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Progressive encephalomyelitis with rigidity (PER) is a rare disorder of unknown aetiology, characterised by muscular rigidity, abnormal postures, painful muscle spasms, and myoclonus, and is caused by inflammation in the brainstem or spinal cord.1,2 We report a case of PER with positive anti-amphiphysin antibodies in the serum and CSF.3 This association has not been previously reported and raises the possibility that PER may have an autoimmune pathogenesis similar to that of stiff person syndrome (SPS).4
A 37 year old female presented having had symptoms of PER for about three months. Spasms began with several minutes of paroxysmal painful muscle stiffness in the left upper limb, followed by pain and muscle spasms in the upper limbs, shoulders, neck, and back. These spasms were easily evoked by light touches, conversations, and by being startled. The patient remained bedridden and showed left dominant weakness of the limbs, with contractures in the upper limbs and difficulty in relaxing the muscles. She also developed abducent nerve palsy. Her deep tendon reflexes were absent and her plantar responses were both flexor. The serum antinuclear antibody was positive (1:160); anti-glutamic acid decarboxylase (GAD) antibody was negative. CSF testing revealed 18 white cells / mm (98% lymphocytes)3 and 160 mg/dl of protein. The MRI scan of the brain and spinal cord and the EEG were entirely normal. Surface electromyography in the arm and neck muscles showed continuous motor unit discharge elicited by passive movement of the right arm or by conversation (fig 1(A)).
The diagnosis of PER was based on the marked limb and trunk rigidity, the severe spasms provoked by sensory or emotional stimuli, and the cranial nerve palsy with mild pleocytosis as well as protein elevation in the CSF indicating inflammation of the brainstem and spinal cord. Matsuno et al3 also reported the clinical features of this patient.
Diazepam and baclofen were minimally beneficial; plasmapheresis had no effect on the symptoms. After treatment with intravenous injection of high dose methylprednisolone and sequential oral prednisolone, the patient showed dramatic progress. Her abducent nerve palsy was improved, and she could walk without assistance eight months after admission. She did not have any spasms or muscle pain. However, after two years, she developed a breast cancer.
Supernatants of total rat brain were prepared by homogenisation in 10 volumes of ice cold RIPA buffer, pH 7.4, containing freshly added protease inhibitors (0.1 mM PMSF, 1 μg/ml each of leupeptin, aprotinin, and pepstatin A), followed by centrifugation at 1000 g for 10 minutes at 4°C. Rat brain homogenates and immunoprecipitates were separated by SDS gel electrophoresis. The patient’s sera were used at 1:1000 dilution.
Western blotting and immunoprecipitation were performed as previously described.5 A band with an apparent molecular mass of 128 kD was recognised using the patient’s serum samples (fig 1(B)). To prove that anti-amphiphysin antibodies recognised the 128 kD antigen, the patient’s sera were used to immunoprecipitate the 128 kD antigen from rat brain extracts. The presence of amphiphysin in the immunoprecipitate was demonstrated by Western blotting, using mouse anti-amphiphysin antibody. The 128 kD autoantigens, which were immunoprecipitated by the patient’s sera and the CSF, comigrated with amphiphysin and were recognised by an anti-amphiphysin antibody (fig 1(B)).
As far as we are aware, this is the first reported case of PER with anti-amphiphysin antibody. Anti-amphiphysin antibodies have been identified in several patients with paraneoplastic neurological disorders, such as encephalomyelitis, sensory neuropathy, cerebellar degeneration, opsoclonus-myoclonus, and SPS.2 Although specificity of the antibodies for one type of tumour or one neurological syndrome is poor, in our patient the PER had an autoimmune basis with anti-amphiphysin antibodies.
Gouider-Khonja et al4 reported a 50 year old woman whose initial clinical presentation mimicked SPS, with later diffuse involvement of the CNS leading to a diagnosis of PER. Meinck et al2 suggested that PER was one of the variant forms of SPS, because of the similarity of their clinical and autoimmune features. In like manner, paraneoplastic SPS and PER have been found to be related to autoantibodies such as amphiphysin,5 GAD,2 and gephyrin.6
The suggested aetiology of both SPS and PER is autoimmune disorder of the CNS directed against suprasegmental or spinal inhibitory GABAergic neurons.2,4 The differences between SPS and PER could depend on the distribution and degree of the autoimmune reaction; SPS involves the spinal interneurons, whereas PER expands to the brainstem or other areas of the CNS.2,4 More clinical and laboratory based studies are needed to further our understanding of the pathogenesis of SPS and PER.
Part of this work was supported by Research Projects Grants in Aid for Scientific Research numbers 60180957(A H) and 80203751(N O), from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.