The Stiff-Person Syndrome: An Autoimmune Disorder Affecting Neurotransmission of -Aminobutyric Acid

Dr. Dalakas (Neuromuscular Diseases Section, National Institutes of Neurological Diseases and Stroke [NINDS], National Institutes of Health [NIH], Bethesda, Maryland): In 1956, Moersh and Woltman (1) reported a series of 14 patients with unexplained fluctuating rigidity and spasms who had visited the Mayo Clinic over a 32-year period. These authors called this entity the stiff-man syndrome because the patients did not have extrapyramidal disease, pyramidal tract dysfunction, or any other known neurologic disorder that could explain the stiffness. Since that report was published, several cases of this rare disorderwhich is preferably called the stiff-person syndromehave been reported in both men and women, and new cases are increasingly being recognized. The stiff-person syndrome causes substantial disability and is therefore of interest to various specialists, including neurologists, internists, rheumatologists, diabetologists, immunologists, and rehabilitation physicians (1-6). During the past 2 years, we studied the stiff-person syndrome to better define the disease, explore its pathogenetic mechanisms, and apply specific therapies. It may seem that the stiff-person syndrome is elusive and requires a high degree of suspicion for diagnosis; however, in a typical presentation, the stiff-person syndrome is not difficult to identify. In our series, 20 consecutive patients12 of whom have participated in a controlled trialpresented with two sets of symptoms: muscular rigidity and episodic spasms superimposed on the rigidity. The rigidity, which is characterized by tightness and stiffness, begins insidiously, over several months, at the axial musclesespecially the thoracic and lumbar spineand spreads to the legs. The hallmark sign is the continuous contraction of the agonist and antagonist muscles; in the trunk, this produces a boardlike appearance. Hyperlordosis is caused by co-contraction of the abdominal and thoracolumbar paraspinal muscles. In our series, 9 of 12 patients had an asymmetric presentation: One leg was affected more than the other (stiff-limb syndrome) (7), and the stiffness eventually spread to other areas of the body, including the trunk. If the stiffness spreads to the respiratory and thoracic musculature, patients may have difficulty breathing. Eight of 12 patients experienced breathing problems caused by chest restriction and thoracic muscle stiffness (which was aggravated by anxiety and fear). Previous reports have stated that the muscles of the face are not involved in this disorder (1-6); however, we observed stiffness in the facial muscles in 10 of 12 patients. At times, the patients' faces had the appearance of emotionless masks. In the stiff-person syndrome, rigidity fluctuates at first but gradually becomes fixed, affecting both the agonist and antagonist muscle groups and resulting in rigidity of the abdominal wall, hyperlordosis, difficulty walking or bending, and frequent falls. On palpation, the muscles feel similar to rocks, particularly in the lumbar spine, which is rigid. In almost all of our patients, we had to perform lumbar puncture under fluoroscopy. Except for global stiffness in the extremities, results of neurologic examination were normal; patients had normal muscle strength and no evidence of extrapyramidal or pyramidal tract signs. The tendon reflexes were normal or sometimes brisk but without the Babinski sign. The second set of symptoms, episodic spasms, are sudden and may cause falls; patients may fall 3 to 4 times per month. Unexpected noises or tactile stimuli and emotional upset or fear precipitate the spasms, which are sometimes painful. In patients with the stiff-limb syndrome, the spasms are superimposed on the stiff leg and cause limping or difficulty walking. The gait is stiff, deliberate, and slow. Some of our patients did not want to walk unassisted because they were afraid of falling; other patients could not initiate gait. In some patients, unexpected stimuli caused a sudden freeze or fall. Although our 12 patients exhibited normal strength, 8 needed a cane to walk and 5 needed a walker because of truncal stiffness and sudden falls en bloc. Howard (8) found that the spasms usually improve with use of diazepam. The response to high-dose diazepam has been used to help confirm the clinical diagnosis of the stiff-person syndrome, although it is not always a reliable sign. The diagnosis of the stiff-person syndrome remains clinical and one of exclusion. Patients should have the above-described symptoms, normal strength, no abnormal movements or dystonia, and no extrapyramidal or pyramidal tract signs. The blood chemistry is usually normal, but we noted a mildly elevated creatine kinase level in 4 of 12 patients. Diseases that should be differentiated from the stiff-person syndrome include chronic tetanus, which is extremely rare; various types of dystonia and extrapyramidal disease, which are easily excluded on the basis of the clinical examination; psychogenic disease; and neuromyotonia, a rare peripheral nerve disease characterized by rippling painful muscle spasms (which, contrary to those seen in the stiff-person syndrome, persist after nerve block, anesthesia, and sleep and have typical electromyographic findings) (1-6). Several of our patients initially received a tentative diagnosis of a conversion syndrome or some kind of psychogenic process because their presentation was dominated by task-specific phobias and their stiffness was precipitated by unexpected noises or mental anticipation. A good response of the stiffness to diazepam, which is given to control the phobias, is often thought to confirm phobic neurosis rather than the stiff-person syndrome. When overwhelming anxiety and fear overshadow the stiffness from the time of disease onset, it may be difficult to distinguish the stiff-person syndrome from a psychogenic disorder. The origin of the stiff-person syndrome is central. Approximately 10% of patients have seizures, the stiffness improves or disappears during sleep or anesthesia, and the symptoms improve with drugs that enhance brain levels of -aminobutyric acid (GABA), such as diazepam or valproic acid. Malfunction of the inhibitory networks in the central nervous system mediated by GABA or glycinethe two main neurotransmitters that facilitate inhibitionseems to play a major role in the manifestation of the stiffness. A proposed mechanism for the development of stiffness and spasms through the involvement of the main inhibitory network is depicted in Figure 1. Figure 1. Proposed mechanism of development of stiffness in the stiff-person syndrome. a b c d Inhibitory Pathways Defined by Electrophysiology Dr. Mary Kay Floeter (Electromyography Section, NINDS, NIH, Bethesda, Maryland): Electromyography is a useful technique that detects firing of motor-unit action potentials in muscles. Motor-unit action potentials have a characteristic appearance and discharge rate that can be readily distinguished from other abnormal discharges associated with muscle stiffness, such as myotonia. In healthy persons, motor units do not fire when the muscles are at rest; firing occurs only during voluntary contraction. In patients with the stiff-person syndrome, a continuous background of motor-unit firing occurs despite the patient's attempts at muscle relaxation. This continuous, involuntary motor-unit firing at rest is the physiologic hallmark of the stiff-person syndrome. Another abnormality in the stiff-person syndrome is co-contraction: When the patient attempts to contract a muscle to move in one direction, muscles that pull in the opposite direction are involuntarily activated (9). Normally, the timing of the contraction of a muscle that moves the limb in one direction and the contraction of the antagonist muscle that moves it in the opposite direction have a reciprocal relation. The nervous system is usually wired so that contraction of the prime mover muscle is coupled with relaxation in the antagonist muscle. Several circuits in the brain and spinal cord mediate this reciprocal inhibition, including two spinal circuits that use different inhibitory transmitters. One spinal circuit uses a glycinergic inhibitory interneuron that synapses on the motoneurons to produce direct, postsynaptic inhibition; the other circuit relays through a GABAergic interneuron that synapses on the presynaptic terminals of certain sensory inputs. The loss of GABAergic input into motor neurons is thought to produce the tonic firing of motor neurons at rest and lead to their excessive excitation in response to sensory stimulation. To determine whether GABAergic inputs are hypoactive, Floeter and colleagues (10) measured the strength of reciprocal inhibition between pairs of antagonist muscles. Other inhibitory reflexes mediated by glycinergic neurons through spinal cord circuits were also tested. Although certain GABAergic inhibitory reflexes were impaired, the spinal circuits mediating reciprocal inhibition were normal; this finding suggests that the impaired reciprocal inhibition in the stiff-person syndrome is located in supraspinal circuits. Sandbrink and coworkers (11) tested the excitability of the motor cortex by using transcranial magnetic stimulation, a noninvasive technique that uses a coil on the scalp to produce a transient magnetic field within the motor cortex. The magnetic field induces a brief discharge of corticospinal neurons, which evokes a muscle contractionthe motor-evoked potential. A paired-pulse method was used to test intracortical circuits. The first pulse has a very small intensity that is below the threshold for producing a motor-evoked potential but is strong enough to activate intracortical circuits. When this pulse is followed by a second pulse strong enough to cause a motor-evoked potential when received alone, the motor-evoked potential is inhibited at short intervals and facilitated at longer intervals. These changes are thought to reflect the ba