Clinical Neurology and Neurosurgery 111 (2009) 708712
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Clinical Neurology and Neurosurgery
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tiff person syndrome associated with lower motor neuron disease andnfiltration of cytotoxic T cells in the spinal cord
rygve Holmy a,b,, Gjertrud Skorstad a, Line Sveberg Rste c, David Scheie d, Kirsti Alvik c
Department of Neurology, Oslo University Hospital Ullevl, Oslo, NorwayInstitute of Immunology, Faculty of Medicine, University of Oslo, NorwayDepartment of Neurology, Oslo University Hospital Rikshospitalet, Oslo, NorwayDepartment of Pathology, Oslo University Hospital Rikshospitalet, Oslo, Norway
r t i c l e i n f o
rticle history:eceived 15 September 2008eceived in revised form 12 June 2009ccepted 19 June 2009vailable online 17 July 2009
a b s t r a c t
We present a 67-year-old non-diabetic male who presented with muscle cramps, paresis, atrophy andfasciculations in the left leg, followed by rapidly progressive muscle stiffness and superimposed spasmswhich subsequently also affected the right leg and the trunk. GAD65 autoantibodies were elevated inserum and CSF, compatible with systemic and intrathecal synthesis of oligoclonal and high-avidity autoan-tibodies, and GAD65 specific T cells were clonally expanded in the CSF. The patient did not respond toGABAergic and immunomodulatory treatment or plasma exchange, and died from respiratory failure after
tiff person syndrometiff limb syndromerogressive encephalomyelitis with rigidityotor neuron diseaseeuroinflammationcells
18 months. Autopsy revealed unilateral axonal swelling, chromatolysis and vacuolisation of anterior horncells of the lower spinal cord, accompanied by microglia proliferation and discrete infiltration of CD8+cytotoxic T cells. No CD4+ T helper cells, B cells or complement deposition were detected. To our knowl-edge, this is the first report of stiff person syndrome with lower motor signs restricted to a lower limb,and also the first attempt to characterize the infiltrating T cells. The finding of CD8+ cytotoxic T cells inthe absence of B cells in the inflamed area of the spinal cord suggests that the intrathecal synthesis of
kes plutopsy GAD65 autoantibodies ta
Stiff person syndrome (SPS) characterized by muscular rigid-ty and superimposed spasms has been known for more than 50ears . The spectrum of SPS-related disorders also comprises theore localized stiff limb subtype , the jerking man syndrome
3], and progressive encephalomyelitis with rigidity (PER) . Therequent finding of autoantibodies against glutamic acid decarboxy-ase (GAD) 65 and the association with other autoimmune diseasesuggest an immune mediated mechanism [5,6]. Accordingly, trans-er of serum induces a SPS-like phenotype in rats , but it is notlear if or how these antibodies reach GAD65 within the cytoplasmaf neurons. More knowledge of the pathology related to clinicalxpressions of SPS is therefore warranted.
We have previously reported that the GAD65 autoantibodies in
SF and serum are oligoclonal and have high binding avidity .ne patient with substantial intrathecal production of oligoclonalAD65 autoantibodies and clonal expansion of GAD65 specificD4+ T cells  (patient SPS 3 in the original reports) has deceased,
Corresponding author at: Department of Neurology, Ullevl University Hospital,407 Oslo, Norway. Tel.: +47 23073773; fax: +47 23073510.
E-mail address: [email protected] (T. Holmy).
303-8467/$ see front matter 2009 Elsevier B.V. All rights reserved.oi:10.1016/j.clineuro.2009.06.005
ace in areas of the CNS not strictly related to the clinically relevant lesions. 2009 Elsevier B.V. All rights reserved.
thereby allowing combined interpretation of clinical, immunologi-cal and histological data. The symptoms included both stiffness andspasms typical of SPS as well as lower motor signs, and autopsyrevealed unilateral infiltration of cytotoxic T cells and microgliaactivation in the anterior horn of the lower part of the spinal cord.We discuss the potential pathogenic relevance of these findings forthe clinical symptoms and signs in this patient.
2. Case history
A previously healthy 67-year-old male presented with rapidlyevolving and painful flexor cramps of the toes on his left foot, fol-lowed by fasciculations and muscle atrophy in the left leg. Thecondition progressed rapidly with marked muscular rigidity andpainful superimposed spasms. This was most prominent in the leftleg, but subsequently also involved the right limb and truncus lead-ing to frequent falls and immobilisation. Neurological examination7 months after symptom debut revealed generalized atrophy in theleft leg with paralysis of the left ankle. Muscle stiffness was promi-
nent in the left leg but was also found in the right leg and the trunk,corresponding to a stiffness score of five out of six possible points atthe SPS stiffness extent scale . Moreover, auditory, somatosen-sory, emotional and visual stimuli and attempts to move the left legtriggered painful muscle cramps, corresponding to six out of seven
and Neurosurgery 111 (2009) 708712 709
Fig. 1. Neuron damage in the anterior horn of the lower spinal cord. Axonal swellings(A) and anterior horn cell chromatolysis (B) were most pronounced in the lower
T. Holmy et al. / Clinical Neurology
ossible points at the SPS heightened sensitivity scale . The ten-on reflexes were absent in the left leg, weak in the right leg, andormal in both arms. Babinski sign was negative on the right side,nd indifferent on the left.
Electromyography of the left leg 10, 13, 14 and 16 months afterymptom onset showed continuous motor activity and signs ofenervation with positive sharp waves. At month 10 after symp-om onset, routine blood tests including glucose and electrolytes,xtensive radiological examinations of the neuraxis, malignancyorkout, antibodies against gangliosides, voltage gated potassium
hannels, pancreas islets, gephyrin, ampiphysin, DNA and thyroxineroxidase were all normal. Serum creatinine increased gradu-lly to 1717 units/ml (normal
T. Holmy et al. / Clinical Neurology
eport of predominant lower motor involvement in the lower limb.he patient also suffered typical symptoms of SPS with tonicallyaintained rigidity and muscle cramps, supporting the relevance
f the concept SPS plus syndromes .The immunopathological findings comprised intrathecal syn-
hesis of high-avidity oligoclonal IgG antibodies against GAD658], evidence of clonally expanded GAD65125136 specific CD4+ Tells restricted by DRB1*0801 , and infiltration of cytotoxic CD8+
cells and microglia activation in the spinal cord. Lymphocyteuffing of small CNS vessels is a typical finding in PER .imilar findings have been reported in some cases with typical SPS12,14,1821], whereas others have not found evidence of inflam-
ation [22,23]. Vacuolar degeneration of anterior horn cells at theumbar segments of the spinal cord associated with prominent
icroglia proliferation has previously been described in a patientith atypical SPS . T cell infiltration and microglia activationay play a primary pathogenic role, but could also be secondary
o neuronal damage caused by other factors. Thus, T cell infil-ration and microglia activation is observed also in degenerativeiseases like amyotrophic lateral sclerosis and its animal model25]. This distinction has therapeutic implications, because aggres-ive anti-inflammatory treatment would hardly be beneficial unlesshe inflammation is pathogenic. CD8+ cytotoxic T cells may recog-ize antigen presented on HLA class I molecules by neurons ,nd are believed to be important effector cells in inflammatory CNSisorders . HLA class I expression has not been studied in SPS orER, but has been demonstrated on neurons in both inflammatorynd degenerative CNS diseases . It is therefore conceivable thatnfiltrating T cells could contribute to the irreversible and destruc-ive changes observed in some patients with SPS-related disease,ncluding the focal neurodegeneration observed in our patient.owever, although the co-localization of inflammation and lowerotor neuron involvement makes it tempting to speculate on a
ausal relationship, it should be emphasized that the T cell infil-