Stiff Person Syndrome

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69 Stiff Person Syndrome

Ted M. Burns, Juliana Lockman, H. Royden Jones, Jr.

This chapter concentrates on the most common of the very uncommon motor neuron hyperactivity disorders, namely the stiff person syndrome. Two other potentially related syndromes characterized by incomplete relaxation or inhibition of motor neurons—Isaac (Merten) syndrome and neuromyotonia—are discussed in Chapter 70.

Clinical Vignette

A 53-year-old woman with myeloid metaplasia reported a 6-month history of severe back pain, difficulty walking, and occasional falls. No lumbosacral disc disorder could be identified. During the past month, these spasmodic muscle pains of her legs, back, and abdomen were induced by attempting to sit up, stand, or walk. Occasionally, these spasms led to stiffening of her entire body; at their extreme these induced urinary incontinence. At times, the severity of the pain led her to cry out to such a degree that it caused one observer to liken her distress to that of a “bellowing cow”! These outbursts led to her being referred to a psychiatrist.

Neurologic examination demonstrated an anxious and alert middle-aged woman. The primary finding was her spontaneous reaction to the slightest sensory stimuli wherein she totally stiffened, reminding this neurologist (HRJ) of a tetanus patient. Other than hyperlordosis, marked hyperreflexia at her knees and a right Babinski sign, her basic neurologic examination was normal. However, on a neurosurgeon’s brusque attempt to get her out of bed to stand, she developed severe painful body spasm and fell into the hospital room wall as if a chain saw had cut her legs off.

Head and cervicothoracic spine magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) study were normal, as was serum B₁₂ level. Nerve conduction studies were normal. Her needle electromyography (EMG) study demonstrated prolonged motor unit activity in contracting muscles during episodes of stiffness and spasm but was otherwise normal. Double-antibody radioimmunoassay demonstrated a high level of serum glutamic acid decarboxylase 65 (GAD-65) antibodies (138 nmol/L; reference range: ≤0.02 nmol/L). The patient was diagnosed with stiff person syndrome (SPS).

Increasing doses of diazepam alleviated symptoms at a dose of 60 mg daily. A course of plasmapheresis treatments followed by prednisone (80 mg daily) led to gradual symptomatic improvement. She was successfully tapered off corticosteroids during a 2-year period and diazepam over 5 years.

The stiff person syndrome (SPS, originally known as the stiff man syndrome) was first described by Moersch and Woltman in 1956. Classic stiff person syndrome is a chronic autoimmune disease characterized by spine and leg rigidity with lumbar hyperlordosis and painful spasms. Women are more often affected than men at a ratio of 2 : 1. This disorder generally presents in the fourth through sixth decades. Its onset is typically insidious and the course is usually progressive.

Laboratory studies that are classically abnormal in SPS include an elevated serum GAD-65 antibody titers (>20 nmol/L), needle EMG findings of continuous motor unit activity in at least one axial muscle, and normal brain MRI and CSF studies. Variants of SPS include those with focal limb dysfunction (stiff limb syndrome), encephalomyelitis (“SPS Plus”), and those associated with paraneoplastic antibodies, namely, amphiphysin as seen with breast cancer. Although most instances of SPS do not have a family history, at least one instance of such is reported. Interestingly the parent and propositus had a stiff limb variant and the daughter a purely intermittent axial presentation initially diagnosed as hysteria or anxiety disorder because of her presentation with recurrent opisthotonus.

Etiology

The findings that support an autoimmune basis for SPS are the following: (1) SPS is associated with autoantibodies, both the classic GAD-65 antibodies and a paraneoplastic variant, amphiphysin antibodies; (2) SPS is frequently accompanied by other autoimmune disorders such as type 1 diabetes, thyroiditis, vitiligo, and pernicious anemia; and (3) intravenous immunoglobulin (IVIg) and plasma exchange provide effective treatments for some patients.

The precise pathophysiologic role for the specific antibodies is unclear, although it is speculated that the autoimmune lesions are directed at a site on the inhibitory spinal interneurons (Fig. 69-1). Although a direct relation is inferred, this is not fully substantiated. Factors supporting a direct role for antibodies are (1) the finding of elevated intrathecal GAD antibodies; (2) the antibody concentration correlates with the degree of motor excitability; (3) GAD antibodies, obtained from serum of stiff person patients, inhibit both GAD and GABA synthesis in vitro.

Figure 69-1 Renshaw Cell Bias.

Clinical Presentation

Classic SPS

Typically this is characterized by spine and leg rigidity with lumbar hyperlordosis as a key feature (Figs. 69-2 and 69-3). Lower extremity rigidity can cause full extension of the legs, making walking difficult. Patients often also experience superimposed painful spasms that may be precipitated by sudden noise, anxiety, or touch. The spasms can be of such abrupt onset and power that these individuals may unexpectedly and precipitously fall. Patients soon recognize that emotional stress often provokes their spasms. They may develop agoraphobia secondary to the fear of falling in public. Neurologic examination sometimes reveals paraspinal and abdominal musculature contraction with lumbar hyperlordosis and lower limb rigidity. However, these findings are often not present until late in the clinical course. The muscle stretch reflexes may be normal to brisk, with occasionally extensor plantar responses.

Figure 69-2 Stiff Person Syndrome.

Figure 69-3 End-Stage Stiff Person Syndrome.

Stiff Person Syndrome—Primary Limb Involvement

This variant of stiff person syndrome presents focally with rigidity and spasms involving one or more limbs. In “stiff limb syndrome,” motor symptoms predominantly affect the limb distally. In contrast to the more traditional SPS, axial involvement is less prominent. However, significant proximal muscle involvement does eventually occur if the SPS is not diagnosed and treated early. This was illustrated by one of our patients who had spontaneous quadriceps spasms leading to automobile accidents. These were spontaneous and precipitous contractions leading him to suddenly apply excess pressure to the accelerator on one occasion and the brake on another. GAD autoantibody titers are elevated less frequently in these patients. The EMG pattern is even less predictable in these more limited forms.

Stiff Person Syndrome with Encephalomyelitis (SPSE)

Patients with stiff person syndrome with encephalomyelitis typically present with a subacute onset of axial or limb rigidity accompanied by pyramidal tract signs (e.g., abnormally brisk muscle stretch reflexes, Babinski sign), brainstem dysfunction, cognitive decline, and myoclonus. The variant syndrome is often paraneoplastic, and amphiphysin antibodies are frequently present. Paraneoplastic stiff person syndrome is associated with several malignancies, including breast adenocarcinoma, small cell lung cancer, colon cancer, and Hodgkin lymphoma. It is not unusual for the SPS to be the first sign of the underlying malignancy. Thus, when amphiphysin antibodies are positive, it is important to ensure careful follow-up. One patient had two negative mammograms over a 1-year period only to self-discover a breast mass a short time later.

Differential Diagnosis

Frequently SPS patients have a history of a number of nondiagnostic visits to a variety of physicians, including a few neurologists. They are often inappropriately labeled as hysteric or having a functional somatoform disorder leading to recurrent psychiatric evaluations. Other erroneous diagnoses sometimes applied to these patients include chronic tetany, tetanus, dystonia, stroke, and arthritis. The possibility of a spinal cord disorder (i.e., a myelopathy with spondylosis or disc herniation), or a basal ganglia disorder also requires consideration.

In any acute setting, the possibility of tetanus must be considered because of the board-like stiffening of the abdomen and the severity of muscle spasms. Sparing of the jaw muscles and absence of trismus in SPS makes tetanus unlikely. Spasms are generally less violent and of less acute onset in SPS than in tetanus, but this is not invariable. Chronic tetanus is rare and typically presents with trismus and risus sardonicus.

Hereditary hyperekplexia or startle disease with startle-induced spasms is a rare disorder caused by mutations in the glycine receptor, a receptor for a major inhibitory central nervous system (CNS) neurotransmitter. Startle-induced spasms may also be seen in focal spinal cord lesions such as tumors or syringomyelia.

Patients with psychogenic muscle contraction or spasm usually have a consistently inconsistent as well as more variable presentation; this diagnosis must only be entertained after long periods of careful observation and recurrent laboratory testing. Such cases occur occasionally but warrant consideration. Other causes of muscular rigidity include disorders of muscle or neuronal membrane hyperexcitability. Two channelopathies with muscle rigidity, namely myotonia congenita and Isaac syndrome, deserve consideration in the differential diagnosis, but neither of these is associated with the pain typically seen with SPS. Multiple sclerosis, poliomyelitis, Lyme disease, spinal myoclonus, tumors, and even strychnine poisoning are also in the differential and might deserve consideration in some cases.

Diagnostic Approach

Stiff person syndrome is primarily a clinical diagnosis, and diagnostic criteria include:

1) Stiffness and rigidity initially affecting axial muscles or occasionally an individual limb.

2) Progressive involvement affecting proximal limb muscles.

3) Abnormal axial posture with increased lumbar hyperlordosis.

4) Superimposed muscle spasms.

5) No brainstem, extrapyramidal, or lower motor neuron signs.

6) No sphincter and sensory disturbance, and no cognitive involvement.

7) Clinical response to diazepam or another benzodiazepine.

8) Markedly elevated GAD-65 autoantibody titers in serum support the diagnosis; 60–90% of classic SPS patients have very high titers of GAD-65 in serum, usually greater than 20 nmol/L. Significantly lower levels of GAD-65 antibodies are frequently seen in type 1 diabetes mellitus, drug-resistant epilepsy, cerebellar degeneration syndromes, and Batten disease.

9) Early on in this disorder EMG is often normal. However, EMG eventually reveals a characteristic abnormality with concomitant and continuous firing of motor unit potentials in both agonist and antagonist muscles in severely affected individuals. The lack thereof of characteristic EMG findings should not be a reason to dismiss the diagnosis.

Other studies will prove to be very important to exclude competing differential diagnostic considerations. Magnetic resonance imaging of the brain and spinal cord is normal but can be useful in identifying mimics of the variant with encephalomyelitis (see below). The cerebrospinal fluid is usually normal but can occasionally demonstrate increased CSF protein, oligoclonal bands, or IgG. It must be emphasized that if one waits until all of the above classic “requisites” for diagnosis of SPS are fulfilled, the opportunity for significant therapeutic control of the potentially future downhill course of this eventually lethal disorder will be missed. This is illustrated by some of the early variants as noted below.

Treatment and Prognosis

Symptomatic Treatment

These medications may be very helpful but do not address the basic autoimmune process in this chronic disorder.

Benzodiazepines

Diazepam is the first-line symptomatic therapy. It was the first pharmacologic agent shown to dramatically alter the clinical course of SPS. Its use is associated with significant clinical improvement in stiffness, frequency of spasms, and ability to ambulate. Benzodiazepines are GABA_A receptor agonists and thus can act to inhibit the excessive MUP firing leading to the painful muscle contraction of SPS. Common side effects include sedation, somnolence, fatigue, and ataxia. Serious side effects include hypotension, respiratory depression, and long-term physical dependence. Much caution is advised if one considers discontinuation of a benzodiazepine. This should involve a carefully monitored and very slow taper with the avoidance of an abrupt withdrawal as it can be lethal, possibly secondary to arrhythmias.

Baclofen

Baclofen is also considered a first-line therapy. Baclofen is a GABA_B receptor agonist that also can inhibit the excessive muscle contraction of SPS. Common side effects include constipation, nausea, decreased muscle tone, headache, dizziness, and somnolence. Seizures and even death secondary may occur with abrupt withdrawal of baclofen.

Immunosuppressants/Immunomodulators

Corticosteroids

Corticosteroids are the first-line immunosuppressive therapy requiring a high dose (e.g., prednisone 1 mg/kg/d). Once patients become asymptomatic, they usually require long-term maintenance therapy, followed by a gradual taper as tolerated. The usual side affects need to be monitored.

Intravenous Immunoglobulin

Intravenous immunoglobulin (IVIg) is another consideration for SPS patients refractory to symptomatic management with first-line agents. IVIg is generally well tolerated; its biggest downside is cost and availability. Corticosteroids, in contrast, are very inexpensive but generally cause more side effects. It is not clear whether long-term treatment with one modality per se is better than the other.

Plasma Exchange

Plasma exchange has demonstrated mixed clinical efficacy. It is sometimes considered in combination with first-line agents as a short-term management option.

Azathioprine

Azathioprine is a reasonable long-term option for patients who fail conventional regimens, but clinical improvement is often delayed 4–6 months after initiation of therapy.

Rituximab

Rituximab, an anti-CD-20 monoclonal antibody that attacks B lymphocytes, has been reported to lead to clinical improvement of SPS. GAD-65 antibodies become undetectable and the EMG normalizes within weeks. However, more studies of Rituximab in SPS need to be performed before it becomes a first-line immunosuppressive choice.

Other Issues

Psychiatric problems commonly accompanying SPS include anxiety, depression, and substance abuse. These may exacerbate both the chronic stiffness and the frequency of spasms. Psychiatric consultation can play an important role in the identification and treatment of such problems.

Additional Resources

Amato AA, Cornman EW, Kissel JT. Treatment of stiff-man syndrome with intravenous immunoglobulin. Neurology. 2004;44:1652-1654.

Barker RA, Revesz T, Thom M, et al. Review of 23 patients affected by the stiff person syndrome: clinical subdivision into stiff trunk (man) syndrome, stiff limb syndrome, and progressive encephalomyelitis with rigidity. J Neurol Neurosurg Psychiatry. 1998;65:633-640.

Burns TM, Jones HRJr, Phillips LHII, et al. Two generations of clinically disparate stiff man syndrome, confirmed by significant elevations of GAD65 autoantibodies. Neurology. 2003;61:1291-1294.

Dalakas MC, Li M, Fujii M, et al. Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD 65 antibodies. Neurology. 2001;57:780-784.

Lockman J, Burns TM. Stiff-person syndrome. Current Treatment Options Neurol. 2007;9:234-240.

Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome): report of a case and some observations in 13 other cases. Mayo Clin Proc. 1956;31:421-427. The initial and very classic paper with exquisitely detailed patient history

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