Autoimmune stiff person syndrome and related myelopathies: understanding of electrophysiological and immunological processes

Stiff person syndrome (SPS) is a disabling autoimmune central nervous system disorder characterized by progressive muscle rigidity and gait impairment with superimposed painful spasms that involve axial and limb musculature, triggered by heightened sensitivity to external stimuli. Impaired synaptic GABAergic inhibition resulting from intrathecal B-cell-mediated clonal synthesis of autoantibodies against various presynaptic and synaptic proteins in the inhibitory neurons of the brain and spinal cord is believed to be an underlying pathogenic mechanism. SPS is most often idiopathic, but it can occur as a paraneoplastic condition. Despite evidence that anti-GAD and related autoantibodies impair GABA synthesis, the exact pathogenic mechanism of SPS is not fully elucidated. The strong association with several MHC-II alleles and improvement of symptoms with immune-modulating therapies support an autoimmune etiology of SPS. In this review, we discuss the clinical spectrum, neurophysiological mechanisms, and therapeutic options, including a rationale for agents that modulate B-cell function in SPS.     

Treatment of stiff person syndrome with rituximab

This case report is about the novel use of the anti-CD20 antibody, rituximab, in the treatment of a 41 year old woman with stiff person syndrome. She was admitted to hospital as an emergency with prolonged and painful extensor spasms affecting the neck and back, arms, and legs. The disease had progressed despite a favourable initial response to conventional treatment with intravenous immunoglobulin and cytotoxics. Treatment with rituximab induced a lasting clinical remission.     

Eye movement abnormalities in stiff person syndrome

The authors describe a 38-year-old woman with stiff person syndrome (SPS) and gaze-holding nystagmus, limited abduction, vertical and horizontal ocular misalignment, deficient smooth pursuit, and impaired saccade initiation. There was no evidence of ocular myasthenia, indicating that abnormalities of ocular motor function can occur as a primary manifestation of SPS, perhaps from depletion of GABA.     

Advances in the pathogenesis and treatment of patients with stiff person syndrome

Advances in the clinical diagnosis, prognosis, pathogenesis, and therapies for stiff person syndrome (SPS), based on observations in more than 50 consecutive patients, are presented. The syndrome varies from mild to severe, but if untreated it can be progressive and disabling. SPS remains a largely underdiagnosed condition. Anti-glutamic acid decarboxylase (GAD) antibodies provide an excellent diagnostic marker, but their role in disease pathogenesis is uncertain. Research focused on identifying new autoantigens has provided evidence that γ-aminobutyric acid (GABA)_A receptor-associated protein (GABARAP), a 14-kD protein localized at the postsynaptic regions of GABAergic synapses, is a new antigenic target. In up to 65% of SPS patients, there are circulating anti-GABARAP antibodies that inhibit the GABA_A receptor expression on GABAergic neurons. This review examines the diagnostic criteria for SPS, SPS variants, common errors in diagnosis, and a step-by-step therapeutic approach, including new advances in therapy.     

Isaacs' syndrome, stiff person syndrome and Satoyoshi disease: pathomechanisms and treatment]

Neurological disorders with characteristic clinical manifestations of painful muscle cramp and stiffness are not infrequent. The immune-mediated mechanism with specific antibodies among these diseases is particularly important for treatment. Isaacs' syndrome (acquired neuromyotonia) is an antibody-mediated potassium channelopathy. The suppression of voltage-gated potassium channel (VGKC) by antibodies induces peripheral nerve hyperexcitability. Antibodies may decrease VGKC density by cross-linking F (ab)2 fractions and increasing the degradation rate of VGKCs. Stiff person syndrome (SPS) and its variants show characteristic symptoms and signs of central nervous system hyperexcitability due to antibodies to the GABA-ergic system such as glutamic acid decarboxylase (GAD), amphiphysin 1 and gephyrin. The role of GAD is the subject of debate, however, recent studies reveal the intrathecal synthesis of GAD which is specific for SPS and appears to impair GABA synthesis. Satoyoshi disease is characterized by painful muscle cramp, baldness, intractable diarrhea, bone and joint deformity, and endocrine disturbances. Muscle cramp may be due to inhibition of the spinal interneuron and hyperexciatability of the anterior horn cell. In patients with Satoyoshi disease, sera reacted with an 85 kDa protein of human brain lysate. In all these disorders, suppression or removal of specific antibodies is critical, however, the effects are short-lived, and supplemental treatment to reduce the hyperexcitability of the peripheral or central nervous system will be needed.     

A neuropsychological assessment of phobias in patients with stiff person syndrome

A neuropsychological assessment was performed in 10 patients with stiff person syndrome (SPS) to determine whether their anxiety and phobic symptoms precede stiffness and spasms or represent a reaction to disability. No neurocognitive dysfunction was noted. Patients perceived fears and anxiety as realistic and caused by SPS rather than due to an inherent phobic neurosis.     

Electrophysiological characteristics in four patients from Brazil with stiff person syndrome

Stiff person syndrome (SPS) is a rare immune-mediated disorder of the central nervous system characterized by muscle rigidity and episodic muscle spasms. The diagnosis of SPS is based on electrophysiological studies. We analyzed the electrophysiological features in four patients from Brazil who fulfilled the clinical criteria for SPS. The most common electrophysiological abnormalities were continuous motor unit activity, co-contracting, and the presence of the cutaneomuscular reflex. Despite all patients having clinical characteristics of SPS during the disease, no patient met all the electrophysiological criteria for SPS even after repeat electrophysiological studies. This shows that a diagnosis of SPS should not be restricted to patients with all the classic electrophysiological changes but should be considered in the presence of one or some of those changes.     

Acute ataxia, Graves' disease, and stiff person syndrome.

Stiff person syndrome (SPS) has been associated with autoimmune diseases, such as Type 1 diabetes mellitus and autoimmune thyroid disease (Hashimoto's thyroiditis), among others. The association of SPS with hyperthyroidism is extremely rare. We describe a patient with uncontrolled Graves' disease and undiagnosed SPS, who presented initially with acute ataxia simulating a cerebrovascular accident. Initiation of immunosuppressive therapy dramatically improved the patient's Graves' disease within 2 weeks but the neurological symptoms were not alleviated after a follow-up period of 3 years.     

Paraneoplastic "stiff person syndrome" with metastatic adenocarcinoma and anti-Ri antibodies

A 43-year-old woman presented with clinical and electrophysiologic features of stiff person syndrome (SPS), without abdominal or lumbar paraspinal muscle involvement. Investigations revealed metastatic adenocarcinoma of the lung with positive anti-Ri antibodies. Her clinical condition improved with diazepam, baclofen, tizanidine, and palliative chemotherapy. Screening for an underlying malignancy and anti-Ri antibodies should be considered in patients with SPS when clinical presentation is atypical.     

The stiff leg syndrome.

Four patients had a chronic progressive disorder beginning in middle age and involving stiffness and painful spasms of the lower limbs. Spasms were spontaneous, reflex, and induced by voluntary movement. Patients had rigidity and abnormal postures of one or both legs. There was no truncal rigidity or exaggerated lumbar lordosis. Despite the presence of symptoms for up to 16 years, symptoms and signs of brainstem, pyramidal, and sensory dysfunction were absent. Sphincter disturbance developed after many years in one patient. Extensive investigation, including imaging of the whole neuroaxis, failed to disclose a cause. Anti-GAD antibodies were absent. Baclofen and diazepam led to some reduction in the painful spasms, but patients remained disabled by the condition. There were four core electrophysiological features. (1) Continuous motor unit activity was present at rest in at least one limb muscle. (2) Spasms tended to involve the repetitive grouped discharge of motor units. (3) Cutaneomuscular reflexes were abnormal. (4) There was little or no electrophysiological evidence of long tract disturbance. The patients form a characteristic syndrome, separate from the stiff man syndrome, and distinguishable from encephalomyelitis with rigidity. It is suggested that the condition is due to a chronic spinal interneuronitis.     

GAD antibody positive paraneoplastic stiff person syndrome in a patient with renal cell carcinoma

Stiff person syndrome (SPS) is an unusual cause of muscle rigidity and spasms. It is believed to have an autoimmune pathogenesis and is associated with autoantibodies to glutamic acid decarboxylase (GAD). Paraneoplastic SPS (PSPS) has been described mainly in relation to breast cancer and is associated with antibodies to amphiphysin. Few reports of PSPS document the finding of GAD autoantibodies. We present the first reported case of anti‐GAD positive PSPS in a 53‐year‐old male with occult renal carcinoma. Clinical benefit was marked following nephrectomy and intravenous immunoglobulin treatment. Renal carcinoma should be considered in patients with SPS. © 2007 Movement Disorder Society     

GAD65 IgG autoantibodies in stiff person syndrome: clonality, avidity and persistence

Background and purpose:  Persistent intrathecal production of IgG autoantibodies against glutamic acid decarboxylase 65 (GAD65 IgG) and oligoclonal IgG of undetermined specificity has been reported in stiff person syndrome (SPS).
Methods:  To chart the avidity and clonal patterns of GAD65 IgG, we performed scatchard plot of binding characteristics and isoelectric focusing-immunoblot of cerebrospinal fluid (CSF) and serum from five SPS patients.
Results:  Oligoclonal GAD65 IgG bands, predominantly restricted to the IgG1 subclass, were detected in CSF and serum in all patients. The distribution of GAD65-specific IgG bands in serum and CSF revealed intrathecal synthesis of oligoclonal GAD65 IgG in all five patients, whilst radioimmunoassay demonstrated intrathecal synthesis of GAD65 IgG in four. The binding avidity of GAD65 IgG from CSF was more than 10 times higher than in serum in two of the patients but did not differ substantially in the remaining three. These differences were not related to symptom severity. The pattern of oligoclonal GAD65 IgG bands in CSF and serum in three patients examined remained unchanged for up to 7 years after symptom debut.
Conclusion:  This study confirms the persistent systemic and intrathecal production of GAD65-specific IgG in SPS, and further shows that this immune response is oligoclonal and mediated by a stable population of affinity maturated B cell clones.