Neurology India, Vol. 58, No. 3, May-June, 2010, pp. 449-451
Glutamic acid decarboxylase antibody-positive paraneoplastic stiff limb syndrome associated with carcinoma of the breast
Pankaj A Agarwal1, Nasli R Ichaporia2
1 Department of Neurology, Aditya Birla Memorial Hospital, Pune, Maharashtra, India
Date of Acceptance: 02-Jan-2010
Code Number: ni10114
Stiff limb syndrome (SLS) is a rare "focal" variant of stiff person syndrome which presents with rigidity and painful spasms of a distal limb, and abnormal fixed foot or hand postures. Anti-glutamic acid decarboxylase antibodies (GAD-Ab) are variably present in most cases. Most reported cases of SLS are unassociated with cancer. We describe a patient with SLS as a paraneoplastic manifestation of breast carcinoma, in whom GAD-Ab was present. The patient responded very well to oral diazepam, baclofen and steroids.This is the third reported case of SLS as a paraneoplastic accompaniment to cancer.
Keywords: Glutamic acid decarboxylase antibody, paraneoplastic, stiff limb syndrome
Stiff limb syndrome (SLS) is a rare "focal" variant of the stiff person syndrome (SPS) and presents with rigidity and painful spasms of a distal limb, and abnormal fixed foot or hand postures with sparing of trunk muscles. , Most reported cases were not associated with cancer, and glutamic acid decarboxylase (GAD)-antibodies (Ab) are variably present.  We describe a patient with SLS as a paraneoplastic manifestation of carcinoma of the breast, in whom GAD-Ab were positive. This is the third reported case of SLS occurring as a paraneoplastic accompaniment to cancer.
A 55-year-old lady presented with a two-month history of stiffness of right leg and painful spasms of right foot. She initially noticed an ache in the foot, followed by difficulty in walking due to stiffness in the leg. It was followed two weeks later by involuntary abnormal posturing of the right foot and toes. A month later, she experienced intermittent, painful spasms of the leg during which her foot would be plantar flexed and inverted for several minutes, making it impossible for her to stand or walk. Frequent spasms disturbed her sleep. She had lost five kilograms of weight in the last six months. Past medical history was unremarkable. Family history was remarkable for esophageal carcinoma in her mother and breast carcinoma in her maternal grandmother.
On examination, the right foot was held in a position of plantar flexion at the ankle, with overriding and flexion of the toes [Figure - 1]. Active and passive ankle movements were tight and restricted, severely limiting dorsiflexion, further plantar flexion, inversion or eversion. Spontaneous intermittent, superimposed, painful spasms involving knee extension, ankle flexion, and foot inversion were present and these spasms were also stimulus sensitive to tactile, auditory or emotional stimulation. The right lower limb was rigid. Power in all limbs was normal. Deep tendon reflexes and sensory examination were normal. Her gait was affected by her inability to bear weight on her right foot. General examination showed a well-defined, mobile, hard, 2 ΄ 2 ΄ 2 cm lump in the outer quadrant of the right breast, with palpable axillary lymph nodes.
On electrophysiological studies, motor and sensory nerve conduction was normal. Electromyography (EMG) showed continuous motor unit activity (CMUA) at rest, despite attempted relaxation, in the right hamstrings, tibialis anterior and gastrocnemius muscles. Motor unit morphology was normal, and interference pattern showed grouped discharges during spasms. Magnetic resonance imaging of the spine and brain, and electroencephalogram were normal. Serum creatine phosphokinase (CPK) was elevated, 3024 U/L (N <200 IU/L). Anti GAD antibodies were present (13.13 U/ml, N: <1.050 U/ml). Anti-128-kd antigen (amphiphysin) antibodies could not be tested. Other autoantibodies (against thyroid microsomal, β-pancreatic, gastric parietal cells) were absent. Cerebrospinal fluid (CSF) examination was normal and negative for oligoclonal bands.
She underwent wide local excision of the breast mass with sentinel node biopsy. Histopathology revealed infiltrating ductal carcinoma with metastases in apical, axillary and interpectoral nodes. She received intensive chemotherapy for the breast cancer. Although she was offered intravenous immunoglobulin and plasma exchange, she refused both options. She was treated with baclofen 30 mg/day, diazepam 60 mg/day and prednisolone 60 mg/day. Gradual improvement was seen over several weeks, and by three months, pain and spasms had reduced substantially, and she could stand and bear weight on the right foot. [Figure - 2] shows the distinctly improved foot posture at 3 months of treatment. Attempts at tapering steroid dosage failed as she had relapse of pain and spasms. At one-year follow-up, she continues to be able to bear weight on her right foot with minimal pain and is on baclofen 20 mg/day, diazepam 10 mg/day and prednisolone 10 mg/day.
Three distinct subtypes of SPS have been described: progressive encephalomyelitis with rigidity (PERM), classic stiff trunk (man) syndrome and SLS.  Most patients with SLS have neither anti-GAD nor other autoantibodies. The characteristic electrophysiological features in SLS are CMUA at rest in the affected limb and interference pattern consisting of hypersynchronous grouped segmented discharges during spasms. , The response to diazepam and baclofen is partial, with half of the patients becoming wheelchair-bound. The long duration of disease in most cases of SLS argues against a paraneoplastic etiology, and indeed most cases are not associated with cancer.  SLS differs from classic SPS. The latter involves paraspinal and abdominal muscles, and rarely if ever, is the foot affected. Hyperlordosis is also present. , Insulin-dependent diabetes, and anti-GAD and other autoantibodies are both frequently present in SPS and this is not in SLS. Also unlike SLS, most SPS patients respond to diazepam, baclofen and immunotherapy and remain ambulatory.
The clinical characteristics and the investigative data of the reported cases including our patients are given in [Table - 1]. ,,,,,,, The overall clinical profile is rather heterogeneous with female gender predominance. The age at presentation is quite variable, from the third to the seventh decade. The lower limb is affected in most cases, with only two cases exhibiting upper limb signs. An association with other autoimmune diseases like thyroid disease, insulin-dependent diabetes, and polyarthritis has been seen in a few cases. Of the 22 patients reviewed including our cases, GAD-Ab were positive in the serum in nine (41%) patients and in three patients in cerebrospinal fluid. Other autoantibodies, thyroid microsomal and gastric parietal cell, have also been found in three cases.
A review of the literature reveals two other reports of SLS presenting as a paraneoplastic syndrome, one case with breast cancer  and the other with multiple myeloma.  Both the patients were positive for GAD-Ab and negative for anti-amphiphysin. One case responded well to low-dose diazepam, and there was no response to clonazepam and steroids in the other. Similar to these two patients with paraneoplastic SLS, our case both had a shorter (few months) history than non-paraneoplastic SLS cases; and also responded well to GABA-ergic drugs and steroids. It has been suggested that the the underlying mechanism of SLS could be an inflammatory autoimmune disturbance of inhibitory GABA-ergic pathways due to a chronic spinal interneuronitis. , Besides GAD-Ab, further evidence supporting a disturbance in GABA-ergic transmission comes from the findings of positive responses to GABA-ergic drugs, and to immunoglobulins , and plasma exchange  in some cases.
Thus, although SLS has been classically thought to be unassociated with cancer, this case highlights that some cases of SLS may be paraneoplastic. Although this case was Gad -Ab positive, the precise role of GAD-Ab in the pathogenesis of SPS and its variants remains undetermined.
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