BACKGROUND: Antibodies against glutamic acid decarboxylase (GAD) are associated with Stiff Person Syndrome (SPS). CASE REPORT: A 50-year-old woman presented with symptoms progressed over 9 years, resulting in a cerebellar ataxia and right upper limb tremor. Investigations revealed elevated serum and CSF anti-GAD antibody titres (98.6 and 53.4 μ/ml, respectively). Treatment included intravenous immunoglobulin and immunomodulation (infliximab and rituximab), improving her stiffness, but with no impact on the ataxia-related symptoms. Subsequent high-dose steroids led to diabetic ketoacidosis and unmasking of an insulin-dependent diabetes mellitus. DISCUSSION: This case illustrates several key features: (1) the combined clinical picture of SPS and cerebellar ataxia is a rare phenotype associated with anti-GAD antibodies; (2) the cerebellar ataxia described was progressive and poorly responsive to immunomodulatory therapy; and (3) the potential for development of further autoimmune sequelae in response to immunosuppression, namely, the development of insulin-dependent diabetes in response to treatment with high-dose oral steroids

Baber, W

Church, A

Jones, LA

Llewelyn, JG

Morris, HR

Peall, KJ

Robertson, NP

Wardle, M

English

UCL Discovery

1Case ReportsA Case of Treatment Resistance and Complications in a Patient with Stiff Person Syndrome and Cerebellar AtaxiaLliwen A. Jones1, Waqaar Baber2, Mark Wardle1, Neil P. Robertson1, Huw R Morris3,4,5, Alistair Church3, John G. Llewelyn1,3 & Kathryn J. Peall6*1Neurology Department, University Hospital of Wales, Heath Park, Cardiff, UK, 2School of Medicine, Cardiff University, Wales, UK, 3Royal Gwent Hospital, Cardiff Road, Newport, UK, 4Royal Free Hospital, Pond Street, London, UK, 5Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK, 6Neuroscience and Mental Health Research Institute, Hadyn Ellis Building, Cardiff University, Cardiff, UKIntroductionAntibodies against glutamic acid decarboxylase (GAD), the rate-limit-ing enzyme involved in γ-aminobutyric acid (GABA) synthesis, are associ-ated with several neurological disorders, including Stiff  Person Syndrome (SPS), epilepsy, myasthenia gravis, limbic encephalitis and cerebellar ataxia.1,2 However, concurrent presentation of  SPS, cerebellar ataxia and positive anti-GAD antibodies has only been reported in a limited number of  cases previously.3–5 Here, we describe such a case which demonstrates (1) this rare combination of  clinical features, including SPS and cerebellar ataxia, with limb and bulbar features; (2) symptom resistance, most nota-bly the cerebellar ataxia, to multiple immunomodulatory therapies; and (3) development of  further autoimmune sequelae, namely, insulin- dependent diabetes, following treatment with high-dose steroids. Figure 1 summarises symptom progression, treatment and anti-GAD titres over a 12-year period. The patient discussed has provided written informed con-sent for the publication of  this report.Case descriptionThe patient first presented at the age of  50 years, with a 9-month his-tory of  intermittent right lower limb stiffness, described by the patient as ‘spasms’. She described an inability to use her right foot on the brake pedal of  her car and had difficulty placing her right heel on the ground. Columbia University LibrariesFreely available onlineTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgAbstractBackground: Antibodies against glutamic acid decarboxylase (GAD) are associated with Stiff  Person Syndrome (SPS).Case report: A 50-year-old woman presented with symptoms progressed over 9 years, resulting in a cerebellar ataxia and right upper limb tremor. Investigations revealed elevated serum and CSF anti-GAD antibody titres (98.6 and 53.4 µ/ml, respectively). Treatment included intravenous immunoglobulin and immunomod-ulation (infliximab and rituximab), improving her stiffness, but with no impact on the ataxia-related symptoms. Subsequent high-dose steroids led to diabetic keto-acidosis and unmasking of  an insulin-dependent diabetes mellitus.Discussion: This case illustrates several key features: (1) the combined clinical picture of  SPS and cerebellar ataxia is a rare phenotype associated with anti-GAD antibodies; (2) the cerebellar ataxia described was progressive and poorly responsive to immunomodulatory therapy; and (3) the potential for development of  further autoimmune sequelae in response to immunosuppression, namely, the development of  insulin-dependent diabetes in response to treatment with high-dose oral steroids.Keywords: Stiff  Person Syndrome, GAD autoantibodies, cerebellar ataxia, movement disorder, cerebellum, autoimmune, anti-GAD, treatmentCitation: Jones LA, Baber W, Wardle M, Robertson NP, Morris HR, Church A, et al. A Case of  Treatment Resistance and Complications in a Patient with Stiff  Person Syndrome and Cerebellar Ataxia. Tremor Other Hyperkinet Mov. 2019: 9. doi: 10.7916/tohm.v0.677*To whom correspondence should be addressed. E-mail:PeallKJ@cardiff.ac.ukEditor: Elan D. Louis, Yale University, USAReceived: May 1, 2019; Accepted: August 12, 2019; Published: October 1, 2019Copyright: © 2019 Jones et al. This is an open-access article distributed under the terms of  the Creative Commons Attribution–Noncommercial–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original authors and source are credited; that no commercial use is made of  the work; and that the work is not altered or transformed.Funding: None.Financial Disclosures: None.Conflicts of Interest: The authors report no conflicts of  interest.Ethics Statement: All patients that appear on video have provided written informed consent; authorisation for the videotaping and for publication of  the videotape was provided.Jones LA, Baber W, Wardle M, et al. Complications of Treatment in Stiff Person SyndromeColumbia University LibrariesTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.org 2There was no previous medical or medication history. There was a strong family history of  thyroid disease (brother, mother, two maternal aunts, maternal grandmother) and adult-onset diabetes mellitus (DM) (mother and father). She had involuntary contraction of  the right lower limb muscles with the right foot held in plantar flexion. The remainder of  the neurological examination was normal. Serum, imaging and neu-rophysiological investigations were unremarkable, with the exception of  strongly positive anti-GAD antibodies in both serum and CSF at 98.6 µ/ml (normal range: 0–5 µ/ml) and 53.4 µ/ml (positive), respectively. She underwent two courses of  intravenous immunoglobu-lin (IVIg) treatment (2 g/kg) over two consecutive months with complete symptom resolution.Four years later her symptoms returned with additional balance diffi-culties and recurrent falls. She reported no autonomic or sensory symp-toms, and cognition was normal. These symptoms progressed over the subsequent year limiting activities of  daily living. Clinical examination at this time demonstrated ongoing involuntary stiffness of  the right side, but no overt clinical signs of  ataxia. Ten further courses of  IVIg over the subsequent 2 years provided only temporary functional improvement to her symptoms of  stiffness, lasting 6–8 weeks at a time, with further symptom progression, including dysarthria, dysphagia for liquids, right upper limb weakness and tremor. Examination at this time (5 years after initial presentations) revealed dysarthria, increased right-sided limb tone, mild right upper limb weakness, rigidity and hypertrophy of  the paraspinal muscles. Repeat serum anti-GAD antibody titres were ele-vated at >2,000 µ/ml (0–5 µ/ml) (5 years post-initial presentation; Figure 1); all other serum and CSF investigations, including serum cop-per, ataxia genetics screen, anti-tissue transglutaminase (TTG), -Caspr, -Lgi1, -Purkinje cell, -Hu, -Yo and -Ri antibodies, were negative or within normal limits. CSF anti-GAD antibody titres were not repeated after their initial measurement at presentation (53.4 µ/ml, 2002; Figure 1). Treatment with IV methylprednisolone (500 mg/day for 5 days) and plasma exchange (3 cycles in 5 days) provided no objective improvement.Eight years after her initial presentation, the patient reported increased difficulties with balance, swallowing and blurred vision. Clinical examination at this point revealed dysarthria, increased right-sided limb tone, with moderate finger to nose ataxia (right-side only) and dysdiadochokinesia. Examination of  her eye movements demon-strated square wave jerks in the primary position, broken smooth pur-suit movements and rotatory nystagmus at the extremes of  gaze. There was evidence of  paraspinal muscle spasm, rigidity and hypertrophy. She was able to walk unaided with circumduction and stiffness of  the right leg.The patient’s symptoms continued to progress, and 9 years after symptom onset, there was evidence of  impaired horizontal saccades, gaze-evoked nystagmus, dysarthria, immobility and a right-side pre-dominant, upper limb cerebellar ataxia with evidence of  dysmetria and intention tremor (Videos 1, 2 and 3). In spite of  a course of  immuno-modulatory treatment (two infusions of  infliximab and a single dose of  rituximab), her symptoms continued to deteriorate with no functional use of  the right hand and limited mobility. Examination at this time demonstrated broken-down smooth pursuit movements with gaze evoked nystagmus and mild dysarthria. She had moderate-to-severe fin-ger to nose ataxia on the right, alongside mild alternating movement ataxia. Finger-to-nose movement and rapid alternating movements were normal on the left. There was moderate heel-knee-shin ataxia and ongoing paraspinal muscle spasm. Drawing a spiral demonstrated Figure 1. Schematic Timeline of  the Clinical Progression of  Symptoms, Investigations and Treatment Received over a 12-Year Period. X-axis, progression of  years; Blue boxes, progression of  symptoms; Purple boxes, trend of  antibody titres; Green boxes, treatment given; anti-GAD, anti-glutamic acid  decarboxylase; IVIg, intravenous immunoglobulin.Jones LA, Baber W, Wardle M, et al. Complications of Treatment in Stiff Person SyndromeColumbia University LibrariesTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.org 3unsteadiness on the right, but was normal on the left. Oral prednisolone (80 mg/day) was commenced, but she rapidly developed pneumonia and diabetic ketoacidosis (DKA) having had no previous diabetic symp-toms. She was admitted to critical care for the management of  sepsis, DKA and respiratory failure and commenced on regular insulin following recovery. Anti-GAD antibody titres remained elevated (>2,000 µ/ml), and treatment was focused on symptom optimisation with diazepam, baclofen and amitriptyline.Video 1. Demonstrates Intention Tremor and Past-Pointing with Finger-Nose Testing in the Right Upper Limb. The video were undertaken at the same time point (2012), 10 years following symptom onset (Figure 1).Video 2. Demonstrates Slowed and Hypometric Right Horizontal Saccades. The video were undertaken at the same time point (2012), 10 years following symptom onset (Figure 1).Jones LA, Baber W, Wardle M, et al. Complications of Treatment in Stiff Person SyndromeColumbia University LibrariesTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.org 4DiscussionThis case illustrates some of  the systemic features of  disease associated with GAD auto-antibodies, which are more typically associated with the destruction of  pancreatic islet beta cells in autoimmune type 1 diabetes.6 Interestingly, in spite of  >45 case reports and case series describing cohorts of  individuals with features of  SPS and raised anti-GAD titres,7 the con-stellation of  symptoms described in this case, namely, the combination of  SPS and insidious-onset but progressive cerebellar ataxia, remains rarely reported. This potentially indicates a sub-group, or more severe pheno-type, of  this disorder that warrants further, independent investigation.Another key feature of  this case is the differential response of  the distinct symptom groups to immunomodulatory therapy. Initial treatment with IVIg proved successful in improving the SPS symptoms, maintaining good symptom control for more than 4 years. However, with subsequent onset of  the cerebellar ataxia, neither more frequent treatment with IVIg nor escala-tion of  immunomodulatory treatment (including steroids, plasma exchange and Rituximab) provided symptomatic relief. Hence, 5 years after symptom onset and an initial good response to treatment, this patient effectively devel-oped a “treatment resistance” to all available forms of  immunosuppression, with an ongoing worsening of  her clinical signs and symptoms.Finally, attempts at treatment escalation with further immunosup-pressive therapies ultimately resulted in the development of  additional autoimmune sequelae. While development of  DM following steroid treatment is widely recognised, the importance of  GAD function in pancreatic islet beta cells potentially makes this patient group more vul-nerable to the serious potential side effects of  immunosuppressive and immunomodulatory therapy. This emphasises the importance of  patient information and education regarding the potential side effects of  ther-apy before embarking on a treatment programme, and to advise seeking prompt medical advice in the case of  illness.AcknowledgementsThe authors would like to thank the patient discussed for providing consent to publication.References1. Solimena M, Folli F, Denis-Donini S, Comi GC, Pozza G, De Camilli P,et al. Autoantibodies to glutamic acid decarboxylase in a patient with  Stiff-Man Syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 1990;322(22):1555–1560.2. Ariño H, Gresa-Arribas N, Blanco Y, Martínez-Hernández E, Sabater L, Petit-Pedrol M, et al. Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of  immunotherapy. JAMA Neurol 2014;71(8):1009–1016. doi: 10.1001/jamaneurol.2014.10113. Rakocevic G, Raju R, Semino-Mora C, Dalakas MC. Stiff  person syn-drome with cerebellar disease and high-titer anti-GAD antibodies. Neurology 2006;67(6):1068–1070. doi: 10.1212/01.wnl.0000237558.83349.d04. Schaefer SM, Moeller JJ. Anti-GAD antibody syndrome with concomitant cerebellar ataxia, stiff  person syndrome, and limbic encephalitis. Neurol Clin Pract 2015;5(6):502–504. doi: 10.1212/CPJ.00000000000001485. Kono S, Miyajima H, Sugimoto M, Suzuki Y, Takahashi Y, Hishida A. Stiff-person syndrome associated with cerebellar ataxia and high glutamic acid decar-boxylase antibody titer. Intern Med 2001;40(9):968–971.6. Ali F, Rowley M, Jayakrishnan B, Teuber S, Gershwin ME, Mackay IR. Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies. J Autoimmun 2011;37(2): 79–87. doi: 10.1016/j.jaut.2011.05.0057. Sarva H, Deik A, Ullah A, Severt WL, Disease P, Sinai M, et al. Clinical spectrum of  Stiff  Person Syndrome: a review of  recent reports. Tremor Other Hyperkinet Mov (N Y) 2016;6:34.Video 3. Demonstrates Dysarthria with Staccato Speech. The video were undertaken at the same time point (2012), 10 years following symptom onset (Figure 1).

A Case of Treatment Resistance and Complications in a Patient with Stiff Person Syndrome and Cerebellar Ataxia

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A Case of Treatment Resistance and Complications in a Patient with Stiff Person Syndrome and Cerebellar Ataxia

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