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Stiff person syndrome (SPS) is a rare disorder of the central nervous system characterised by progressive fluctuating rigidity and painful spasms of the body musculature. We describe a patient with SPS with positive glutamic acid decarboxylase (GAD) antibodies who developed diplopia. Thymoma was detected by computed tomography (CT), and after thymectomy his symptoms improved. One month after thymectomy, he tested positive for antiacetylcholine receptor (AchR) antibodies.
A 45 year old man presented with a four week history of back pain and stiffness of his trunk causing difficulty in bending forward and turning over while lying down, which he attributed to a minor injury sustained while playing squash. He later developed asymmetrical stiffness of the legs and difficulty walking. His past medical history was notable for an episode of dysphagia (two weeks’ duration) associated with heartburn six months ago; a gastroenterological evaluation and an endoscopy at that time were normal. He recovered spontaneously and there was no recurrence.
On examination his mental status, speech, and cranial nerves were normal. He had exaggerated lumbar lordosis. Neurological examination showed normal bulk with increased tone of the flexors and extensors of the knee and ankles. Power and coordination were normal, deep tendon reflexes were brisk, but he had flexor plantar responses. There was no evidence of fatigable muscle weakness. Sensory examination was normal.
A chest radiograph and magnetic resonance imaging (MRI) of the brain and the spinal cord were normal. He was anti-GAD antibody positive at 3.4 U/ml (radioimmunoassay; normal 0–1 U/ml). Full blood count, vitamin B12, folate, thyroid function tests, liver function tests, urea, electrolytes, glucose, cortisol, immunoglobulins, and electrophoresis were normal. Antinuclear antibody and smooth muscle, mitochondrial, parietal cell, gliadin, reticulin, microsomal, thyroid peroxidase and antineutrophil cytoplasmic antibodies were negative. Cerebrospinal fluid (CSF) examination revealed 9 lymphocytes/mm3. CSF protein and glucose were normal at 0.31 g/l and 3.1 mmol/l, respectively and oligoclonal bands were absent.
The spasms were controlled with diazepam, but his symptoms recurred on reducing the dose. A diagnosis of SPS was made. Treatment with intravenous immunoglobulins (400 mg/kg per day for five days) was not beneficial. He later improved on baclofen 20 mg/day and clonazepam 0.5 mg at bedtime.
Four months after the onset of stiffness, he developed diplopia. Visual acuity was 6/4 in both eyes. He had variable alternating esotropia of up to 10 prism dioptres at distance and esophoria at near. Eye movement examination showed bilateral mild abduction deficit, variability of horizontal and vertical saccades with a tendency to be slow, and slight endpoint nystagmus. There was no ptosis or weakness after sustained upgaze for one minute. Eye movement recordings, obtained with a high resolution video pupil tracker (EyeLink, Sensomotoric Instruments, Berlin, Germany; sample rate 250 Hz) confirmed the clinical findings (fig 1, top panel). Anti-AChR antibodies were negative. The neurological findings were unchanged.
Motor and sensory nerve conduction studies and ulnar and radial repetitive nerve stimulation were normal. Concentric needle electromyography (EMG) showed sporadic fasciculation potentials in the tibialis anterior. Single fibre EMG from 34 potential pairs from the orbicularis oculi revealed only one site with definitely abnormal jitter. A chest CT scan revealed a thymic mass. Histological examination confirmed thymoma with minimal involvement of the perithymic fat. His symptoms improved over a month after thymectomy.
One year from the onset of symptoms, one month after thymectomy, he tested positive for anti-AChR antibodies (44×10−10M/l) (radioimmunoassay in the same laboratory, normal 0–5×10−10 M/l) and remained positive for anti-GAD antibodies (2.0 U/ml). His eye movements improved significantly after thymectomy as evidenced by eye movement recordings that showed less variability of saccadic velocity (fig 1, bottom panel). Eighteen months after the onset of symptoms he is off medications and back to his normal routine. He has mild intermittent stiffness of his back, precipitated by anxiety. Occasional mild diplopia at far distance persists.
SPS was first described by Moersch and Woltman in 1956 and was subsequently shown to be associated with anti-GAD antibodies in 40–60% of cases1 and anti-amphiphysin antibodies in some paraneoplastic cases.
In 1990, Piccolo et al2 reported a case of generalised myasthenia in a patient with SPS. This patient had radiological evidence of thymoma. A patient in the series of Vincent et al1 had SPS with anti-GAD antibodies, neuromyotonia and myasthenia with anti-AChR antibodies. Nicholas et al3 reported a case of SPS associated with histologically proved thymoma, who developed ocular myasthenia after thymectomy.
Hagiwara et al4 described a patient with SPS associated with invasive thymoma but not with myasthenia or anti-AChR antibodies. However, since the patient reported by Piccolo et al2 developed myasthenia six years after spontaneous resolution of SPS, and our patient’s anti-AChR antibodies turned positive after one year, it is possible that the patient reported by Hagiwara et al4 will develop myasthenia in the future. Saravanan et al5 described a patient with SPS associated with ocular myasthenia. Neither anti-AChR nor anti-GAD antibodies were detected.
At the time of initial presentation, our patient did not have any clear signs of generalised myasthenia, although the transient dysphagia he experienced prior to the development of symptoms of SPS may have represented symptoms of bulbar myasthenia. Notably, Hagiwara et al’s patient also reported dysarthria,4 which could have been due to myasthenia. The diplopia, variable velocity of saccades and endpoint nystagmus were likely due to ocular myasthenia. This patient became seropositive after 12 months, even though his myasthenic symptoms improved after thymectomy.
Five cases of SPS associated with myasthenia gravis have been reported. This is the first report of abnormalities on eye movement recordings strongly suggesting myasthenia gravis in SPS before the patient became seropositive for anti-AChR antibodies. Our patient is probably the third patient with SPS and myasthenia with histologically proven thymoma and the second such patient with positive anti-GAD and anti-AChR antibodies. Our report suggests that patients with SPS can develop other autoantibody mediated disorders even after many months and should be followed up over a long period even if they are asymptomatic. In addition, when patients with SPS have eye movement abnormalities or bulbar symptoms, myasthenia gravis should be suspected even if they are negative for anti-AChR antibodies at presentation. Thymoma should be investigated for, as thymectomy may improve both SPS and myasthenia.
Competing interests: none declared