Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all...

Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System

Objective: To evaluate the clinical spectrum of anti-GAD-positive patients with stiff-person syndrome (SPS) and provide reproducible means of assessing stiffness. Background: SPS can be difficult to diagnose. Delineation of the clinical spectrum in a well defined population will increase diagnostic sensitivity. Methods: In 20 anti-GAD-positive patients with SPS (six men, 14 women), screened among 38 referred patients, the authors assessed symptoms and signs, degree of disability, associated conditions, and immunogenetic markers. Degree of bending, distribution of stiff areas, timed activities, and magnitude of heightened sensitivity were examined monthly for 4 months in five patients. Results: Average age at symptom onset was 41.2 years. Time to diagnosis was delayed from 1 to 18 years (mean 6.2). Stiffness with superimposed episodic spasms and co-contractures of the abdominal and thoracic paraspinal muscles were characteristic. All had stiff gait and palpable stiffness in the paraspinal muscles. Stiffness was asymmetric or prominent in one leg in 15 patients (stiff-leg syndrome) and involved facial muscles in 13. In one patient spasms lasted for days (status spasticus). Twelve patients needed a cane and seven a walker due to truncal stiffness and frequent falls (average three to four per month). Distribution of stiffness and degree of heightened sensitivity were two reproducible indices of stiffness and spasms. Autoimmune diseases or autoantibodies were noted in 80% and an association of with DRβ 1 0301 allele in 70%. Conclusions: SPS is 1) frequently misdiagnosed due to multifaceted presentations and asymmetric signs, 2) disabling if untreated, and 3) associated with other autoimmune conditions.–1535

https://n.neurology.org/content/neurology/55/10/1531.full.pdf

The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome.

The stiff man syndrome (SMS) and its variants, focal SMS, stiff limb (or leg) syndrome (SLS), jerking SMS, and progressive encephalomyelitis with rigidity and myoclonus (PERM), appear to occur more frequently than hitherto thought. A characteristic ensemble of symptoms and signs allows a tentative clinical diagnosis. Supportive ancillary findings include (1) the demonstration of continuous muscle activity in trunk and proximal limb muscles despite attempted relaxation, (2) enhanced exteroceptive reflexes, and (3) antibodies to glutamic acid decarboxylase (GAD) in both serum and spinal fluid. Antibodies to GAD are not diagnostic or specific for SMS and the role of these autoantibodies in the pathogenesis of SMS/SLS/PERM is the subject of debate and difficult to reconcile on the basis of our present knowledge. Nevertheless, evidence is emerging to suggest that SMS/SLS/PERM are manifestations of an immune-mediated chronic encephalomyelitis and immunomodulation is an effective therapeutic approach. © 2002 Movement Disorder Society

Stiff man syndrome and related conditions.

The stiff-person syndrome, a rare and disabling disorder, is characterized by muscle rigidity and episodic spasms that involve axial and limb musculature. Continuous contraction of agonist and antagonist muscles caused by involuntary motor-unit firing at rest are the hallmark clinical and electrophysiologic signs of the disease. Except for global muscle stiffness, results of neurologic examination are usually normal. Results of conventional computed tomography and magnetic resonance imaging of the brain are also normal. The cause of the stiff-person syndrome is unknown; however, an autoimmune pathogenesis is suspected because of 1) the presence of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of the inhibitory neurotransmitter g-aminobutyric acid (GABA); 2) the association of the disease with other autoimmune conditions; 3) the presence of various autoantibodies; and 4) a strong immunogenetic association. Anti-GAD antibodies, which are found in high titers in most patients, seem to be directed against conformational forms of GAD. New evidence suggests that these antibodies may be pathogenic because they interfere with the synthesis of GABA. In addition, a reduction in brain levels of GABA, which is prominent in the motor cortex, has been demonstrated with magnetic resonance spectroscopy in patients with the stiff-person syndrome. The stiff-person syndrome is clinically elusive but potentially treatable and should be considered in patients with unexplained stiffness and spasms. Drugs that enhance GABA neurotransmission, such as diazepam, vigabatrin, and baclofen, provide mild to modest relief of clinical symptoms. Immunomodulatory agents, such as steroids, plasmapheresis, and intravenous immunoglobulin, seem to offer substantial improvement. Results of an ongoing controlled trial will elucidate the role of these agents in the treatment of the disease. Ann Intern Med. 1999;131:522-530.

The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid.

Phenotypic heterogeneity of sporadic Creutzfeldt-Jakob disease (CJD) has been linked to biochemically distinct types of the protease-resistant form of the prion protein (type 1 and type 2 PrP(Sc)). We investigated 14 cases of sporadic CJD and found that both type 1 and type 2 PrP(Sc) coexisted in 5 subjects. The distinct PrP(Sc) isoforms were associated with different patterns of PrP deposition and severity of spongiform changes, suggesting that the PrP(Sc) type plays a central role in determining the neuropathologic profile of CJD.

Sporadic Creutzfeldt-Jakob disease: co-occurrence of different types of PrP(Sc) in the same brain.

Objective: To test inhibitory spinal circuits in patients with stiff-person syndrome(SPS). Background: Patients with SPS have fluctuating muscle stiffness and spasms, and most have antibodies against GABAergic neurons. We predicted they would also have abnormalities of spinal GABAergic circuits. Design/Methods: Physiologic methods using H-reflexes were used to test reciprocal inhibition in the forearm and thigh, vibration-induced inhibition of flexor carpi radialis and soleus H-reflexes, recurrent inhibition, and nonreciprocal(1b) inhibition of soleus H-reflexes. Results: Vibration-induced inhibition of H-reflexes was diminished in eight of nine patients tested, but the presynaptic period of reciprocal inhibition was normal in most patients. Both circuits are presumed to involve presynaptic inhibition and GABAergic interneurons. Presumed glycinergic circuits, including the first period of reciprocal inhibition and nonreciprocal (1b) inhibition, showed occasional abnormalities. Recurrent inhibition was normal in all five patients tested. Conclusion: Differences between the two presumptive GABAergic circuits may indicate that not all populations of GABAergic neurons are uniformly affected in SPS. The involvement of presumptive glycinergic circuits in some patients could point to impairment of nonGABAergic neurons, unrecognized involvement of GABAergic neurons in these inhibitory circuits, or, more likely, alterations of supraspinal systems that exert descending control over spinal circuits.

D. Jacobowitz

Papers

Physiologic studies of spinal inhibitory circuits in patients with stiff-person syndrome.