 (3.3)
Dural sinuses filling defect, n (%)
0 (0)
16 (14.2)
13 (43.3)
1 (33.3)
34 (40.5)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
64 (26.4)
Arterial thrombosis, n (%)
0 (0)
3 (2.7)
0 (0)
0 (0)
3 (3.6)
3 (60)
1 (100)
0 (0)
0 (0)
0 (0)
10 (4.1)
Arterial stenosis, n (%)
0 (0)
2 (1.8)
0 (0)
0 (0)
6 (7.1)
2 (40)
0 (0)
0 (0)
0 (0)
0 (0)
10 (4.1)
Arterial aneurysm, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
2 (2.4)
1 (20)
0 (0)
0 (0)
0 (0)
0 (0)
3 (1.2)
Arterial beading, n (%)
0 (0)
1 (0.9)
0 (0)
0 (0)
2 (2.4)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
3 (1.2)
Multiple findings††, n (%)
0 (0)
27 (23.9)
6 (20)
1 (33.3)
22 (26.2)
1 (20)
0 (0)
0 (0)
0 (0)
0 (0)
57 (23.6)
Normal imaging, n (%)
0 (0)
20 (17.7)
3 (10)
1 (33.3)
7 (8.3)
0 (0)
0 (0)
1 (50)
0 (0)
2 (100)
34 (14)
RA rheumatoid arthritis, SLE systemic lupus erythematosus, APS antiphospholipid syndrome, MCTD mixed connective tissue disease, BD Behçet’s disease, TA Takayasu arteritis, CS Cogan syndrome, GPA granulomatosis with polyangiitis, VKH Vogt–Koyanagi–Harada syndrome, n number
Findings that were present in the first available neuroimaging are described. †The atrophic changes were generalized and assessed by eyeballing. ††Multiple findings refer to combined lesions of the above
Table 5
The anatomical locations of the neuroimaging findings of the study cohort
Characteristics
RA
n = 1
SLE
n = 113
Primary APS
n = 30
MCTD
n = 3
BD
n = 84
TA
n = 5
CS
n = 1
GPA
n = 2
VKH
n = 1
Sarcoidosis
n = 2
Total cohort
n = 242
Affected organ/system
Brain, n (%)
1 (100)
69 (61.1)
14 (46.7)
1 (33.3)
36 (42.9)
0 (0)
0 (0)
1 (50)
1 (100)
0 (0)
123 (50.8)
Spinal cord, n (%)
0 (0)
1 (0.9)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Dural venous sinuses, n (%)
0 (0)
9 (8)
10 (33.3)
1 (33.3)
24 (28.6)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
44 (18.2)
Arteries, n (%)
0 (0)
1 (0.9)
0 (0)
0 (0)
1 (1.2)
5 (100)
1 (100)
0 (0)
0 (0)
0 (0)
8 (3.3)
> 1 organ/system, n (%)
0 (0)
13 (11.5)
3 (10)
0 (0)
16 (19)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
32 (13.2)
Cerebral cortex, n (%)
0 (0)
23 (20.4)
7 (23.3)
0 (0)
4 (4.8)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
34 (14)
Cerebral white matter, n (%)
0 (0)
24 (21.2)
6 (20)
0 (0)
16 (19)
1 (20)
0 (0)
0 (0)
0 (0)
0 (0)
47 (19.4)
Cerebral white matter, subcortical, n (%)
0 (0)
22 (19.5)
3 (10)
0 (0)
13 (15.5)
0 (0)
0 (0)
0 (0)
1 (100)
0 (0)
39 (16.1)
Cerebral white matter, periventricular, n (%)
1 (100)
0 (0)
3 (10)
0 (0)
12 (14.3)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
16 (6.6)
Basal ganglia, n (%)
0 (0)
2 (1.8)
2 (6.7)
1 (33.3)
9 (10.7)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
14 (5.8)
Diencephalon, n (%)
0 (0)
0 (0)
0 (0)
1 (33.3)
11 (13.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
12 (5)
Cerebellum, n (%)
0 (0)
10 (8.8)
3 (10)
0 (0)
2 (2.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
15 (6.2)
Brainstem, n (%)
0 (0)
2 (1.8)
0 (0)
0 (0)
19 (22.6)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
21 (8.7)
Ever spinal cord, n (%)†
0 (0)
4 (3.5)
0 (0)
0 (0)
2 (2.4)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
6 (2.5)
Carotid, n (%)
0 (0)
1 (0.9)
0 (0)
0 (0)
5 (6)
3 (60)
1 (100)
0 (0)
0 (0)
0 (0)
10 (4.1)
Vertebral artery, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
3 (3.6)
2 (40)
0 (0)
0 (0)
0 (0)
0 (0)
5 (2.1)
Cerebral arteries, n (%)
0 (0)
5 (4.4)
0 (0)
0 (0)
4 (4.8)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
9 (3.7)
Ever dural venous sinuses, n (%)
0 (0)
15 (13.3)
13 (43.3)
1 (33.3)
34 (40.5)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
63 (26)
Diffuse distribution, n (%)††
0 (0)
23 (20.4)
3 (10)
0 (0)
20 (23.8)
0 (0)
0 (0)
1 (50)
0 (0)
0 (0)
47 (19.4)
Multiple anatomical sites, n (%)§
0 (0)
27 (23.9)
6 (20)
1 (33.3)
20 (23.8)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
54 (22.3)
Normal study, n (%)
0 (0)
20 (17.7)
3 (10)
1 (33.3)
7 (8.3)
0 (0)
0 (0)
1 (50)
0 (0)
2 (100)
34 (14)
Findings that were present in the first available neuroimaging are described. †“Ever spinal cord” refers to spinal cord involvement in isolation or in combination with other organs, such as brain. ††Diffuse distribution refers to diffusely distributed lesions of the same pattern, such as atrophic changes and altered signals. §Multiple anatomical sites refer to lesions of different locations and patterns
Table 6
The etiological diagnosis of the neuroimaging findings of the study cohort
RA
n = 1
SLE
n = 113
Primary APS
n = 30
MCTD
n = 3
BD
n = 84
TA
n = 5
CS
n = 1
GPA
n = 2
VKH
n = 1
Sarcoidosis
n = 2
Total cohort
n = 242
Ever vascular pathology, n (%)
1 (100)
81 (71.7)
30 (100)
2 (66.7)
76 (90.5)
5 (100)
1 (100)
1 (50)
1 (100)
0 (0)
199 (82.2)
Thrombosis, n (%)
0 (0)
41 (36.3)
26 (86.7)
2 (66.7)
45 (53.6)
3 (60)
1 (100)
0 (0)
0 (0)
0 (0)
118 (48.8)
Embolism, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Vasculitis/vasculopathy, n (%)
1 (100)
55 (48.7)
9 (30)
1 (33.3)
46 (54.8)
5 (100)
1 (100)
1 (50)
1 (100)
0 (0)
121 (50)
Hemorrhage, n (%)
0 (0)
2 (1.8)
0 (0)
0 (0)
3 (3.6)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
5 (2.1)
Ever parenchymal pathology, n (%)
0 (0)
4 (3.5)
2 (6.7)
0 (0)
6 (7.1)
0 (0)
0 (0)
1 (50)
0 (0)
0 (0)
13 (5.4)
Inflammation, n (%)
0 (0)
4 (3.5)
2 (6.7)
0 (0)
5 (6)
0 (0)
0 (0)
1 (50)
0 (0)
0 (0)
12 (5)
Demyelination, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
1 (1.2)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.4)
Mass lesion, n (%)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Combined vascular and parenchymal pathology, n (%)
0 (0)
3 (2.7)
2 (6.7)
0 (0)
4 (4.8)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
9 (3.7)
Indeterminate pathology, n (%)
0 (0)
31 (27.4)
0 (0)
1 (33.3)
6 (7.1)
0 (0)
0 (0)
0 (0)
0 (0)
2 (100)
40 (16.5)
RA rheumatoid arthritis, SLE systemic lupus erythematosus, APS antiphospholipid syndrome, MCTD mixed connective tissue disease, BD Behçet’s disease, TA Takayasu arteritis, CS Cogan syndrome, GPA granulomatosis with polyangiitis, VKH Vogt–Koyanagi–Harada syndrome, n: number
Table 7
The relation between the clinical presentations and the location of lesions on neuroimaging
Cerebral cortex
n (%)
Cerebral subcortex
n (%)
Cerebral white matter
n (%)
Cerebral periventricular white matter
n (%)
Diencephalon
n (%)
Basal ganglia
n (%)
Cerebellum
n (%)
Brainstem
n (%)
Spinal cord
n (%)
Carotid artery
n (%)
Vertebral artery
n (%)
Cerebral artery
n (%)
Dural sinuses
n (%)
Disturbed consciousness, n = 14
1 (7.1)
0 (0)
2 (14.3)
2 (14.3)
1 (7.1)
0 (0)
2 (14.3)
3 (21.4)
0 (0)
1 (7.1)
0 (0)
1 (7.1)
2 (14.3)
Cognitive impairment, n = 14
3 (21.4)
3 (21.4)
5 (35.7)
5 (35.7)
0 (0)
4 (28.6)
3 (21.4)
4 (28.6)
0 (0)
0 (0)
0 (0)
1 (7.1)
4 (28.6)
Psychosis, n = 16
3 (18.8)
2 (12.5)
6 (37.5)
3 (18.8)
1 (6.3)
2 (12.5)
0 (0)
2 (12.5)
0 (0)
0 (0)
0 (0)
1 (6.3)
1 (6.3)
Seizures, n = 47
10 (21.3)
5 (10.6)
7 (14.9)
9 (19.1)
0 (0)
2 (4.3)
4 (8.5)
2 (4.3)
0 (0)
2 (4.3)
1 (2.1)
1 (2.1)
7 (14.9)
Mono/hemiplegia, n = 47
16 (34)
11 (23.4)
11 (23.4)
7 (14.9)
9 (19.1)
9 (19.1)
6 (12.8)
11 (23.4)
0 (0)
2 (4.3)
1 (2.1)
4 (8.5)
3 (6.4)
Hemihypesthesia, n = 1
0 (0)
0 (0)
1 (100)
0 (0)
1 (100)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (100)
1 (100)
1 (100)
Paraplegia, n = 2
0 (0)
1 (50)
1 (50)
1 (50)
0 (0)
1 (50)
1 (50)
1 (50)
0 (0)
0 (0)
0 (0)
0 (0)
1 (50)
Tri/quadriplegia, n = 10
2 (20)
0 (0)
2 (20)
5 (50)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (20)
Ataxia, n = 4
1 (25)
0 (0)
2 (50)
2 (50)
0 (0)
1 (25)
2 (50)
2 (50)
0 (0)
0 (0)
0 (0)
1 (25)
0 (0)
Extrapyramidal syndromes, n = 1
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Encephalitis, n = 17
1 (5.9)
2 (11.8)
5 (29.4)
6 (35.3)
2 (11.8)
3 (17.6)
2 (11.8)
5 (29.4)
0 (0)
1 (5.9)
0 (0)
1 (5.9)
2 (11.8)
Brainstem syndrome, n = 7
0 (0)
0 (0)
1 (14.3)
1 (14.3)
1 (14.3)
2 (28.6)
0 (0)
7 (100)
0 (0)
0 (0)
0 (0)
0 (0)
1 (14.3)
Benign increased intracranial tension, n = 14
0 (0)
1 (7.1)
5 (35.7)
0 (0)
1 (7.1)
0 (0)
0 (0)
1 (7.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Hydrocephalus, n = 2
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
PRES, n = 1
0 (0)
0 (0)
0 (0)
1 (100)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
Transverse myelitis, n = 6
1 (16.7)
1 (16.7)
1 (16.7)
2 (33.3)
0 (0)
0 (0)
0 (0)
1 (16.7)
6 (100)
0 (0)
0 (0)
0 (0)
1 (16.7)
Neurogenic bladder, n = 8*
2 (22.2)
2 (22.2)
2 (22.2)
4 (44.4)
1 (11.1)
2 (22.2)
1 (11.1)
2 (22.2)
4 (44.4)
0 (0)
0 (0)
0 (0)
3 (33.3)
Intracranial hemorrhage, n = 2
1 (50)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (50)
0 (0)
1 (50)
1 (50)
Pulsating carotid aneurysm, n = 1
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
1 (100)
0 (0)
0 (0)
0 (0)
Transient ischemic attacks, n = 11
1 (9.1)
3 (27.3)
3 (27.3)
2 (18.2)
0 (0)
0 (0)
1 (9.1)
0 (0)
0 (0)
1 (9.1)
0 (0)
0 (0)
4 (36.4)
Dural sinus thrombosis, n = 58
2 (3.4)
6 (10.3)
5 (8.6)
2 (3.4)
0 (0)
1 (1.7)
1 (1.7)
1 (1.7)
1 (1.7)
1 (1.7)
0 (0)
1 (1.7)
58 (100)
Primary headache, ` = 10
1 (10)
3 (30)
3 (30)
3 (30)
0 (0)
0 (0)
0 (0)
1 (10)
0 (0)
0 (0)
0 (0)
0 (0)
1 (10)
*The 9th patient with neurogenic bladder had acute inflammatory demyelinating polyradiculoneuropathy. n number, PRES: posterior reversible encephalopathy syndrome
Anzeige
One lupus patient had brainstem syndrome presenting with bulbar palsy. Six patients with Behçet’s disease (BD) had brainstem syndrome with a constellation of different manifestations, including disturbed consciousness in 3 (50%) patients, mono/hemiplegia in 2 (33.3%) patients, ataxia in 1 (16.7%) patient and cranial neuropathies in 5 (83.3%) patients involving the oculomotor (4 patients) and bulbar (2 patients) nerves.
Seven lupus patients developed encephalitis presenting with a constellation of manifestations indicative of global brain dysfunction, including disturbed consciousness in 5 (71.4%) patients, impaired cognition in 3 (42.9%) patients, psychosis in 3 (42.9%) patients, mono/hemiplegia in 1 (14.3%) patient, paraplegia in 1 (14.3%) patient, seizures in 5 (71.4%) patients, extrapyramidal manifestations in 1 (14.3%) patient, neurogenic bladder in 1 (14.3%) patient and cranial neuropathy of oculomotor and abducent nerves in 2 (28.6%) patients. The condition was associated with dural sinus thrombosis in 1 (14.3%) patient, benign increased intracranial tension in another one (14.3%) and aseptic meningitis in a third one (14.3%).
Ten BD patients presented with encephalitis in the form of disturbed consciousness in 1 (10%) patient, impaired cognition in 2 (20%) patients, psychosis in 4 (40%) patients, mono/hemiplegia in 4 (40%) patients, paraplegia in 1 (10%) patient, tri/quadriparesis in 5 (50%) patients, epilepsy in 2 (20%) patients, ataxia in 1 (10%) patient, neurogenic bladder in 2 (20%) patients, and cranial neuropathy in 6 (60) patients affecting the oculomotor (2 patients), abducent (1 patient) and bulbar (5 patients) nerves. The condition was associated with dural sinus thrombosis in 1 (10%) patient and aseptic meningitis in 2 (20%) patients.
Data about the second attack of neuropsychiatric disease in relapsing patients are shown in Table 8.
Table 8
New-onset neurological diagnoses during follow-up in the study cohort
SARD systemic autoimmune rheumatic diseases, SLE systemic lupus erythematosus, APS antiphospholipid syndrome, BD Behçet’s disease, TA Takayasu arteritis, GPA granulomatosis with polyangiitis, n number
Anzeige
Notably, all patients with a history of convulsions within the study cohort had generalized tonic clonic seizures.
Discussion
Neurological manifestations developed 3.73 ± 5.38 years after the disease onset in the lupus cohort. The early onset of neuropsychiatric (NPS) lupus and the tendency to affect younger patients have been reported [10], supporting our finding. The development of new organ system involvement after the first five years of disease onset has been rarely reported [11]. This could be explained by the burden of disease activity and the high cytokine drive noted during the disease evolution.
The most common clinical presentations were seizures (27%), hemiplegia (12.2%), dural sinus thrombosis (12.2%), mixed clinical presentations (12.2%), benign increased intracranial tension (8.7%), psychosis (7.8%) and cerebritis (6.1%).
In agreement with our results, seizures were reported among the most common manifestations of NPS lupus [12]. On the contrary, a lower frequency of seizures was reported in other studies: 11.6% [13] and 17% [10]. A frequency of psychosis similar to ours was reported (7.7%) [14]. On the other side, a higher frequency of 43% was documented by others [13]. A lower prevalence of cerebrovascular accidents (CVA) was reported in one study (7%) [13]. At the same time, a greater prevalence was reported in another (14.5%) [14].
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Only 3.5% of our lupus patients had transverse myelitis; none had an acute confusional state, confirming the rarity of both [7, 14]. Interestingly, ‘longitudinal extensive transverse myelitis’ describes disease characteristics in SLE as rapid and extensive, involving > 2 segments [7].
The vestibulocochlear nerve was our the most commonly involved cranial nerve in our lupus patients. On the contrary, the optic nerve was reported as the most commonly affected one in another study, with different patterns of involvement: ischemic neuropathy, isolated neuritis, and neuromyelitis optica spectrum disorders (NMOSD) [15]. Overall, the vestibulocochlear nerve was the most commonly affected cranial nerve in the study cohort. This could be explained by the high vascularity of the vestibulocochlear system making it susceptible to thrombosis, vasculitis and immune complex deposition [16, 17]. Furthermore, some of the antirheumatic medications are ototoxic [18‐20].
The most common imaging findings in this study were foci of altered signals (50.4%), atrophic changes (27.4%), infarcts/encephalomalacia (26.6%) and dural sinus thrombosis (14.2%). The cerebral cortex and white matter were the regions of predilection (60%). Vascular etiology accounts for lesions in > 70% of patients.
In agreement with the study results, high signal intensity lesions of white matter on T2-weighted images were reported to be the commonest MRI abnormality in NPS lupus [21], with a predilection to the periventricular/subcortical white matter and less commonly the deep grey matter. ‘Lupoid sclerosis’ is a term used to describe multiple sclerosis (MS)-like demyelinating disease in SLE [7]. The following could be used to differentiate SLE from MS: absence of central vein sign, sparing of the corpus callosum, concomitant deep grey matter lesions [7, 15], absence of oligoclonal bands, the existence of pleocytosis and positivity for lupus-specific antibodies favors the diagnosis of SLE. However, oligoclonal bands could be detected in both [21]. Notably, these lesions could be detected with other SARDs and without clinical neurological deficits; they do not necessarily correlate with disease activity or respond to immunosuppression [7, 15].
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Similar to our finding, cerebral infarcts, cortical, subcortical or deep, were reported as a common finding in SLE patients, particularly in association with APS. Ischemic stroke, secondary to APS or cardiac vegetation, is more common than hemorrhagic stroke, secondary to a ruptured aneurysm [21].
In agreement with this study, diffuse cerebral atrophy was reported as a common finding in lupus patients. It usually correlates with disease duration, the presence of antiphospholipid antibodies (aPL), and the development of cognitive dysfunction [15].
Spontaneous intracerebral hemorrhage and posterior reversible encephalopathy syndrome (PRES) syndrome were less commonly reported in SLE patients [2], supporting the study findings.
In this study, 17.7% of symptomatic patients had normal imaging. In this context, Luyendijk and colleagues stated that MRI is mainly informative in the setting of focal neurologic deficits, seizures, chronic cognitive dysfunction, and aPL-related disease, while it is mostly normal in the setting of headaches, acute confusional state and psychiatric syndromes [21]. As a pathogenic mechanism, direct neuronal injury could explain normal neuroimaging with some neurological presentations [15].
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Neurological involvement developed 3.77 ± 4.25 years after disease onset in our BD population. This finding is in agreement with the previous observation that neurological involvement tends to develop 3–5 years after disease diagnosis, rarely the presenting disease feature [15].
Dural sinus thrombosis, isolated cranial neuropathy, hemiplegia, encephalitis and brainstem syndrome developed in 30.6%, 19.1%, 16%, 10.6% and 6.4% of patients, respectively. In agreement with this study, headache and hemiparesis were reported as the main neurological presentations of BD. On the other side, dural venous thrombosis was reported as the most common pattern of neurovascular structural abnormalities [22].
Only 2.1% of our patients had transverse myelitis, which supports the rarity of this presentation. While dorsal segments are commonly affected in SLE patients, the cervical cord is commonly involved in BD, where lesions could extend from the brainstem. As with SLE, cord lesions are extensive, involving > 2 segments. Interestingly, there are two MRI patterns of cord involvement in BD: the common “Bagel sign” lesion of a central hypointense core and a surrounding hyperintense rim on T2 with or without enhancement, and the less common “Motor Neuron” pattern of symmetric involvement of the anterior horn cells [23].
This study’s most common neuroimaging findings were foci/areas of altered signals (45.2%) and dural sinus-filling defects (40.5%). The basal ganglia, diencephalon and brainstem were preferentially affected (46.4%).
In agreement with this result, Tunisian BD patients’ most common MRI abnormalities included lesions of high T2 intensity and T1 iso/hypointensity in the basal ganglia or brainstem (50%) and acute infarcts (42.9%). In contradiction to our results, a lower frequency of dural sinus thrombosis (7%) was reported in Tunisian patients [22]. Arterial occlusion, aneurysms and dissection were less commonly reported in BD [24], a finding consistent with ours.
In agreement with our study, the mesodiencephalic junction and pontobulbar region were reported as common sites of involvement in neuro-BD, while the cerebral hemispheres are less commonly affected in isolation [15].
Although neurological involvement developed a long duration after the APS onset in this study (5 ± 5.77 years), neurological affection could be the presenting feature of the disease [25, 26].
A relapsing disease course was detected in 26.7% of our patients. The high risk of relapse in APS is well known: a thrombotic event is a risk factor for another [25].
The most common clinical presentations in the study cohort were dural sinus thrombosis (36.7%), hemiplegia (33.3%) and seizures (16.7%). In agreement with these results, stroke and transient ischemic attacks (TIAs) were reported as the most common neurological manifestations of APS. Seizures were reported as a common manifestation, particularly in SLE-associated APS [25]. None of our patients had an extrapyramidal disease, which is consistent with the rarity of chorea in APS [26]. On the other side, cerebral venous sinus thrombosis was reported as an uncommon manifestation [27], contradicting our findings.
Ischemic optic neuropathy was reported in one-third of the study patients, a finding that is consistent with the predilection of the disease to this cranial nerve [28].
Only one of the study patients had symptomatic cognitive impairment. Cognitive dysfunction associated with APS could range from subtle dysfunction to dementia. Its underlying pathogenic mechanism is likely related to the development of multiple small vessel infarcts [29]. A relapsing and remitting MS-like disease has been reported in APS [30].
Transverse myelitis was not reported in our APS patients, a rare disease complication commonly associated with SLE [31]. Other reported disease manifestations include acute organic brain syndrome, secondary to fulminant ischemic encephalopathy associated with catastrophic APS, cerebellar ataxia, idiopathic intracranial hypertension [32] and anterior spinal artery syndrome [33].
The most common lesions evident on neuroimaging in this study were dural sinus filling defects (43.3%), infarcts/encephalomalacia (40%) and altered signals (30%). In agreement with the study results, subcortical foci of hyperintensity were reported as the most common imaging abnormalities [34]. Cortical, subcortical or deep lesions secondary to small, medium or large vessel disease could be detected [35]. Notably, infarcts and altered signal intensity lesions could be clinically silent, while normal neuroimaging may be expected in symptomatic patients [29].
The average duration between RA onset and neurological manifestation development was 6.54 ± 5.84 years. Vestibulocochlear neuropathy was the most common clinical presentation. In agreement with these results, several studies reported the common occurrence of isolated cranial neuropathies in RA patients; however, the optic nerve was the most commonly affected cranial nerve as a side effect of tumor necrosis factor inhibitor therapy [36].
The characteristic pattern of neurological involvement in RA patients is myelopathy secondary to atlanto-axial and atlanto-occipital subluxations. Other rare patterns of CNS involvement in RA include pachy/leptomeningitis, hemorrhagic or thrombotic CVA secondary to rheumatoid vasculitis, and compression symptoms secondary to rheumatoid nodules. The lack of these presentations in this study could be explained by the rarity of these complications nowadays with the great advances in treatment [4].
The study included one female patient with PSS and trigeminal neuralgia. Others reported the rarity of neurological affection in PSS patients. Trigeminal neuropathy has been reported as the most common cranial neuropathy in PSS patients [37].
Unexpectedly, CVA in PSS patients has been linked to pulmonary arterial hypertension and scleroderma renal crisis. Spinal cord compression secondary to calcinosis has been rarely reported [37].
The most frequent imaging abnormality in PSS patients is T2 hyperintense white matter lesions. Other less common findings include cerebral atrophy (10%), cortical hyperintense lesions (6%), calcifications (4%), and rarely leptomeningeal enhancement and Moyamoya-like vasculopathy changes [15].
An average duration of 2.75 ± 2.63 years had elapsed between MCTD onset and neurological involvement in our patients. The clinical spectrum in our patients included isolated trigeminal neuralgia, isolated vestibulocochlear neuropathy, hemiplegia and dural sinus thrombosis.
In agreement with the study results, trigeminal neuralgia and primary headache were reported as the most common neurological manifestations in MCTD. Other rare manifestations include psychosis, seizures, aseptic meningitis, transverse myelitis, cerebral infarcts, intracranial hemorrhage, cauda equina syndrome, adhesive arachnoiditis, optic neuritis and NMOSD [38].
The study included one female patient with RPC who presented with a relapsing pattern of isolated vestibulocochlear neuropathy. Cranial neuropathies have been reported as the most common neurological presentations in those patients. Headache, ataxia, hemiplegia, transverse myelitis, aseptic meningitis, and encephalopathy have also been reported [39].
In this study, a female patient with Vogt–Koyanagi–Harada (VKH) syndrome presented with a regressive course of vestibulocochlear neuropathy coinciding with the disease onset. The disease is characterized by an early onset of neurological involvement with the most commonly reported neurological presentations being aseptic meningitis. Other presentations include cranial neuropathies, encephalopathy, and myelitis [40].
The study included two patients with CS presenting with progressive isolated vestibulocochlear neuropathy 0.13 ± 0.18 years after disease onset. Carotid artery thrombosis was accidentally discovered in one. Our results agree with concurrent or sequential ocular involvement and vestibulocochlear neuropathy in patients with typical CS [41].
The study included three patients with GPA. Neurological insults developed 1.8 ± 2.77 years after disease onset. One patient developed hydrocephalus with a relapsing course despite surgical treatment. One patient had relapsing neuropathy involving the vestibulocochlear and facial nerves. The third one had regressive isolated vestibulocochlear neuropathy. Cranial neuropathies were reported as the most common neurological presentations in GPA, with vestibulocochlear neuropathy being the commonest, which is in agreement with our results. Strokes secondary to CNS vasculitis and pachymeningitis have been rarely reported [42].
The study included five patients with neurosarcoidosis. A mean duration of 1.3 ± 1.2 years between disease onset and neurological involvement had elapsed. Three patients had isolated optic neuritis associated with ocular sarcoidosis; one had benign increased intracranial tension; the last had combined benign intracranial tension and vestibulocochlear neuropathy.
The most characteristic presentation of neurosarcoidosis is hypophysitis [43]. Other patterns include cranial neuropathies, parenchymal CNS disease and aseptic meningitis [15].
The facial nerve is the most commonly affected cranial nerve; however, optic nerve involvement is the most frequently evident cranial neuropathy on neuroimaging, a finding that agrees with ours. Communicating, presumably due to ependymal inflammation, and non-communicating hydrocephalus have been reported [15].
The most common brain MRI findings in patients with neurosarcoidosis are treatment-irresponsive, non-enhancing T2/FLAIR white matter lesions. Less commonly, treatment-responsive enhanced parenchymal lesions representing sarcoid granulomas can be seen; they are commonly supratentorial, multiple and subcentimetric [15].
Findings denoting ischemia are uncommon and usually associated with perivascular enhancement following the course of brain perforators supplying the deep structures. Hemorrhagic lesions are also uncommon [15].
Enhanced nodular or smooth meningeal thickening primarily involves the basal portion of the cranium with or without a dural tail could be seen denoting the involvement of pachy/leptomeninges [15].
Involvement of the spinal cord is rare; the cervical and upper thoracic segments are the most commonly affected. Lesions tend to be extensive, affecting > 2 segments. Spinal cord neurosarcoidosis could be intramedullary (the commonest), epidural/intradural extramedullary, or osseous (vertebral). On MRI, intramedullary involvement appears as typical fusiform cord enlargement, with low intensity on T1, high intensity on T2 and patchy enhancement. On axial images, crescent-shaped layering of posterior subpial enhancement accompanied by central canal enhancement gives the characteristic trident sign [44].
Five patients with TA were included in the study, with a mean duration of 2 ± 1.58 years elapsing between disease onset and neurological involvement. Four patients were asymptomatic, with carotid/vertebral artery abnormalities detected on vascular imaging, while one patient had TIAs.
Neurologic symptoms were present in 10 out of 20 (50%) TA patients in a Canadian study. Among them, 30% of patients had a stroke, 10% had TIAs and 25% had visual symptoms with a predilection for the external carotid arteries [45]. This observation is consistent with our findings.
As shown in Table 7, it is evident that some neuroimaging findings are incidental and do not correlate with the clinical presentations reflecting the systemic nature of the disease. In the same context, there were 64 patients with dural sinus thrombosis on neuroimaging. The clinical presentations in those patients were as follows: 56 patients had manifestations of increased intracranial tension in isolation or in combination with other neurological presentations, while the others had incidentally detected dural sinus thrombosis with a different clinical presentation, including epilepsy (2 patients), encephalitis (1 patient), brainstem syndrome (1 patient), hemihypoesthesia (1 patient), intracranial hemorrhage (1 patient), and cranial neuropathy (2 patients).
The study’s power includes screening a large cohort of patients. Moreover, the data were collected from a tertiary care center, ensuring enrollment in the full spectrum of disease neurological presentations, including rare and complicated cases.
Several points should be taken in consideration: (1) The study’s retrospective design allowed only the documentation of symptomatic patients. (2) Due to defective documentation, some data, such as the onset and course of the neurological disease, needed to be included. (3) The reported course of the neurological disease could not represent its natural history as the influence of treatment on the disease course could not be neglected; however, this issue was outside the scope of this study. (4) There were few patients with diseases other than SLE and BD. This could be explained by their relatively low frequency in Egypt [46] and the infrequent CNS involvement in those diseases compared with SLE and BD. (5) CNS involvement was the primary focus of the study. (6) The neuroimaging modalities were not standardized for all patients as this is a retrospective study reflecting real-life practice rather than a controlled research study. Despite that CT was informative in 18 out of those 24 patients with CT, while 6 patients had a normal CT. Patients with normal CT were diagnosed with TIA (1 patient), epilepsy (3 patients), 1 patient with combined psychosis and epilepsy and 1 patient with meningoencephalitis. Overall, the role of CT in the presence of a contraindication for MRI should be appreciated.
Conclusions
Patients with SARDs could present with protean neurological syndromes. Neuroimaging findings do not necessarily correlate with neurological manifestations. Normal neuroimaging cannot exclude CNS involvement and vice versa. Therefore, neuroimaging abnormalities should be interpreted within the context of the patient’s clinical picture and the results of other investigations.
Acknowledgements
Not applicable.
Declarations
Ethics approval and consent to participate
The study was approved by the Research Ethics Committee of ### (N-68-2019) and conformed to the 1995 provisions of the Declaration of Helsinki. Due to the retrospective study design, informed consent was waived. All procedures performed were part of routine care.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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