Introduction

The stiff-man syndrome (SMS, also known as stiff-person syndrome) is a rare central nervous system autoimmune disease, but is likely underrecognized. This disorder has only been rarely reported in children. Most of the available literature is in case report form, and a recent series from the Mayo Clinic reported 8 cases identified over a 25-year period. These patients were frequently diagnosed initially with other disorders, including dystonia, musculoskeletal disorders, and functional disorders. In this chapter, we will review the clinical features, both neurological and immunological, as well as electrophysiological findings. We will also discuss differential diagnosis of SMS among children. There will be some discussion regarding pathophysiology. Finally, we will review current treatment options (symptomatic and immunotherapeutic) and prognosis.

Historical Perspective

In 1956 Moersch and Woltman reported 14 patients (all adults) who presented to the Mayo Clinic with chronic fluctuating truncal and limb muscle rigidity and spasms; 8 were men. They encountered their first case in an Iowan farmer in 1924, and acquired the other cases over the subsequent 32 years before publishing the report. The authors named the disorder “stiff-man syndrome,” noting that muscle involvement was “fairly symmetrical,” the lower extremities were affected more commonly than the upper extremities, and proximal limb segments were affected more severely. In 12 patients, back and abdominal muscles were involved (“hard,” “firm,” “board-like”) but 2 lacked truncal symptoms. There was frequently significant disability from painful spasms and falls, and many patients had fixed spinal deformities from long-standing rigidity. Chest wall spasms caused respiratory impairment in some patients. In 1963, it was reported that diazepam brought about considerable improvement in stiffness and spasms of affected patients, a phenomenon that was incorporated into diagnostic criteria for SMS. Distinctive neurophysiological findings were also reported and localized the disorder to hyperexcitability of brainstem and spinal motor neurons. In 1988, De Camilli and colleagues recognized that SMS was an organ-specific autoimmune disorder, recognizing seropositivity of most patients for a neuroendocrine autoantibody specific for glutamic acid decarboxylase 65-isoform (GAD65). This same antibody was subsequently recognized to also be a marker of a much more common autoimmune disease, type 1 diabetes mellitus.

Since the original description, more limited forms of SMS (sometimes paraneoplastic) including “stiff-limb” and “stiff-trunk” have been reported (often GAD65 Ab seronegative). Furthermore, some with high GAD65 Ab values have other neurological disorders coexisting with SMS, including epilepsy, cerebellar ataxia, brainstem disorders, and myelopathies. Another form has been described as rapidly progressive with diffuse CNS findings known as progressive encephalomyelitis with rigidity and myoclonus (PERM). These patients frequently have whole body symptoms, and eye and bulbar signs in addition to more classic SMS symptoms. Other autoantibody markers that have been discovered and aid the diagnosis of the SMS spectrum include amphiphysin-IgG (only in adults), detected in patients with paraneoplastic neurological autoimmunity associated with breast adenocarcinoma or small-cell lung carcinoma, and glycine receptor α1 subunit (GlyRα)-IgG, which was first encountered in patients with the PERM phenotype but is also encountered among 20% of patients with SMS, both GAD65-IgG positive and negative cases.

The pediatric stiff-man literature is limited to 1 series of 8 patients and 12 other reported cases, and many of the data discussed herein also pertains to the adult literature.

Epidemiology

SMS is very rare, even in adults; in one review, the prevalence was estimated at approximately 1 in 1,250,000. In one large series of stiff-man patients, 68% were female and 90% were white, with a median age of symptom onset at 40 years old. In that series, 67% had at least one additional autoimmune disease, 43% had type 1 diabetes mellitus and 35% had autoimmune thyroid disease. The frequency of SMS in the pediatric population is unknown. Clardy et al. identified only 8 patients with pediatric-onset SMS in the Mayo Clinic from 1984 to 2012, representing 5% of the total SMS cases during that time period. Of these patients, the median age of onset was 11 years, and half were female. Half of those children had type 1 diabetes mellitus. Only 12 additional individual cases of pediatric SMS have been reported in the literature.

Pathophysiology

Convergent clinical, serological, and electrophysiological evidence is indicative of SMS being an autoimmune disease of CNS inhibitory synaptic signaling. Patients have symptoms of exaggerated startle, and continuous muscle contractions, consistent with a loss of inhibitory control at a brainstem and spinal cord level. More often than not, SMS patients have a coexisting autoimmune disease, including type 1 diabetes. There is an association between SMS and the DQB1*0201 allele, which is also a susceptibility allele for type 1 diabetes mellitus. Also, 80% of SMS patients are seropositive for GAD65-IgG, an antibody that is also detected in 90% of patients with type 1 diabetes. This serological finding implicates autoimmunity directed against GABA synthesis. Other antigens pertinent to inhibitory synaptic transmission implicated in SMS pathophysiology include the α1 subunit of the glycine receptor, GABA receptor associated protein (GABARAP), gephyrin (1 patient described), and amphiphysin (relevant to paraneoplastic disorders in adults).

GAD65-IgG ( Figure 11.1 ) recognizes a cytoplasmic-facing synaptic vesicle protein, and thus is unlikely to be pathogenic. Consistent with this, responses to antibody-depleting therapies in SMS patients seropositive for GAD65-IgG are variable, and post-therapy normalization is uncommon. IgGs specific for cytoplasmic and nuclear autoantigens are considered surrogate markers of inflammatory organ-specific autoimmune disorders mediated by cytotoxic T cells, a hypothesis supported by autopsy findings in some SMS patients. In contrast, the glycine receptor is a cell surface antigen, and thus is accessible to antibody. Although the pathogenicity of GlyRα1-IgG is yet unproven ( Figure 11.2 ), detection of this may predict immunotherapy-responsiveness. In one series, immunotherapy responses were noted more frequently in GlyRα1-IgG-positive SMS patients (6 of 7 improved) than in seronegative patients (7 of 25 improved). Similar responses to immunotherapy have also been documented for other neurological disorders characterized serologically by IgGs that target neuronal cell surface proteins. GABARAP antibody is detected primarily in patients who are also GAD65-IgG seropositive.

GAD65-IgG detected by indirect immunofluorescence on mouse cerebellum, A , and other brain regions (coronal section), B. Characteristic synaptic staining pattern is most prominent in the granular layer (GL) of cerebellum and globus pallidus (Gp). Less intensely stained regions include molecular layer of cerebellum (ML), thalamus (Th), caudate and putamen (C/P), hippocampus (Hi) and cerebral cortex (Cx).

Reproduced with permission from Lippincott, Williams and Wilkins.

GlyRα1-IgG demonstrated in HEK293 cells expressing the human GlyRα1 subunit. The reactivity of serum from two representative patients with HEK293 cells expressing the human GlyRα1 subunit is shown in panels A and D . Serum from a control patient lacks reactivity with transfected cells ( G ). Panels B , E and H show the reactivity with a commercial GlyRα1 monoclonal antibody. Note that the immunostaining co-localizes with that of patient antibodies ( C and F , but not I ). Scale bar, 20 μm.

Reproduced with permission from the American Medical Association.

Neurophysiology studies of SMS confirm a CNS hyperexcitable phenotype with impaired inhibition of H-reflexes and excessive, poorly habituating motor activity in response to acoustic startle.

Neurological Presentation

Symptom onset is characteristically acute or subacute in all (see Case Examples 11.1–11.3 ). Lower extremity stiffness or spasms causing gait difficulties are the most common initial symptoms. Other axial presenting symptoms include isolated severe lumbar paraspinal muscle spasms resulting in marked lumbar lordosis, intrascapular muscle spasms, and midthoracic back pain. Reported presentations also include exaggerated startle, limb muscle cramps, and breathing difficulties when exercising. Respiratory failure due to chest wall spasms is a rare complication. Abdominal pain due to muscle spasms is also common. Emotional stress, startle and anxiety may precipitate or worsen symptoms, and can lead to falls. One patient has been reported to have exaggerated startle and limb symptoms brought on by being asked to speak in front of the class at school. This frequently resulted in falling over “stiff as a board” without protective reflexes, resulting in facial injury.

The principal exam findings are of stiffness (increased muscle tone) in affected parts of the body, usually limbs and lower back. The classic exaggerated lumbar lordosis should not resolve completely with forward flexion or lying supine. Paraspinal muscles may be hypertrophied and tense to palpation. At initial evaluation, myelopathic findings (usually isolated brisk deep tendon reflexes) are documented in over half of patients. Rare manifestations include a focal jerking limb. Coexisting neurological disorders (reported only in adults to date) include epilepsy, parkinsonism, and peripheral neuropathy (mainly in those with diabetes mellitus).

Three main phenotypes are recognized. Classic SMS patients have stiffness and spasms largely confined to the low back and proximal lower extremities. Variants may include patients with stiffness and spasms confined to one lower extremity (“stiff-limb”) or the axis (“stiff-trunk”), and patients with whole body spasms. This latter group of patients includes those with progressive encephalomyelitis with rigidity and myoclonus (PERM), a severe disorder characterized by one or more of the following: encephalopathy, brainstem signs, and myelopathy, as well as axis and limbs stiffness and spasms. All three phenotypes have been reported in children.

Coexisting Autoimmune Diseases

Other autoimmune diseases are commonly encountered among patients with GAD65-IgG positive SMS, particularly type 1 diabetes and autoimmune thyroid disease. In one large series of adults and children, 67% had ≥1 coexisting autoimmune disease. The onset of diabetes may predate or postdate the onset of SMS. Among the Mayo pediatric SMS series, 5 of 8 patients had a coexisting autoimmune disorder and all were GAD65-IgG positive. Four patients had type 1 diabetes mellitus, 2 patients had thyroid disease and 2 patients had vitiligo. Of the 4 pediatric SMS patients with diabetes mellitus, the diagnosis of diabetes preceded the onset of SMS symptoms in 2 patients, and in 2 patients diabetes was diagnosed after the first onset of SMS. Other autoimmune diseases both organ specific (premature ovarian failure, Addison disease, Sjögren’s syndrome, and celiac disease) and non-organ specific (systemic lupus erythematosus) have been reported to coexist with SMS. In contrast, just 4 of 12 pediatric SMS patients reported individually in the literature had GAD65-IgG positivity and just one had a coexisting autoimmune disease (type 1 diabetes).

In the Mayo Clinic pediatric series, serological testing revealed GAD65-IgG in 7 patients (median value, 754 nmol/L; range, 0.06–3847 nmol/L; normal value 0.00–0.02 nmol/L). GlyRα1-IgG was detected in 3 of 8 patients (1/7 was positive in serum, 2/3 were positive in CSF). One or more other autoantibody specificities were detected in 3 patients: antinuclear antibody, 2; thyroid peroxidase antibodies, 2; insulin antibody, 1.

Oncological Findings

Cancer has not been reported among pediatric patients with SMS. Indeed cancer has only been rarely reported among adult patients with GAD65-IgG positive SMS. In the Mayo series, among 99 patients, both adults and children, just 3 had carcinoma (thyroid, renal cell, and colon). Other rare single case reports among GAD65 antibody-positive SMS patients include carcinoma of kidney and breast, neuroendocrine carcinoma, and thymoma. Among GlyRα1-IgG-positive patients, only a minority (1 of 10 in 1 series) have cancer detected. Reported oncological associations include Hodgkin lymphoma, thymoma, and lung cancer.

Differential Diagnosis

Disorders that increase muscle tone, whether producing spasticity or rigidity, can be mistaken for SMS. One of these disorders is hereditary hyperekplexia, a disease that is present at birth and is characterized by baseline increased muscle tone, which disappears during sleep. Hyperekplexia is also characterized by an overactive startle response, resulting in increased rigidity. In most cases, symptoms improve markedly after the first year of life, but residual milder symptoms, including rigidity in response to startle, can persist throughout life. This is a genetic disorder; the most common gene mutation is in the GLRA1 gene, which encodes the α1 subunit of the glycine receptor. These mutations uncouple receptor binding from the chloride channel function, disrupting normal neuronal inhibitory pathways. The other identified genes are SLC6A5, GLRB, GPHN , and ARHGEF9 .

Dystonic disorders may have some similarities to SMS. Dopa-responsive dystonia (Segawa’s disease) is due to a defect in the GTP-cyclohydrolase I gene. Early presentation includes an abnormal gait with posturing of a lower extremity, which can worsen later in the day and with exercise. Over time, more widespread clinical features with parkinsonism become more apparent, and can be helpful in distinguishing this entity. One large study of 66 patients reported the mean age of onset as 6.5 years. Identification of this disorder is important, given the marked symptomatic response to levodopa in these patients. Spinal fluid evaluation, which shows low homovanillic acid, biopterin, and neopterin levels (dopamine metabolites) can be useful when this diagnosis is suspected. Early-onset primary dystonia (DYT1) can present with limb posturing and eventually progress to other limbs in a more generalized form. This is an autosomal dominant disorder, caused by a mutation in the TOR1A gene, but has low penetrance (~30%), so a clear family history may not be present.

Hereditary spastic paraparesis (HSP) is a familial condition which results in spasticity, predominantly involving the lower extremities. There are multiple genes identified, and the pattern of inheritance may be autosomal dominant, autosomal recessive, or X-linked. This can present in childhood, and an SPG3 mutation should be considered in autosomal dominant childhood onset HSP; this can also be associated with peripheral neuropathy, optic atrophy, and seizure activity. Isaac’s syndrome is characterized by muscle stiffness, often involving the trunk as well as limbs; this usually presents in adulthood but can also be seen in childhood, and can be associated with voltage-gated potassium channel complex antibodies. Schwartz-Jampel syndrome is an autosomal recessive genetic disorder that can result in muscle stiffness, usually presenting within the first few years of life. It is typically associated with skeletal and cartilage deformities and a dysmorphic appearance, which can be an important clue to diagnosis. EMG can show continuous motor activity and myotonia. This is caused by a defect in the HSPG2 (perlecan) gene.

Tetanus is a rare disease in the United States because of widespread vaccination, but can occur after infection of even a minor wound by Clostridium tetani . This disease can result in spasms of muscles, including trismus, which can be stimulus sensitive. Patients can have opisthotonus, with profound spasms of paraspinal muscles. Infection can also be accompanied by fever and autonomic instability. A very early case in the literature of SMS in a child was initially felt to represent recurrent tetanus. Dystonic drug reactions should be considered if there is a time link to drug exposure. Strychnine poisoning (primarily from exposure to rodenticides) could be considered. Strychnine inhibits glycine receptors, leading to muscle spasms including opisthotonus, which can be stimulus sensitive.

Testing