Association of stiff-person syndrome with autoimmune endocrine diseases

Table 1 Clinical features of patients with stiff-person syndrome

Characteristic	Total number	Classical SPS	SLS
Number of patients (n)	14	12	2
Male (%)	9 (64.3)	7 (58.3)	2 (100)
Age of onset (yr)	39.3 (28.0-54.0)	35 (26.0-56.0)	46.7
Follow-up duration (yr)	6 (2.7-13.3)	9 (2.1-14.9)	4.3
Clinical feature
Low back stiffness and spasm (n)	12	12	0
Lower limb stiffness and spasm (n)	14	12	2
Lumbar lordosis (n)	8	8	0
Neck stiffness and spasm (n)	9	9	0
Upper limbs stiffness and spasm (n)	10	10	0
Abdominal wall stiffness and spasm (n)	11	11	0
Falls (n)	10	8	2
Exacerbating factors
Cold, noises, and emotional stress (n)	14	12	2
Excessive startle (n)	9	8	1
Neurological/psychiatric feature
Seizure/epilepsy (n)	2	2	0
Gait disturbances (n)	12	10	2
Parkinsonism (n)	2	2	0
Alzheimer’s disease (n)	2	2	0
Depression (n)	5	4	1
Anxiety (n)	8	7	1
Panic disorder (n)	2	2	0

SPS: Stiff-person syndrome; SLS: Stiff limb syndrome; GAD: Glutamic acid decarboxylase.

Table 2 Autoimmune diseases and autoantibodies associated with stiff-person syndrome

Variable	Classical SPS	SLS
Number of patients (n)	12	2
Associated disease
≥2 coexisting autoimmune diseases (n)	1	0
Type 1 diabetes mellitus (n)	2	0
Latent autoimmune diabetes in adults (n)	1	0
Autoimmune thyroid disease (n)	2	0
Sjögren syndrome (n)	1	0
Myasthenia graves (n)	1	0
Malignancy1 (n)	1	0
Thymoma (n)	1	0
Other disease (n)	12	nil
Associated autoantibody (n/N)3
GAD antibody	3/7	0/2
IA-2 antibody	0/2	nil
Anti-TPO	2/5	nil
ATA	1/1	nil
Ach-R antibody	1/1	nil
ANA	1/1	nil
Anti-Ro antibody	1/1	nil

¹One patient had lung cancer.

²One patient had type 2 diabetes mellitus.

³Number of patients positive for the associated antibody/number of patients tested for the associated antibody. SPS: Stiff-person syndrome; SLS: Stiff limb syndrome; GAD: Glutamic acid decarboxylase; IA-2: Islet antigen 2; TPO: Thyroid peroxidase; ATA: Anti-thyroglobulin antibody; AchR: Acetylcholine receptor; ANA: Anti-nuclear antibody.

Table 3 Correlation of associated diseases and glutamic acid decarboxylase autoantibodies among stiff-person syndrome patients

Subgroup	Seropositive		Seronegative		Unknown
	Classical	SLS	Classical	SLS	Classical	SLS
Patient number	3	0	4	2	5	0
Type 1 diabetes mellitus	1	0	0	0	1	0
Latent autoimmune diabetes in adults	1	0	0	0	0	0
Autoimmune thyroid disease	2	0	0	0	0	0
Sjögren syndrome	0	0	1	0	0	0
Myasthenia graves	0	0	1	0	0	0
Malignancy1	0	0	1	0	0	0
Thymoma	0	0	1	0	0	0
Type 2 diabetes mellitus	0	0	0	1	0	0

¹Lung cancer with paraneoplastic syndrome. SPS: Stiff-person syndrome; SLS: Stiff limb syndrome; GAD: Glutamic acid decarboxylase.

Table 4 Summary of two stiff person syndrome cases associated with autoimmune diabetes

	Case 1: T1DM	Case 2: LADA
Gender	Female	Male
Age of diagnosis of DM	43	30
Age of diagnosis of SPS	32	33
Age of requirement for insulin	43	42
HbA1c at diagnosis of DM (%)	13.2	13.1
Basal C-peptide (ng/mL)	0.31	0.26
Glucagon-stimulated C-peptide (ng/mL)	0.6	0.41
Initial GAD Ab (U/mL) (Ref < 1 units)1	1496 (before T1DM)	110 (before LADA)
GAD-Ab titer before receiving plasmapheresis (U/mL) (Ref < 5 units)2	> 2000 (after T1DM)	> 2000 (after LADA)
GAD-Ab titer after receiving plasmapheresis (U/mL) (Ref < 5 units)2	> 2000	> 2000
IA2 antibody (U/mL) (Ref < 7.5)	0.97	0.65
Anti-TPO (IU/mL) (Ref < 5.6)	< 1.0	18.81
Medications	Diazepam, clonazepam, baclofen, lamotrigine, azathioprine	Diazepam, clonazepam, baclofen, tizanidine
IVIG	No	Yes (IVIG 0.4/kg/d)
Plasmapheresis	Yes, 10 times	Yes, 15 times

¹Radioimmunoassay;

²Enzyme -linked immunosorbent assay. SPS: Stiff-person syndrome; T1DM: Type 1 diabetes mellitus; LADA: Latent autoimmune diabetes in adults; GAD: Glutamic acid decarboxylase; IA-2: Islet antigen 2; TPO: Thyroid peroxidase; IVIG: Intravenous immunoglobulin.

Table 5 Coexisting diseases and related autoantibodies in stiff-person syndrome patients

Autoimmune disease	Associated antibody	Neoplasm	Associated antibody
Type 1 DM	Anti-GAD Anti-IA2	Breast cancer	Gephyrin
LADA		Lung cancer	Amphiphysin
Hashimoto’s thyroiditis	Anti-TPO, ATA, anti-TSHR	Thyroid cancer	ATA
Graves’ disease		Colon cancer
Pernicious anemia	Anti-parietal cells	Renal cell carcinoma
Celiac disease	Anti-transglutaminase antibodies (anti-tTG), anti-endomysial antibodies	Thymoma	Anti-AchR
Myasthenia graves	Anti-AchR	Neuroendocrine tumor
Sjögren syndrome	ANA, anti-Ro	Hodgkin lymphoma
Systemic lupus erythematosus	ANA, ds-DNA	Multiple myeloma
Vitiligo
Autoimmune polyglandular Syndrome type 1 or type 2 or type 3

DM: Diabetes mellitus; LADA: Latent autoimmune diabetes in adults; GAD: Glutamic acid decarboxylase; IA-2: Islet antigen 2; TPO: Thyroid peroxidase; ATA: Anti-thyroglobulin antibody; AchR: Acetylcholine receptor; ANA: Anti-nuclear antibody; TSHR: Thyroid-stimulation hormone receptor.