Download Stiff Person Syndrome

Stiff Person’s Syndrome
History and pathophysiology:
-First described by Moersch and Woltman in 1956, as “Stiff-Man Syndrome”
-14 patients with fluctuating, but progressive rigidity, and painful muscle spasm leading to gait
difficulties, falls and a ‘wooden-man’ appearance
-Anti-GAD association discovered by Solimena et al in 1988
-Glutamic acid decarboxylase (GAD) is rate-limiting enzyme to make GABA
-Prevalence: One in a million
-Average age of onset: 40 (usually between age 20-50)
-Women > men in 2:1 ratio (hence changing name from Stiff Man to Stiff Person in 1991)
-Associated with a variety of other autoimmune conditions
Symptoms:
•
Gradually progressive fluctuating rigidity of axial muscles (namely abdomen and
thoracolumbar region) and proximal limbs (legs >arms) that eventually becomes constant.
– This can produce a slowness resembling PD
– Often lessens/remits in sleep
•
Superimposed stimulus-sensitive painful muscle spasms (startle, sudden movements, strong
emotions)
•
Classic hyperlordosis with board-like abdomen.
•
Can be asymmetric, limb-predominant, and frequently involves facial muscles too; often with
episodes of breathing difficulty resulting from combination anxiety and chest tightness.
•
Frequently associated with imbalance/falls; gait is often slow and imbalanced due to
combination of anxiety/fear and stiffness. Falls are often “tree-like”.
•
Also can present with eye movement abnormalities, and significant
phobias/agoraphobia/anxiety/depression
•
Watch for autonomic crises (10% of SPS have sudden death)
DDx:
-Stiff Leg Syndrome (+ GAD65, but limited to one leg, no spine involvement)
-Parkinson’s or Parkinson Plus condition
-Hyperekplexia or similar condition/channelopathy NOS
-Dystonia (paroxysmal kinesiogenic/nonkinesiogenic or otherwise)
-PERM (Progressive encephalomyelitis with rigidity and myoclonus)
-Hereditary Spastic Paraparesis
-Spinal cord process (myelopathy, AVM)
-Neuromuscular (MND, Neuromyotonia, HSP, myelopathy, etc)
-Functional Movement Disorder
-Tetanus
Workup:
-Initial labs/studies: GAD65, HA1C/GTT, CMP, CBCPD, CPK, ESR/CRP, MRI brain/spine, trial of
valium.
-If positive GAD65: TSH, ANA, ENA-10, ESR/CRP, celiac panel, thyroid antibodies, etc.
-If negative GAD65: Amphyphisin/paraneoplastic panel, check for cancer.
-Consider: LP (basic stuff + o-bands/IGG index and GAD-65), EMG
One potential diagnostic criteria for Stiff Person Syndrome:
Major criteria
1. Stiffness in the axial and limb muscles, prominently in the abdominal and
thoracolumbar paraspinal muscles leading to a fixed deformity
2. Superimposed painful spasms precipitated by unexpected noises, emotional stress, or tactile stimuli
3. Simultaneous muscle activity in agonist and antagonist muscles.
4. Absence of other neurological disorders or cognitive impairment that could
explain the stiffness
Minor criteria
5. Positive anti-GAD65 (or antiamphiphysin) antibodies in serum, assessed by
immunocytochemistry, Western blot or radioimmunoassay
6. Clinical response to benzodiazepines
-High titers of Anti-GAD65 antibody in 80% of cases, but GAD-65 can also cause a lot of other
neurologic conditions too (cerebellar ataxia, seizures, limbic encephalitis). Can also be seen in Type
1 diabetes, but if GAD65 is found in CSF, it is specific for neurologic disease.
-Other possible antibodies causing SPS include anti-GABARAP (65%), or anti-amphiphysin (10%,
associated with breast cancer)
-Look for other concomitant autoimmune diseases (DM1 and thyroid, in particular)
Tx:
1) GABA agonists: Benzos (usually valium 40-100mg/day; could do PR as rescue) > baclofen (1060mg/day); also consider Botox (if focal issues)
2) IVIG (often still need to be on benzo too)
3) Steroids, PLEX, Rituximab, Cellcept
4) Intrathecal baclofen pump (as rescue therapy for severe cases)
-Also, physical therapy regardless.
References:
-Excellent review on GAD-65 conditions: “Stiff Person syndrome and other anti-GAD-associated
neurologic disorders”, Dayalu et al, 2012.
-Hadavi, Shahrzad, et al. "Stiff person syndrome." Practical neurology 11.5 (2011): 272-282.
-McKeon, Andrew, et al. "Stiff-man syndrome and variants: clinical course, treatments, and outcomes." Archives of
Neurology 69.2 (2012): 230-238.