atypical clinically diagnosed stiff-person syndrome response to dantrolene—a refractory case

$: Atypical clinically diagnosed stiff-person syndrome response to Dantrolene—A refractory case$
LETTERS TO THE EDITOR

INTRAMUSCULAR FIBROUS TISSUEDETERMINES MUSCLE ECHO INTENSITY INAMYOTROPHIC LATERAL SCLEROSIS

Ultrasound is a rapidly evolving technique that can beused in the diagnostic work-up of neuromuscular disor-ders.1 Affected muscles show diminished muscle thick-ness and increased echo intensity (EI).2–4 Previous stud-ies have shown that fat and fibrous tissue each canincrease EI. However, the exact cause of increased echointensity is not fully known.2,5,6

We compared the findings of an in vivo quantitativemuscle ultrasound study with the postmortem histopath-ological examination of a 62-year-old woman who hadamyotrophic lateral sclerosis (ALS). This patient died 27months after symptom onset. On autopsy, the diagnosisof ALS was confirmed.

Transverse ultrasound scans and total cross-sectionalmuscle specimens of nine different muscles were takenfrom the same standardized anatomical sites (Fig. 1).7

Autopsy was performed with the informed consent ofthe patient within 12 hours after death. Muscle speci-mens were fixed in 4% formalin; the fibers were orien-tated transversely for embedding in paraffin. The largestcross-sectional area of each sample was selected and cutin 4-lm-thick sections, which were stained with Massontrichrome. The percentages of perimysial and endomy-sial tissue and the percentage of interstitial fat weredetermined by digital image analysis.8

Ultrasound examinations were performed 3 monthsbefore the patient’s death. Details of the standardized pro-tocol and system settings have been described elsewhere.7

EI was determined quantitatively using histogram analy-sis, where the mean gray value of the muscle is expressedas a value between 0 (¼ black) and 255 (¼ white).7 Wefound that EI was increased in all muscles (mean 73, range52–91) to about twice the normal value (range 28–42).7

Histological examination showed a comparable per-centage of intramuscular fat (median 8.6%, range 4.9–16.2%) and fibrous tissue (12.5%, range 6.7–28.5%; Fig.1D). Fibrous tissue seemed to be more evenly distributedwithin the muscle, whereas fat was seen in small collec-tions (Fig. 1C). The sternocleidomastoid muscle was con-sidered an outlier and was not used for calculation of cor-

relations. EI was strongly correlated with fibrous tissue (r ¼0.86, P ¼ 0.007; Fig. 1D), and this correlation remainedafter correction for fat content (r ¼ 0.81, P ¼ 0.026). EIand the amount of fatty tissue were not correlated (r ¼�0.46, P ¼ 0.248), nor was there a correlation after correc-tion for fibrous tissue (r ¼ �0.07, P ¼ 0.886).

In both this study of a human neurogenic disorder andin a study of canine muscular dystrophy, fibrous tissue wasthe main contributing factor to increased muscle EI.5 How-ever, other studies have indicated that intramuscular fat alsocontributes to increased EI, as shown in patients with inflam-matory myopathies,2 in those with little or no fibrous tis-sue,2,6 and in obese subjects.9 In this study the amounts offibrous and fatty tissue were comparable, making it possibleto study the influence of both variables on EI simultaneously.The influence of fibrous tissue on EI appeared to be strongerthan that of fat, possibly due to differences in their distribu-tion within the muscle. Overall, this suggests that fibrosis isthe most important determinant of muscle EI in ALS.

Ilse M.P. Arts, MD1

H. Jurgen Schelhaas, MD, PhD1

Kiek C.N. Verrijp2

Machiel J. Zwarts, MD, PhD1

Sebastiaan Overeem, MD, PhD1

Jeroen A.W.M. van der Laak, PhD2

Martin M.Y. Lammens, MD, PhD2

Sigrid Pillen, MD, PhD1

1Department of Neurology, Donders Institute for Brain, Cognitionand Behavior, Centre for Neuroscience, Radboud UniversityNijmegen Medical Centre, Nijmegen, The Netherlands

2Department of Pathology, Radboud University Nijmegen MedicalCentre, Nijmegen, The Netherlands

1. Walker FO, Alter KE, Boon AJ, Cartwright MS, Flores VH, Hobson-Webb LD, et al. Qualifications for practitioners of neuromuscular ultra-sound: position statement of the American Association of Neuromuscu-lar and Electrodiagnostic Medicine. Muscle Nerve 2010;42:442–444.

2. Reimers CD, Fleckenstein JL, Witt TN, Muller-Felber W, PongratzDE. Muscular ultrasound in idiopathic inflammatory myopathies ofadults. J Neurol Sci 1993;116:82–92.

3. Arts IM, van Rooij FG, Overeem S, Pillen S, Janssen HM, SchelhaasHJ, et al. Quantitative muscle ultrasonography in amyotrophic lateralsclerosis. Ultrasound Med Biol 2008;34:354–361.

4. Pillen S, Arts IM, Zwarts MJ. Muscle ultrasound in neuromusculardisorders. Muscle Nerve 2008;37:679–693.VC 2011 Wiley Periodicals, Inc.

Letters to the Editor MUSCLE & NERVE March 2012 449

5. Pillen S, Tak RO, Zwarts MJ, Lammens MM, Verrijp KN, Arts IM,et al. Skeletal muscle ultrasound: correlation between fibroustis-sue and echo intensity. Ultrasound Med Biol 2009;35:443–446.

6. Reimers K, Reimers CD, Wagner S, Paetzke I, Pongratz DE. Skeletalmuscle sonography: a correlative study of echogenicity and morphol-ogy. J Ultrasound Med 1993;12:73–77.

7. Arts IM, Pillen S, Schelhaas HJ, Overeem S, Zwarts MJ. Normal val-ues for quantitative muscle ultrasonography in adults. Muscle Nerve2010;41:32–41.

8. van der Steen AF, Thijssen JM, van der Laak JA, Ebben GP, deWilde PC. Correlation of histology and acoustic parameters of

liver tissue on a microscopic scale. Ultrasound Med Biol 1994;20:177–186.

9. Nijboer-Oosterveld J, van Alfen N, Pillen S. New normal values forquantitative muscle ultrasound: obesity increases muscle echo inten-sity. Muscle Nerve 2011;43:142–143.

Published online in Wiley Online Library (wileyonlinelibrary.com).DOI 10.1002/mus.22254

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FIGURE 1. (A) An example of an ultrasonography scan of the biceps brachii, (B) a graphic representation of the scan, and (C) muscle

histopathology. Perimysial tissue is light gray in this image, muscle tissue is dark gray. Fat (not colored with this stain) was less evenly

distributed within the muscle compared with fibrous tissue (arrows). (D) Correlation of muscle echo intensity and the percentage of fi-

brous tissue. (E, F) Association between echo intensity and fat and between fat and fibrous tissue, respectively. The numbered

markers represent the following muscles: 1—right biceps; 2—left biceps; 3—right forearm flexors; 4—left forearm flexors; 5—right

quadriceps; 6—left quadriceps; 7—right tibialis anterior; 8—left tibialis anterior; 9—left sternocleidomastoid muscle. The latter muscle

was considered an outlier and was not used for calculation of correlation. [Color figure can be viewed in the online issue, which is

available at wileyonlinelibrary.com.]

450 Letters to the Editor MUSCLE & NERVE March 2012

SUBACUTE INFLAMMATORYDEMYELINATING POLYNEUROPATHYDISCLOSED BY MASSIVE NERVE ROOTENHANCEMENT IN CMT1A

Diffuse enlargement of peripheral roots and nerves ischaracteristic of hypertrophic hereditary neuropathy[Charcot–Marie–Tooth type 1 (CMT1) and Dejerine–Sottas diseases].1 A superimposed inflammatory processin a subgroup of patients with CMT disease is not a par-ticularly rare phenomenon, and this can raise importantconsiderations in the management of patients.2

We describe a 42-year-old patient with CMT1A associ-ated with the PMP22 duplication who first noticed mus-cle weakness of the hands and legs with mild gait diffi-culties at 20 years of age. The course of the disease wasslowly progressive until 1 month before admission to ourdepartment when, after 2 weeks of gastrointestinal dis-turbances and diarrhea, he developed intense low backpain, distal weakness of lower limb muscles, and severedifficulty walking and climbing stairs. In the followingdays, his condition rapidly worsened, and he becamebed-bound. Neurological examination showed bilateralpes cavus, atrophy, and moderate weakness of the distalintrinsic hand muscles; severe proximal and distal lowerlimb muscle weakness bilaterally; areflexia; and distalglobal hypesthesia in a glove-stocking distribution. Thepatient needed some help in arising from bed becauseof moderate truncal muscle weakness. The Lasegue signwas positive bilaterally at 30�. Cranial nerves, respiratorymuscles, and autonomic function were normal. Extensivebiochemical and hematological investigations, includingthyroid function, serum vitamin B12 and folate, autoim-

mune profile, anti-ganglioside GM1 antibodies, and se-rology for Campylobacter jejuni and hepatitis B and C werenegative.

Cerebrospinal fluid (CSF) examination showed ele-vated protein levels (1.5 g/L) with a normal cell count,but no oligoclonal bands. Electrophysiological studiesshowed motor nerve conduction velocity (MNCV) of 12m/s, amplitude of 2.3 mV, and distal latency (DL) of11.3 ms in the left ulnar nerve, and MNCV of 18 m/s,amplitude of 1.5 mV, and DL of 9.4 ms in the left me-dian nerve. No conduction blocks or temporal disper-sion were detected. No distal compound muscle actionpotentials from tibial or fibular nerves and sensory nerveaction potentials from median, ulnar, and sural nerveswere recorded. Fibrillation potentials and positive sharpwaves in both tibialis anterior and gemelli muscles weredetected on electromyography (EMG). Lumbosacralmagnetic resonance imaging (MRI) revealed hypertro-phy of multiple nerve roots with marked gadolinium–DTPA enhancement (Gd-DTPA) (Fig. 1A and B). Acourse of 2 g/kg of intravenous immunoglobulin over 5days was administered after 7 weeks of clinical progres-sion. The patient had rapid clinical recovery and promptregression of painful symptoms. Four months after ther-apy, lumbosacral MRI showed no Gd-DTPA rootenhancement (Fig. 1C).

This is the case of a patient who, 12 years after aCMT1A diagnosis, experienced a rapidly disablingincrease of painful distal weakness associated with lum-bosacral nerve root hypertrophy and marked Gd-DTPAenhancement on MRI examination. Spinal roots andplexus hypertrophy have been reported on MRI inpatients with long-duration chronic inflammatory demye-linating polyneuropathy (CIDP) in which gadoliniumenhancement is associated with an active phase of thedisease.3

The 7-week progression of symptoms and absence ofrelapse after therapy is consistent with the diagnosis of asubacute inflammatory demyelinating polyneuropathy(SIDP), a monophasic entity whose progression to nadiris between 4 and 8 weeks and in which relapses are notusually described.4 Serial lumbar MRI with gadolinium isa very sensitive tool for studying and monitoring inflam-matory processes and treatment responses and, inselected cases, it may be clinically useful when EMG orspinal fluid studies are not diagnostic.5 Identification ofan SIDP and early aggressive immunotherapy allows forfast and complete recovery. We suggest that, in genetichypertrophic neuropathies with rapid, painful worsen-ing, a superimposed inflammatory process must be sus-pected. If so, appropriate therapy should be undertakenrapidly to alleviate symptoms and avoid disablingsequelae.

Anna Mazzeo, MD1

Claudia Stancanelli, MD1

Massimo Russo, MD1

Francesca Granata, MD2

Luca Gentile, MD1

Rita Di Leo, MD1

FIGURE 1. MRI examination of the patient. (A) Sagittal SE T1-

weighted image after gadolinium–DTPA (Gd-DTPA) administra-

tion with a fat-saturation technique at clinical onset. Note the

enhancement of a hypertrophic nerve root (arrow). Axial SE T1-

weighted images after Gd-DTPA administration with a fat-satu-

ration technique: (B) at clinical onset, and (C) 5 months later.

Note enhanced hypertrophic nerve roots (arrow) in (B) and dis-

appearance of the contrast enhancement after therapy in (C).


Giuseppe Vita, MD1

Eduardo Nobile-Orazio, MD3

Antonio Toscano, MD1Department of Neurosciences, Psychiatry and Anaesthesiology,University of Messina, Messina, Italy

2Department of Radiological Sciences, University of Messina,Messina, Italy

3Second Neurology, Department of Translational Medicine,IRCCS Humanitas Clinical Institute, Milan University, Rozzano,Milan, Italy

1. Dyck PJ, Thomas PK. Peripheral neuropathies, 4th ed. Philadelphia:W.B. Saunders; 2004.

2. Ginsberg L, Malik O, Kenton AR, Sharp D, Muddle JR, Davis MB, et al.Coexistent hereditary and inflammatory neuropathy. Brain 2004;127:193–202.

3. Duggins AJ, McLeod JG, Pollard JD, Davies L, Yang F, ThompsonEO, et al. Spinal root and plexus hypertrophy in chronic inflamma-tory demyelinating polyneuropathy. Brain 1999;122:1383–1390.

4. Oh SJ, Kurokawa K, de Almeida DF, Ryan HF Jr, Claussen GC. Suba-cute inflammatory demyelinating polyneuropathy. Neurology 2003;61:1507–1512.

5. Gorson KC, Ropper AH, Muriello MA, Blair R. Prospective evalua-tion of MRI lumbosacral nerve root enhancement in acute Guillain–Barre syndrome. Neurology 1996;47:813–817.


---------------------------------------------------------PRETREATMENT ANTIBODIES AGAINSTACID a-GLYCOSIDASE IN A PATIENTWITH LATE-ONSET POMPE DISEASE

A 37-year-old woman with late-onset Pompe disease wasreferred to our center. She had an a-1,4-glucosidaseactivity (GAA) of 0.28 nmol/mg protein/min in fibro-blasts (reference range 0.01–0.3) and severely reducedactivity on muscle biopsy (17% of controls). DNA analy-sis revealed compound heterozygosity for the IVS1–13T>G mutation in one allele and the c.2066–2070dup mutation on the other. On examination, shehad a waddling gait and symmetrical weakness of hipflexors (4/5 according to the MRC scale). Pulmonaryfunction testing revealed a 28% decline in forced vitalcapacity (FVC) from sitting to the supine position. Thepatient started enzyme replacement therapy (ERT) withrecombinant human alglucosidase alfa (rhGAA), andblood samples for antibody titer determination wereobtained before the first infusion. Unexpectedly, she wasseropositive at baseline with an antibody titer of 100,and titers rapidly increased during the next assessmentsat weeks 12 and 24 (51,200 and 102,400, respectively).

No baseline antibody titers were detected in 11 otheradult Pompe patients (5 women, age range 37–72 years;6 men, age range 35–70 years). Antibody status wasdetermined by enzyme-linked immunosorbent assay andwas confirmed by a radioimmunoprecipitation assay. Theantibodies neither inhibited GAA enzymatic activity inthe patient’s serum nor interfered with the uptake ofrhGAA by human fibroblast cells in culture (GenzymeGeneral Clinical Lab Sciences). During treatment thepatient occasionally reported post-infusion fatigue andconjuctival erythema. After 6 months she decided to dis-continue ERT for personal reasons. A follow-up of anti-body status 26 weeks later revealed a titer of 6400.

Antibodies against rhGAA initially develop in mostpatients on ERT with a tendency, in the majority, towarddecreasing levels with continued therapy.1,2 Infants with-out endogenous enzyme [cross-reactive immunologicalmaterial (CRIM)-negative patients] are prone to develophigh antibody titers that affect treatment outcome.3 It isnot clear if sustained high antibody titers occur in adultpatients who all are CRIM-positive due to some residualprotein activity, although it seems that, if they occur,they affect the response to ERT.4 Our patient had pre-treatment antibodies against rhGAA. The cause of thispreexisting immunity remains unclear. Possibly, muscledestruction from any cause, even from the disease itself,may lead to the exposure of endogenous GAA to theimmune system. Immunologic recognition of GAAreleased from muscle might generate anti-GAA antibod-ies. However, muscle destruction and subsequent expo-sure of GAA to the immune system may occur in everypatient with Pompe disease. We speculate that additionalunknown genetic and environmental factors may definethis immune response in our case.

We are unaware of other patients with late-onsetPompe disease who have had antibodies against rhGAAat baseline. Previously, this has only been described in1 infantile-onset patient.5 No other reports regardingthe presence of antibodies against rhGAA before theinitiation of treatment in Pompe patients have beenpublished. Possibly, these patients represent a raregroup that develops an immune response, determinedby as-yet-unknown genetic or environmental factors,against endogenous GAA. Further investigation isneeded to elucidate why these antibodies occur andwhether they influence disease outcome and the effi-cacy of treatment. It also remains to be determinedwhether these patients require more intensive antibodymonitoring during follow-up.

Constantinos Papadopoulos, MD,

George K. Papadimas, MD, PhD,

Konstantinos Spengos, MD, PhD,

Panagiota Manta, MD, PhD

First Department of Neurology, University of Athens School ofMedicine, Eginition Hospital, Athens, Greece

1. Kishnani PS, Nicolino M, Voit T, Rogers RC, Tsai AC, WatersonGE, et al. Chinese hamster ovary cell-derived recombinant humanacid alpha-glucosidase in infantile-onset Pompe disease. J Pediatr2006;149:89–97.

2. van der Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J,Groeneveld GJ et al. A randomized study of alglucosidase alfa inlate-onset Pompe disease. N Engl J Med 2010;362:1396–1406.

3. Kishnani PS, Goldenberg PC, DeArmey SL, Heller J, Benjamin D,Young S, et al. Cross-reactive immunologic material status affectstreatment outcomes in Pompe disease infants. Mol Genet Metab2010;99:26–33.

4. de Vries JM, van der Beek NA, Kroos MA, Ozkan L, van Doorn PA,Richards SM, et al. High antibody titer in an adult with Pompe dis-ease affects treatment with aglucosidase alfa. Mol Gen Metab 2010;101:338–345.

5. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL,et al. Recombinant human acid (alpha) glucosidase: major clinicalbenefits in infantile-onset Pompe disease. Neurology 2007;68:99–109.


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POLG1 Arg953Cys MUTATION: EXPANDEDPHENOTYPE AND RECESSIVEINHERITANCE IN A BRAZILIAN FAMILY

Polymerase c (POLG) is a nuclear DNA–encoded enzymeresponsible for mitochondrial DNA (mtDNA) replication.A heterodimer composed of one alpha (140 kDa) encodedby POLG1 and two beta (41 kDa) subunits encoded byPOLG2, POLG resides in the inner mitochondrial mem-brane. The alpha subunit is catalytic and contains both po-lymerase and exonuclease activities, whereas the beta subu-nit facilitates DNA binding and promotes DNA synthesis.1

The first pathogenic mutation of POLG1 was describedin 2001 in families with autosomal dominant or recessivechronic progressive external ophthalmoplegia (PEO) andmultiple deletions of mtDNA inmuscle.2 Subsequent reportsexpanded the clinical spectrum associated with POLG1muta-tions. Autosomal dominant mutations usually cause PEOwith or without parkinsonism, whereas autosomal recessivemutations have been associated with Alpers syndrome (hep-atopathy, psychomotor regression, and refractory seizures),SANDO (sensory ataxia, neuropathy, dysarthria, ophthalmo-plegia), male infertility, premature menopause, cataracts, orearly-onset parkinsonism and neuropathy.3–8

In 2004, Luoma et al. described a heterozygousc.C2857T mutation, which changes an arginine to a cys-teine at amino acid position 953 (p.Arg953Cys), in apatient with PEO, muscle weakness, ataxia, asthma, andhypothyroidism.7

We describe a family with 3 affected siblings. The indexcase was a 33-year-old man with PEO, parkinsonism, neu-ropathy, and cardiomyopathy who harbored the

p.Arg953Cys mutation, as described by Luoma et al., in ahomozygous state. He initially presented with gait abnor-malities and PEO at 20 years of age. At age 30, he began tohave cognitive impairment and depressive and psychoticsymptoms. His oldest brother had similar symptoms anddied at 30 years of age during abdominal surgery. An oldersister had PEO and depression, and she committed suicideat age 29. The other 3 younger siblings were asymptomaticand had normal neurological examinations. The parentswere first cousins, but neither had neurological problems.At age 33, a neurological evaluation of the index patientrevealed masked face, bradykinesia, action tremor, stoopedposture, rigidity, complete ophthalmoplegia, and mildproximal limb weakness. Parkinsonism improved with pra-mipexole 3 mg/day. Electromyography and nerve conduc-tion studies showed a myopathic pattern and a sensorypolyneuropathy. Brain MRI showed diffuse cortical atro-phy, and echocardiography revealed a moderate cardiomy-opathy. Muscle biopsy showed numerous ragged-red fibers,which were COX-negative, and succinate dehydrogenase(SDH)-hyperreactive fibers (‘‘ragged blue’’ fibers). MultiplemtDNA deletions in muscle were detected by Southernblot analysis. Direct sequencing of POLG1 showed thep.Arg953Cys mutation in homozygosity. The mutation washeterozygous in the 2 asymptomatic brothers and absent inthe asymptomatic younger sister (Fig. 1).

In 2004, Luoma et al. reported an apparently sporadicpatient with isolated PEO associated with the p.Arg953Cysmutation. It was not stated whether the mutation washomozygous or heterozygous.8 Also, they were unable tostudy the parents of the patient and there were insuffi-cient data to define the mode of inheritance. Based onthis description, it was assumed that the p.Arg953Cysmutation causes autosomal dominant PEO, until now(see http://dir-apps.niehs.nih.gov/polg/).9

This study has clearly shown that p.Arg953Cys is anautosomal recessive mutation in our family and co-segre-gates with a more complex clinical phenotype: ophthal-moplegia; gait abnormalities; parkinsonism; sensory neu-ropathy; cardiomyopathy; and depression.

Juliana Gurgel-Giannetti, MD, PhD1

Sarah Teixeira Camargos, MD, PhD2

Francisco Cardoso, MD, PhD2

Michio Hirano, MD,3

Salvatore DiMauro, MD3

1Neuropediatric Service, Department of Pediatrics, MedicalSchool, Federal University of Minas Gerais, Belo Horizonte, MinasGerais, Brazil

2Neurology Service, Department of Internal Medicine, MedicalSchool, Federal University of Minas Gerais, Belo Horizonte, MinasGerais, Brazil

3Department of Neurology, Columbia University Medical Center,New York, New York, USA

1. Ropp PA, Copeland WC. Cloning and characterization of the humanmitochondrial DNA polymerase, DNA polymerase gamma. Genomics1996;36:449–458.

2. van Goethem G, Dermaut B, Lofgren A, Martin JJ, van BroeckhovenC. Mutation of POLG is associated with progressive external ophthal-moplegia characterized by mtDNA deletions. Nat Genet 2001;28:211–212.

FIGURE 1. Family pedigree and POLG gene sequencing: (A)

Patient (index case): homozygous for the C2857T mutation. (B,

C) Asymptomatic siblings: heterozygous for the C2857T muta-

tion. (D) Asymptomatic sibling: absence of the mutation. [Color

figure can be viewed in the online issue, which is available at

wileyonlinelibrary.com.]


3. Rovio AT, Marchington DR, Donat S, Schupp HC, Abel J, Fritsche E,et al. Mutations at the mitochondrial DNA polymerase (POLG)locus associated with male infertility. Nat Genet 2001;29:261–262.

4. van Goethem G, Martin JJ, Dermaut B. Recessive POLG mutationspresenting with sensory and ataxic neuropathy in compound hetero-zygote patients with progressive external ophthalmoplegia. Neuro-muscul Dis 2003;13:133–142.

5. Naviaux RK, Nguyen KV. POLG mutations associated with Alpers’syndrome and mitochondrial DNA depletion. Ann Neurol 2004;55:706–712.

6. Mancuso M, Filosto M, Bellan M. POLG mutations causing ophthal-moplegia, sensorimotor polyneuropathy, ataxia, and deafness. Neu-rology 2004;62:316–318.

7. Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN,Chalmers RM, et al. Parkinsonism, premature menopause, and mi-tochondrial DNA polymerase gamma mutations: clinical and molecu-lar genetic study. Lancet 2004;364:875–882.

8. Filosto M, Mancuso M, Nishigaki Y, Pancrudo J, Harati Y, Gooch C,et al. Clinical and genetic heterogeneity in progressive external oph-thalmoplegia due to mutations in polymerase c. Arch Neurol 2003;60:1279–1284.

9. http://dir-apps.niehs.nih.gov/polg. Human DNA Polymerase gammaMutation Database, 01/07/2011.


---------------------------------------------------------ATYPICAL CLINICALLY DIAGNOSEDSTIFF-PERSON SYNDROME RESPONSE TODANTROLENE—A REFRACTORY CASE

A 75-year-old woman had progressive ambulatory dys-function for 3 years, which was characterized by episodicpainful spasms and worsening axial and proximal musclestiffness. She felt increasingly ‘‘frozen,’’ accompanied byanxiety when she encountered obstacles, unexpectednoise, or contact. She experienced falls that resulted infractures. Examination revealed increased tone in theabdominal wall and paraspinal muscles without opistho-tonos. She had diffuse hyperreflexia without other py-ramidal signs, and motor, sensory, and cognitive exami-nations were normal. Laboratory studies were negativefor glutamic acid decarboxylase (GAD), anti-thyroid,amphiphysin, and gephyrin antibodies. Serum Lymetiters, collagen vascular disease screen, human T-lympho-cyte virus (HTLV) titers and creatine kinase (CK) wereall normal. Brain magnetic resonance imaging (MRI)and mammography were negative. Electromyography wasnegative for a primary muscle disorder; evaluation forco-contraction of agonists and antagonists with two-chan-nel recording was not completed. Her history was nega-tive for Hodgkin disease, colon, breast, or small-cell lungcancer, or thymoma.

Treatment of rigidity with baclofen 10 mg threetimes daily and diazepam 1 mg twice daily improvedsymptoms and functional status.1 Further titration waslimited by sedation, which increased the risk for falls.Based on the patient’s clinical presentation and findingson examination, which fulfilled the Gordon clinical diag-nostic criteria, she was diagnosed with stiff-person syn-drome (SPS). Indications included a prodrome of epi-sodic aching stiffness of axial muscles; progression tostiffness of proximal limbs; painful spasms elicited bytriggers; increased lumbar lordosis; normal sensation,motor function, and intellect; and response tobenzodiazepines.2

After a fall, she was admitted to rehabilitation whereshe required maximum assistance for transfers and mod-

erate assistance for grooming and feeding and hadunsafe ambulation (Table 1). An increase in baclofendose to 20 mg three times daily and addition of diaz-epam help truncal stiffness, but dosing was limited byprofound sedation and hypotension, which limited thediazepam dose to 2 mg/day. With poor tolerance of clas-sic SPS therapies1 outweighing functional improvement,dantrolene was initiated and titrated up to 50 mg fourtimes daily, which produced reduced rigidity andimproved participation and progress in rehabilitation.She advanced to minimal assistance with transfers, modi-fied independent with feeding, supervision with groom-ing, and upper extremity dressing. Walking advanced tominimum assistance with a platform rolling walker(Table 1). A dose-dependent relationship between dan-trolene and function was observed; dose reduction to 25mg four times daily due to concern for hepatotoxicitycaused a marked increase in rigidity and decline in func-tion followed by recovery after resumption at a dose of50 mg four times daily.

SPS is a progressive autoimmune central nervous sys-tem disorder characterized by muscle rigidity and spasmsresulting in a significant functional decline attributed toimpairment of c-aminobutyric acid (GABA)-ergic neuro-transmission mediated by pathogenic autoantibodies.This GAD-antibody-negative patient may have other auto-antibodies or mechanisms resulting in clinical manifesta-tion of the SPS phenotype. A spectrum of SPS character-istics have been noted, including intolerance or lack ofbenefit from baclofen and diazepam or GAD antibodynegativity.3

Aside from symptomatic GABA-enhancing drugs,intravenous immunoglobulin, and promising new B-cell therapies for SPS, the case presented demonstratesthat peripherally acting dantrolene, which dissociatesexcitation–contraction coupling and blocks release of

Table 1. Selected functional levels without and with dantrolene.

FIM domainsAdmission

score

Score withdantrolene 50 mg

twice daily

Self-careFeeding 3 6Grooming 3 5Bathing 2 3UE dressing 3 5LE dressing 1 3

TransfersBed, chair, wheelchair 2 4Toilet 2 3Tub, shower 0 3

LocomotionWalk 0 4

Functional independent measure scores: 7—independent, tasks can bedone in a timely manner and safely; 6—modified independent, patientneeds device to do a task; 5—supervision required; 4—minimal assis-tance, patient at >74% of the effort necessary to do a task; 3—moder-ate assistance, patient between 50% and 74% of the effort necessaryto do a task; 2—maximum assistance, patient can perform <50% ofthe effort necessary to do a task, but at least 25%; 1—dependent,patient can perform <25% of the effort necessary to do a task; 0—nottested.


Ca2þ from the sarcoplasmic reticulum, is an adjunctivetreatment for rigidity and functional decline in atypicalSPS. Further studies are needed to investigate thesafety, tolerability, and efficacy of dantrolene in refrac-tory SPS.

Adam L. Schreiber, DO, MA1

John M. Vasudevan, MD1

S. Kamal Fetouh, MD1

Nethra S. Ankam, MD1

Aamir Hussain, MD2

Goran Rakocevic, MD2

1Department of Rehabilitation Medicine, Thomas JeffersonUniversity, Philadelphia, Pennsylvania

2Department of Neurology, Division of Neuromuscular Medicine,Thomas Jefferson University, Philadelphia, Pennsylvania

1. Dalakas MC. Stiff person syndrome: advances in pathogenesis andtherapeutic interventions. Curr Treat Opt Neurol 2009;11:102–110.

2. Gordon EE, Januszko DM, Kaufman L. A critical survey of stiff-mansyndrome. Am J Med 1967;42:582–599.

3. Levy LM, Dalakas MC, Floeter MK. The stiff-person syndrome: anautoimmune disorder affecting neurotransmission of gamma-amino-butyric acid. Ann Intern Med 1999;131:522–530.


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atypical clinically diagnosed stiff-person syndrome response to dantrolene—a refractory case

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