Stiff man syndrome

Stiff person syndrome (SPS) (or stiff-man syndrome; also known as Moersch-Woltman Condition) is a rare neurologic disorder of unknown etiology characterized by progressive rigidity and stiffness, primarily of the axial musculature, that is superimposed by spasms, resulting in postural deformities. There are also sub-variants: stiff baby syndrome and stiff limb syndrome. Other forms or types of the disease include focal SPS, jerking SPS, and progressive encephalomyelitis with rigidity and myoclonus.

Signs and symptoms
Individuals with stiff person syndrome tend to present in 3 different stages: early, late and end stage. In the early stages, there are few objective findings indicating SPS during the initial assessment. SPS will begin insidiously in the axial muscles. Patients will present with an exaggerated upright posture and have stiffness and pain in the whole back. Sleep disturbances are also common due to muscle spasms waking them. In the late stages, proximal limb muscle become involved and the patient tends to move slower as fast movements will cause the severe spasms. Emotions such as anger have been shown to have a link to causing the spasms, which begin in this stage. Exaggerated lumbar lordosis becomes more evident in the patients. Depression can be comorbid with SPS at this stage due to the patient’s quality of life decreasing. In the end stage, activities of daily living such as eating and simple movements become hard to perform. Skeletal fractures and muscle ruptures occur quite often along with joint deformities.

Those with the illness experience progressive, fluctuating tonic muscle contractions, particularly the axial musculature. These spasms occur in response to environmental stimuli such as voluntary or passive movements, and unexpected somatosensory or auditory stimulation. Often changes in emotion or stress can trigger spasms as well. Common signs of SPS found during assessment are hypertonia, hyperreflexia and rigidity of muscles.

Reflexive integrity in individuals with stiff person syndrome can be assessed via deep tendon reflexes as well as resistance to passive stretch. Deep tendon reflexes are graded using a 0 to 4+ scale. 0 indicates absent reflexes, 1+ indicates hypoactive (decreased) reflexes, 2+ indicates normal reflexes, 3+ indicates hyperactive (increased) reflexes without clonus and 4+ indicates hyperactive reflexes with clonus. During the examination, individuals with stiff person’s syndrome are likely to have deep tendon reflexes which are graded at 2+ (normal) or 3+ (increased reflexes). Furthermore, they are likely to exhibit increased startle reflex as well as an increased head retraction reflex (HRR). Symptoms begin in the region of the trunk and the lower extremities before moving proximally in the upper limbs, and eventually affecting facial and laryngeal muscles used for swallowing and speech. Depression and anxiety are often noted although this may be a result of discomfort due to stiffness, rather than underlying neurochemical abnormalities. MRI detection of GABA in the brain have demonstrated reduced levels in stiff-person syndrome.

In the variant Stiff-limb syndrome, symptoms present focally affecting one or more limbs. Motor symptoms occur predominantly in distal limb muscles rather than axial muscles. However, when patients experience severe spasms, motor symptoms can be seen in the trunk, upper extremities and face. Increased distal limb stiffness in ankles and feet leads to feet being in constant plantar flexion. This in turn affects posture during gait and increases fall risks for the patient.

Causes
Because many patients with SPS have circulating antibodies to the enzyme glutamic acid decarboxylase (GAD), an autoimmune cause of the disease has been postulated. However, GAD antibodies cannot be the sole cause, as most Type I diabetics possess anti-GAD antibodies, yet the frequency of SPS among Type I diabetics is 1 in 10,000. Approximately 60% of patients diagnosed with SPS have anti-GAD antibodies present, while 40% do not and therefore rely on clinical testing for diagnosis. The GAD protein regions (epitopes) recognized by these antibodies may differ in each disease(GAD65ab). A mutation in GLRA1 (glycine receptor) is responsible for some cases of stiff person syndrome. Apart from antibodies to GAD65 seen in the serum, these antibodies are also found in the cerebrospinal fluid of stiff-person syndrome patients. Rarely, SPS is associated with breast cancer and Hodgkin's lymphoma.

Treatment
Treatment is mostly palliative with muscle relaxants which potentiate GABA action, such as benzodiazepines. These treatments lose their effectiveness as the illness progresses.

In the absence of double-blind, placebo-controlled trials to determine treatment efficacy, some authorities recommend human trials of immunosuppressive therapy, plasmapheresis or intravenous immunoglobulin infusion. A recent study funded by the NINDS demonstrated the effectiveness of intravenous immunoglobulin (IVIg) treatment in reducing stiffness and lowering sensitivity to noise, touch, and stress in people with SPS.

Monoclonal antibody rituximab has produced long-lasting remissions. Clinical trials of this treatment have been completed. NINDS also recently tested plasmapherisis as another treatment option.

One case found symptoms improved unexpectedly from propofol administration.

Physical therapy is another treatment option for people with stiff person syndrome. It may help attenuate spasms in some patients, but physiotherapy should be used cautiously in patients for whom passive movements trigger spasms. Some physical therapy treatment approaches may include therapeutic exercise, functional retraining, and training family members..) Therapeutic exercises for people with stiff man syndrome would likely include a stretching program to help patients gain range of motion by reducing muscle spasms and muscle stiffness. Functional retraining would have a large emphasis on gait training to increase endurance, independence, and the ability to climb stairs.  Practicing sitting to standing, in a variety of situations, would aid a person in becoming more independent, especially with activities of daily living.  Training the patient’s family would allow the family to help with home stretches and situations where the person is dependent on another person (i.e. wheelchair transfers, getting dressed, ambulating long distance, etc.) Physical therapy may not change the disease course in the long-term, however, it may help optimize current function as well as have some positive short term effects.

Prognosis
Patients with Stiff-person syndrome usually respond well to muscle relaxants and their condition can stabilize after months to years of progression. Those with Stiff-limb syndrome have a poorer prognosis, as they do not respond well to medications. These patients often require a wheelchair.

Prognosis is variable and there is no reliable predictor of speed and severity of disease onset. Muscle tetany may lead to muscle rupture and broken bones, or problems swallowing and breathing in severe cases.

Epidemiology
This autoimmune disease is very rare, possibly affecting as few as 1 in 1,000,000 persons. It shows no specific prevalence in either sex, has no known genetic predisposition and has no cure. Age of onset is usually 30–50 years of age, but can occur in children aged 3 years old and younger. At this age it is known as Stiff Baby Syndrome.

History
SPS was first described by Moersch and Woltman at the Mayo Clinic in 1956.

Differential Diagnoses
The following differential diagnoses should also be considered when suspecting stiff person syndrome.


 * Tetanus
 * Hyperekplexia
 * Strychnine poisoning
 * Isaac's syndrome also known as Neuromyotonia
 * Spinal multiple sclerosis
 * Paraneoplastic Myelitis
 * Latent autoimmune diabetes of adults (LADA)
 * Spinal Arteriovenous malformation