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Stiff-person syndrome
  1. Juliana Lockman, Senior Neurology Resident,
  2. Ted M Burns, Associate Professor of Neurology
  1. University of Virginia, Department of Neurology, Charlottesville, VA, USA
  1. Correspondence to:
 Dr T M Burns
 University of Virginia, Department of Neurology, PO Box 800394, Charlottesville, VA 22908, USA; tmb8r{at}virginia.edu

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Stiff-person syndrome (originally known as stiff-man syndrome) was first described by Moersch and Woltman in 1956.1 They reported several cases of “progressive fluctuating muscular rigidity and spasm”. Their first patient was a 49-year-old Iowa farmer who presented to the Mayo Clinic, Rochester, Minnesota in 1924 with “muscle stiffness and difficulty walking”. He also complained of rigidity of insidious onset that began in the neck, back and shoulder musculature and progressed over a period of years to involve the abdominal and thigh muscles. Superimposed on the rigidity were intermittent painful spasms so severe that he might “fall like a wooden man”.

As the syndrome gained recognition, many considered it to be a functional disorder, in part because of its rarity and also because of its complex psychiatric overlay and relative lack of objective neurological findings in the initial stages. However, consensus gradually shifted to an organic basis with the discovery of a link with autoantibodies, the association of other autoimmune diseases with the syndrome, and effective therapy with immunomodulatory agents.

DIAGNOSIS

Classic stiff-person syndrome affects women more than men (∼2:1) and generally presents in the fourth to sixth decade.2 The onset is typically insidious and the course is usually progressive. Classic stiff-person syndrome is characterised by predominant spine and leg rigidity, with lumbar hyperlordosis as a key feature. Limb rigidity can cause full extension of the legs, making walking difficult. Along with the background rigidity, patients often experience painful spasms that may be precipitated by sudden noise, stress or touch. Indeed, patients come to recognise that emotional stress often provokes their spasms. The spasms can be of such abrupt onset and power that patients may unexpectedly fall over. Furthermore, patients may develop agoraphobia due to a fear of falling in public. Neurological examination may reveal paraspinal and abdominal musculature contraction with lumbar hyperlordosis, and lower limb rigidity. The tendon reflexes may be normal to brisk, occasionally with extensor plantar responses.

Stiff-person syndrome is a clinical diagnosis2 and diagnostic criteria for the classic syndrome are:

  • stiffness and rigidity in axial muscles

  • progression to involve proximal limb muscles

  • abnormal axial posture with increased lumbar hyperlordosis

  • superimposed muscle spasms

  • no brainstem, pyramidal, extrapyramidal or lower motor neuron signs; no sphincter or sensory disturbance; and no cognitive involvement

  • EMG showing continuous motor unit activity in at least one axial muscle (fig)

  • response to diazepam.


Embedded Image
Figure

Multichannel free run EMG recordings from a 31-year-old woman with primarily axial involvement, manifested by episodic opisthotonos of the head and neck muscles. Surface recordings were made from (1) sternocleidomastoid, (2) lower cervical paraspinal, (3) upper thoracic paraspinal, (4) lower thoracic paraspinal, (5) low lumbar paraspinal, (6) rectus femoris, (7) biceps femoris (short head), and (8) tibialis anterior muscles. The arrow indicates when the ipsilateral patellar reflex was elicited. (Adapted from

.)

Modifications of these criteria often take into account the frequent finding of raised glutamic acid decarboxylase (GAD) autoantibody titres, particularly the GAD65 isoform, and also include allowance of some pyramidal tract involvement. Between 60–90% of classic stiff-person syndrome patients have very high anti-GAD titres, usually over 20 nmol/l. Less extreme elevations can be seen in other disorders such as type-1 diabetes, drug-resistant epilepsy, cerebellar degeneration syndromes and Batten disease. GAD autoantibody titres are best measured using radioimmunoassay or immunohistochemistry. EMG almost always demonstrates continuous motor unit activity between spasms. Magnetic resonance imaging of the brain and spinal cord is normal in most cases but can be useful in identifying mimics of the variant with encephalomyelitis (see below). The cerebrospinal fluid is usually normal but can contain unmatched oligoclonal bands or IgG.

STIFF-LIMB SYNDROME

One variant of stiff-person syndrome presents focally with rigidity and spasms involving one or more limbs. In this “stiff-limb syndrome”, motor symptoms predominantly affect the limb distally with less tendency for axial rigidity and hyperlordosis. The EMG pattern is similar to that in the classic syndrome. GAD autoantibody titres are raised in a smaller proportion, up to 15%.

STIFF-PERSON SYNDROME WITH ENCEPHALOMYELITIS

Forms of stiff-person syndrome with encephalomyelitis have also been described. The patients may present with a subacute or chronic onset and tend to take a progressive course. Axial or limb rigidity is prominent and may be accompanied by long tract signs. Brainstem signs, cognitive decline and myoclonus should suggest this variant. The prognosis is poor. A paraneoplastic basis of autoimmunity is common in this “stiff-person variant-plus” variant; amphiphysin autoantibodies are frequently encountered.

Paraneoplastic stiff-person syndrome is associated with several malignancies, including breast adenocarcinoma, small cell lung cancer, colon cancer and Hodgkin’s lymphoma.

DIFFERENTIAL DIAGNOSIS

A number of neurological diseases must be ruled out before making the diagnosis of stiff-person syndrome, or its variants. These include:

  • neuromuscular disorders (tetanus, neuromyotonia)

  • focal processes involving the spinal cord (tumour, stroke, syringomyelia)

  • other central nervous system diseases (corticobasilar degeneration, hereditary hyperekplexia).

IS STIFF-PERSON SYNDROME AN AUTOIMMUNE DISEASE?

There are several lines of evidence suggesting that stiff-person syndrome has an autoimmune basis:

  • It is associated with autoantibodies, both the classic syndrome and the paraneoplastic variant.

  • It is frequently accompanied by other autoimmune diseases such as type-1 diabetes, thyroiditis, vitiligo and pernicious anaemia.

  • Intravenous immunoglobulin (IVIg) and plasma exchange are an effective treatment for some patients (see below).

Practice points

  • Classic stiff-person syndrome is a clinically diagnosed disease characterised by spine and leg rigidity with lumbar hyperlordosis and painful spasms.

  • Supportive investigations include elevated GAD autoantibody titres >20 nmol/l, an EMG with continuous motor unit activity in at least one axial muscle, normal brain MRI, and normal CSF.

  • Variants of stiff person syndrome include patients with focal limb dysfunction (stiff-limb syndrome), encephalomyelitis (stiff-person syndrome plus), and those with paraneoplastic autoantibodies.

  • The cause is likely to be autoimmune because of the association with autoantibodies, other autoimmune diseases, and response to immunomodulatory therapy.

  • Treatment is with symptomatic care (benzodiazepines and/or baclofen) along with immunomodulation (steroids, IVIg, plasma exchange, and/or chemotherapy).

The precise function of the autoantibodies is unclear. A direct role in pathogenesis has been inferred, but not fully substantiated. One factor against a direct role is the fact that GAD and ampiphysin are both intracellular, normally being found on the cytoplastic side of the presynaptic nerve terminal membrane, and thus seemingly inaccessible to the humoral immune system. On the other hand, passive transfer experiments have demonstrated that serum from a patient with an encephalomyelitic variant and antiampiphysin autoantibodies reproduced a similar syndrome in an animal model. Whether the pathogenic antibody was amphiphysin autoantibody or another antibody is not known. We are unaware of any passive transfer studies for GAD65 antibodies, and maternal transfer has not been demonstrated. Factors supporting a direct role include the fact that GAD autoantibodies are raised intrathecally and their concentration correlates with motor excitability. Also, inhibition of GAD and GABA has been shown in vitro by serum from stiff-person patients with GAD autoantibodies.

TREATMENT

Treatment of classic (non-paraneoplastic) cases consists of symptomatic care and immunomodulation. Benzodiazepines are usually so effective for classic stiff-person syndrome that the diagnosis should be reconsidered if a patient does not benefit. Oral or intrathecal baclofen is also often beneficial. Randomised controlled trials have shown that IVIg provides long-lasting relief for some patients; serious adverse effects include anaphylaxis, congestive heart failure and acute renal failure. Other treatment options are plasma exchange and corticosteroids. Tricyclic antidepressants may worsen the symptoms.

Treatment of the paraneoplastic syndrome includes agents used in classic cases with additional consideration for a chemotherapeutic agent such as cyclophosphamide if there is no improvement.

Psychiatric services can be helpful in managing the stress which contributes to exacerbations as well as the anxiety resulting from living with an unpredictable disease.

Physical therapy may be difficult because of the patient’s tendency to have spasms with even light touch.

REFERENCES

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