Stiff-Person Syndrome
Clinical Features
Stiff-Person Syndrome (SPS) is a rare neurological disorder first described
by Moersch and Woltmann in 1956. The syndrome affects both sexes equally
and is of insidious onset, usually in the fourth or fifth decades and
is characterised by stiffness, more prominent in axial muscles, with
co-contraction of agonist and antagonist and painful spasms precipitated
by sensitive stimuli. The disease can progress to involve the proximal
and distal part of the limbs and patients sometimes show symmetric spine
deformity, typically lordosis. Electromyography reveals the existence
of continuous motor unit activity in the affected muscles at rest. The
physiopathology of this syndrome is regarded as a disequilibrium between
catecholaminergic excitatory and GABAergic inhibitory pathways in spinal
cord and central nervous system. Detection of autoantibodies to glutamic
acid decarboxylase (anti-GAD antibodies) in the serum of 60-70% of patients
suggest and autoimmune mechanism of damage in a subgroup of patients;
this is also supported by detection of oligoclonal bands and intrathecal
synthesis of IgG.
Several variants have recently been characterised according to the relative
distribution of clinical signs. “Encephalomyelitis with rigidity”
is characterised by a subacute course leading to death within three
years; “jerking stiff person syndrome” presents a predominant
brainstem involvement ad “stiff limb syndrome” is a focal
form with predominant involvement of the spinal cord.
A paraneoplastic variant has been described in association with breast
cancer in women harbouring anti-amphiphysin antibodies. In those patients
the onset of stiffness in upper limbs is suggestive of a paraneoplastic
aetiology. Autoimmunity to gephyrin, a cytosolic protein at post-synaptic
inhibitory synapses, has been described in association with undifferentiated
mediastinal tumour. SPS has also been reported in association with neoplasia
of the colon and lung, Hodgkin’s disease, thymoma.
Associated antibodies
Anti-GAD antibodies (figure1) are present in 60% of patients
and stain the axon hillocks of Purkinje cells and diffuse nerve terminals
in the molecular and granular layers of cerebellum. In addition, antibodies
to pancreatic islet cells, gastric parietal cells, thyroid microsomes,
and thyroglobulin are frequently found in patients positive for anti-GAD
antibodies. The relationship of autoantibodies to the pathogenesis of
the disease remains to be determined. Anti-GAD antibodies are also present
in patients with insulin dependent diabetes mellitus and autoimmune
polyendocrine syndrome but the anti-GAD level in these syndromes is
usually much lower than in SPS.
| Figure 1. Immunohistochemistry on
frozen sections of rat cerebellum. Anti-GAD antibodies positive
sera recognise the axon hillocks of Purkinje cells and diffuse nerve
terminals in the molecular and granular layer of cerebellum. |
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Anti-amphiphysin antibodies:
(figure 2) are directed to a 128 kd neuronal protein concentrated in
nerve terminals. Rare paraneoplastic SPS present anti-GAD antibodies
alone or associated with anti-amphiphysin antibodies.
| Figure 2. Immunohistochemistry
on paraffin-section of rat cerebellum. Anti-amphiphysin antibodies
positive sera stain diffusely the synaptic terminals in molecular
layer and granular glomeruli. In addition they recognise the membrane
of Purkinje cells. |
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Treatment
Benzodiazepines are an effective therapy for SPS because they modulate
the levels and activity of GABA. A similar mode of action has been proposed
for baclofen, which can be administered orally or via an intrathecal
route. Sodium valproate and vigabatrin are found to be effective therapies
for a few patients; the mechanism of action may be to potentiate GABAergic
synaptic transmission.
Immunosuppressive agents such as steroids, azathioprine; plasmapheresis
and intravenous immunoglobulin are also effective.
Selected references
1. Helfgott SM. Stiff-man syndrome. From the bedside to the bench. Arthritis
& Rheumatism 1999; 42: 1312-1320
2. Brown P, Marsden CD. The stiff man syndrome and stiff man plus syndromes.
J Neurol 1999; 246: 648-652
3. Dalakas MC, Li M, Fujii M, Jacobowitz D. Stiff person syndrome. Quantification,
specificity and intrathecal synthesis of GAD65 antibodies. Neurology
2001; 57: 780-784
4. Solimena M, Folli F, Denis-Domini S, et al. Autoantibodies to glutamic
acid decarboxylase in a patient with Stiff-Man Syndrome, epilepsy, and
type I diabetes mellitus. N Engl J Med 1988; 318: 1012-20
5. De Camilli P, Thomas A, Cofiell R, et al. The synaptic vesicle-associated
protein amphiphysin is the 128-kD autoantigen of Stiff-Man Syndrome
with breast cancer. J Exp Med 1993; 178: 2219-2223
6. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immune globulin
for stiff-person syndrome. New Engl J Med 2001; 345: 1870-1876
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