Statistics from Altmetric.com
Stiff man syndrome (SMS) is a rare, severe progressive motor disorder characterised by painful spasms, symmetric axial muscle rigidity, and uncontrollable contractions leading to distorted posturing. The disorder has been associated with the autoantigens, glutamic acid decarboxylase (GAD), and amphiphysin, which are cytoplasmic proteins in neurons of the CNS. A large series of patients with SMS found that most have autoantibodies against GAD,1whereas amphiphysin is presumably the predominant autoantigen in paraneoplastic SMS.2 Recently, Brownet al 3 presented four patients with a stiff leg syndrome marked by progressive rigidity and spasms of the lower extremities. This group of patients tested negative for anti-GAD antibody by immunoprecipitation and demonstrated distinct electrophysiological features. By contrast, another report described two patients with stiff leg syndrome who tested positive for anti-GAD antibody.4 Finally, in presenting a group of 13 patients, Barker et al 5 proposed that the nomenclature “stiff limb syndrome” refers to the focal form of SMS when one or more distal limbs are involved; two of their patients were also anti-GAD antibody positive, but none were tested for antibodies to amphiphysin or identified as having an underlying neoplasm. We present a patient clinically consistent with the stiff limb syndrome who was found to have autoantibody to GAD and breast cancer.
A 68 year old woman presented with a 1 month history of painful spasms in her legs. Cramps were associated with tactile stimuli and emotional upset. Within weeks, inversion began at the left and then right ankle, making ambulation difficult. Her medical history was significant for Graves’ disease treated with thyroidectomy and radiation therapy, and hyperlipidaemia. She was a chronic smoker. General examination was noteworthy for lymphadenopathy in the right axilla. Her mental status was worse during periods of lower extremity spasms, during which she became anxious, diaphoretic, and tachycardic. Cranial nerve and motor evaluations were unremarkable, but assessment of the left leg, due to painful spasms elicited by light touch, was difficult. Inversion and plantarflexion were essentially fixed at the left ankle but could be overcome on the right. Deep tendon reflexes were 3+ in the upper and lower extermities, with sustained clonus at the right ankle. Sensory examination, with the exception of hyperaesthesia in the distal lower extremities, and coordination testing were grossly normal. No hyperlordosis or myoclonus was noted. Gait was limited due to ankle posturing.
The laboratory evaluation was noteworthy for a CSF with increased IgG indices (2.5, 3.4; normal, 0.2–0.8) and oligoclonal bands (5, 5) but no pleocytosis. Serological testing for anti-Hu, anti-Yo, and anti-Ri antibodies was unremarkable, and the haemoglobin A1C was 6.6 (5.6–7.7)%. Skin biopsy at three sites on the patient’s leg showed diminished epidermal nerve fibre density and terminal axonal swelling distally, consistent with a small fibre sensory neuropathy.6 The patient would not tolerate EMG. Magnetic resonance images of the brain and the entire spinal cord were normal. Fine needle aspiration of a soft tissue right axillary mass showed metastatic adenocarcinoma. On an open surgical procedure, infiltrating duct carcinoma of the breast was identified. Anti-GAD autoantibodies were positive by immunocytochemical assay and immunoprecipitation, but antibodies to amphiphysin were not detected by immunocytochemistry, immunoprecipitation, or western blotting (Dr P De Camilli, Yale University).
Ongoing therapy with clonazepam and a trial of oral dexamethasone did not improve the lower extremity symptoms. The patient’s ankle posturing continued a slow progression to marked inversion, with spontaneous extension of hallucis longus. The patient died 18 months after symptom onset. Gross necropsy attributed the cause of death to aspiration pneumonia. Neuropathological evaluation showed a grossly normal brain and spinal cord. Microscopically, the lumbar cord had mild reactive gliosis in the anterior horns but no evidence of inflammation. Sections of the frontal cortex, pons, and medulla showed mild diffuse reactive astrocytosis.
Stiff man syndrome is increasingly recognised as a heterogeneous disorder.7 Other case reports have documented patients with “focal” disease involving either lower3-5 or upper extremity posturing,8 which contrast with the “diffuse” axial and subsequent proximal muscle distribution of the classic disorder.9 Our patient differs from those reported with stiff leg syndrome in that an occult malignancy was present. Unfortunately, we were unable to obtain electrophysiological studies for comparison. The search for a paraneoplastic process was based on the findings of axillary lymphadenopathy and an abnormal CSF. Our patient is only the second reported patient with paraneoplastic SMS associated with anti-GAD antibody; the other had upper limb rigidity in the setting of breast cancer and additionally mounted an immune response to amphiphysin.8
Paraneoplastic processes can affect any component of the nervous system and, occasionally, multiple levels, as in the syndrome of sensory neuronopathy-encephalomyelitis. Our patient’s findings were not entirely consistent with criteria for classic SMS9 in that an apparent encephalopathy and a small fibre neuropathy were identified—for example, her dysautonomia (tachycardia and relative hypertension) during spasms may have been a manifestation of involvement of small fibres. The role of autoantibodies in the pathogenesis of SMS and cancer is unclear.2 7 8 Via its probable function in endocytosis,10 amphiphysin has been postulated to play a part in the regulation of growth factor internalisation; however, the absence of an autoimmune response to this autoantigen in our patient suggests that other mechanisms of oncogenesis in SMS exist. Given anecdotal evidence of improvement in paraneoplastic SMS after treating the underlying malignancy,8 we suggest that all patients with SMS, diffuse or focal, be screened for occult cancer.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.