Neurology International 2009; volume 1:e15

Mills’ syndrome: case report intensely then the left one, with no signs of . Correspondence: Osvaldo J.M. Nascimento, Rua. Screen for HIV, HTLV I-II, VDRL, FTA-ABS Siqueira Campos, 53|1204, Copacabana, Rio de Fábio Henrique de Gobbi Porto,1 were negative, as well as serum rheumatolog- Janeiro. E-mail: [email protected] Marco Orsini,1,2 Marco Antônio Araújo ic tests including antiphospholipid antibody, Leite,1,2 José Moreira dos Santos,1 Key words: Mills’ syndrome, hemiplegia. PTH, calcium and protein electrophoresis. Soraia Pulier,1 Mariana Mello,1 Analysis of spinal fluid showed no abnormali- Received for publication: 25 September 2009. Osvaldo J.M. Nascimento1 ties. Revision received: 19 October 2009. Outpatient Needle electroneuromyography showed evi- Accepted for publication: 26 October 2009. Division, Federal Fluminense University, dence of chronic denervation in the left first This work is licensed under a Creative Commons 1 dorsal interosseous and left and right gastroc- UFF Department of Neurology, UFF, Attribution 3.0 License (by-nc 3.0). Antônio Pedro University Hospital nemius muscles. Nerve conduction studies (HUAP); 2Grande Rio University, UNI- were normal. Complementary investigation ©Copyright F.H. de Gobbi Porto et al., 2009 GRANRIO, Rio de Janeiro, Brazil with brain MRI showed subtle hypersignal Licensee PAGEPress, Italy lesion in the right corona radiata, without con- Neurology International 2009; 1:e15 trast enhancement, that is unspecific and doi:10.4081/ni.2009.e15 could not explain the neurologic syndrome, a Introduction mild dilatation of the left lateral ventricle and diffuse bilateral hyperintensities along the low-up in our outpatients’ clinic at regular pyramidal tract extending from corona radiate The syndrome of progressive, ascending or intervals. Another EMG study should be per- to brainstein (Figure A and B). Tractography formed later in this patient to pursue more evi- descending hemiplegia, with no significant did not showed abnormalities in the pyramidal dence of denervation. sensory impairment was first describes by fibers. MRI of the cervical, thoracic and lumbar 1 Mills in 1900, which several cases were report- spinal MRI was normal. The patient was ed later. However, after diagnostic tests and already using riluzole 100 mg per day and lithi- image improvements, the number of reports um carbonate 600 mg per day (introduced only 2 Discussion has shortened. A possible explanation for this before our evaluation by other medical serv- shortage is the identification of other diseases ice). We discussed the possibility of a motor that could mimic the clinical picture. This patient presented a progressive neuron disease with the patient and by con- ascending motor neuron disease, with a clear Currently, the syndrome has an uncertain sensus; we resolved to keep on the medica-useasymmetric involvement, with slow nosological status, since it was described tions despite the lack of certitude about the progression. Although his symptoms were based on clinical examination only. We can 5 diagnosis and the efficacy of lithium therapy. compatible with fasciculations (muscle twitch- find this clinical presentation (Mills syn- At the follow-up visit, one year after initial es sensation), only upper motor neuron find- drome) in cases of amyotrophic lateral sclero- evaluation, neurologic examination showed ings were evident on clinical examination. sis (ALS), predominant upper motor neuron the same pattern of with a slight MRI was nondiagnostic. Needle electroneu- amyotrophic lateral sclerosis (UMN-ALS) and worst in the pelvic girdle muscles on the right romyography showed mild signs of denerva- primary lateral sclerosis (PLS), besides its side and in spasticity. He did not have any sign tion on muscles of cervical segment on left and symptomatic (secondary) forms. We describe a of atrophy or , yet he still com- right side and lumbosacral segment in both case (initial presentation and one year follow- plained sensation of muscles twitches. He was lowers limbs. Other possible causes such as up) of progressive ascending hemiplegia with still able to walk with help of a calf, and denied metabolic, infectious, immunologic, and clinical isolated upper neuron signs and nor- any bulbar or cognitive symptom. Needle elec- hereditary were excluded by history and com- mal sensory examination, discussing its noso- troneuromyography showed normal sensory plementary studies. A PET scan was consid- logical status, electromyographic findings, dif- and motor nerve conduction velocities and ered but unfortunately, the exam was not avail- ferential diagnosis and prognosis. signs of active denervation in distal muscles of able in our service. What should then be the the four extremities at needle electromyogra- diagnosis of this patient? Non-commercialphy. These signs of denervation were repre- According to the current proposed diagnos- sented for positive sharp waves 1 or 2+/4+ or tic criteria, this patient has neither ALS nor Case Report potentials 1 or 2+/4+ and rare fas- PLS.6-8 ciculation potentials with reduced recruitment ALS is a neurodegenerative motor neuron A man, 55-year-old engineer, was evaluated of large-amplitude long-duration motor unit disease, in which the current criterion in the neurology unit presenting a 2-years his- action potentials in the affected muscles; these requires evidence of both upper motor neuron tory of progressive weakness initially on left muscles were the right and left first dorsal and lower motor neuron (LMN) degeneration. lower limb, ascending after 6 months to the left interosseous of the hands and right and left This should be demonstrated by clinical, elec- upper limb. He had difficulties to walk and con- first dorsal interosseous of the foot. This EMG trophysiological, or neuropathological exami- stantly fell down. He described occasional feel- finding was suggesting active denervation but nations. According to the disease’s pattern, the ing of muscle twitches and frequent in did not fulfill the EMG parameters of El symptoms ought necessarily to spread and the left leg. He denied any abnormal sensation Escorial Criteria, which are the needed evi- progress within a segment and from one seg- or altered perception. He didn’t have abnormal dences of lower motor neuron degeneration in ment throughout others (cranial, cervical, tho- bladder and bowel function or difficulties to two muscles supplied by different nerve roots racic and lumbosacral) in order to attend ALS swallow. or nerves in a limb. criteria.6 The El Escorial electrophysiological Neurological examination showed left hemi- We discussed the diagnosis with the patient criterion calls for signs of ongoing/acute den- paresis3 with , spastic hypertonia4 and offered the possibility to remain with rilu- ervation (fibrillation potentials and positive and Babinski sign. Although, on the right side, zol and lithium for possible ALS with atypical sharp waves) and chronic denervation/rein- just the patellar jerk was increased, it was less presentation. The patient remained under fol- nervation (large motor units, reduced interfer-

[page 54] [Neurology International 2009; 1:e15] Case Report ence patters with firing rates higher than 10Hz, and unstable motor units), in at least AB one muscle innervated by cranial, and thoracic segments. Association of at least two muscles innervated by different peripheral nerves and roots are also required in the cervical and lum- bosacral segments.6,9,10 Primary lateral sclerosis is an idiopathic neurodegenerative disorder of UMN, with slowly progressive spastic paresis, usually beginning in the lower limbs and evolving to a spastic tetraparesis, with marked pyramidal signs, and bulbar involvement.11 The two pro- posed criteria7,8 for PLS require the absence of LMN signs on clinical, and electrophysiological examination during the first three years of dis- ease. Other authors prefer four years for a bet- Figure 1. (A) Axial FLAIR MRI: mild rounded foci of high sign intensity in right coro- ter diagnostic specificity.12 Moreover, some na radiata (arrow). (B) Coronal T2 weight MRI: mild dilatation of the right lateral ven- authors doubt the existence of isolated UMN tricle (large arrow) and diffuse bilateral hyperintensities along the pyramidal tract syndrome, arguing that it is one end of a con- extending from corona radiate to brainstein (thin arrows). tinuous spectrum of motor neuron diseases.13 Regardless this discussion, proposed diagnos- tic criterion for PLS excludes any lower motor neuron involvement on EMG, even with asymp- tomatic. upper motor neuron syndrome. Two patients a new form of degenerative disease. J Nerv Predominant upper motor neuron ALS12 is had clinical features similar to the cases onlyMent Dis 1900;27:195-200. evidenced by degeneration mainly in UMN, described by Mills, and demonstrated marked 2. Rajabally YA, Hbahbih M, Abbott RJ. Hemi- with clinical signs and disability due to corti- increases in binding in the superior frontal plegic ALS: Mills syndrome. Neurology cospinal or corticobulbar damage. However, region (supplementary motor region) con- 2005;64:1984-1985. only minor clinical and EMG involvement of tralateral to the affected limbs. use 3. Medical Research Council. Aids to the LMN, which are not severe enough to meet What is called Mills’ syndrome could be all investigation of peripheral nerve injuries. ALS diagnostic criteria, may be present. UMN- the variant of motor neuron diseases spectrum War Memorandum (revised 2nd edition). ALS is different from classical ALS in the pro- (ALS, PLS or UMN-ALS) in a hemiplegic, or London: HMSO, 1943. gression rate and time of survival, which asymmetrical pattern of involvement. A syn- 4. Bohannon RW, Smith MB. Inter-rater reli- enables a better long-term prognosis. drome is a collective of symptoms and signs ability of a modified Ashworth scale of In 1900, Mills1,14 described eight cases of a that could have many etiologies. Therefore, muscle spasticity. Phys Ther 1987;67:206- very slow progressive form of hemiplegia Mills syndrome should be conceptualized as a 207. beginning usually in the extremity of a lower motor neuron syndrome with a hemiplegic or 5. Fornai F, Siciliano G, Manca MA, Murri L, limb, then ascending to the homolateral upper markedly asymmetrical pattern of involvement, Paparelli A, Ruggieri S. Lithium in ALS: limb and believed it was a new motor neuron not like a different disease. This vision is rein- from the bench to the bedside. Amyotro- disease. Some cases were reported later, but forced by recent reports2,20-23 that several dis- phic Lateral Sclerosis 2008;9:123-4. fewer of them after advances in diagnostic eases could cause this patters, including 6. Brooks BR, Miller RG, Swash M, et al. El methods.15-18 In those cases pyramidal signs Waldenström macroglobulinemia, antiphos- Escorial revisited: revised criteria for the were always seen on the side of hemiplegia pholipid syndrome, progressive multiple scle- diagnosis of amyotrophic lateral sclerosis. and often bilaterally, and a moderate amyotro- rosis, myelitis of unknown origin and multiple Amyotroph Lateral Scler Other Motor phy without fasciculations can be commonly infarctions. Moreover, the paucity of neu- Neuron Disord 2000;1:293-299. seen. The symptoms are graduallyNon-commercial progressive, ropathological data from autopsies, and the 7. Pringle CE, Hudson AJ, Munoz DG, and the progression is frequently more ascend- lack of distinction between these motor neu- Kiernan JA, Brown WF, Ebers GC. Primary ing than descending, and the palsy can also ron diseases call in to question the concept of lateral sclerosis: clinical features, neu- involve the facial muscles. Sensory distur- Mills syndrome as a new nosological entity. ropathology and diagnostic criteria. Brain bances are generally absent. There was no With this study, we propose that the clinical 1992; 115:495-520. family history of the syndrome in any of the syndrome of progressive ascending or 8. Zhai P, Pagan F, Statland J, Butman JA, cases. Gastaut et al.14 published in 1994 two descending hemiplegia, or even those with Floeter MK. Primary lateral sclerosis: A further cases, similar to the ones described by bilateral but marked asymmetry, without sig- heterogeneous disorder composed of dif- Mills. The postmortem findings in one of Mills’ nificant sensory impairment, should be called ferent subtypes? Neurology 2003;60;1258- original cases even described lesions at the Mills’ syndrome, considering that there are 65. level of the brainstem and spinal cord, sparing several diseases that may cause it. 9. Makki AA, Benatar M. Diagnostic accuracy the motor cortex.19 The clinical picture present- of thoracic paraspinal electromyography in ed by our patient is very similar to that amyotrophic lateral sclerosis. J Clin described previously. Neurophysiol 2007;24:298-300. A study conducted by Turner et al.20 used an References 10. de Carvalho M, Dengler R, Eisen A, et al. 11C-(R)-PK11195 positron emission tomogra- Electrodiagnostic criteria for diagnosis of phy (PET) to explore and delineate in vivo the 1. Mills CK. A case of unilateral progressive ALS. Clin Neurophysiol 2008;119:497-503. cortical lesion in clinically isolated cases of ascending , probably representing 11. Tartaglia MC, Rowe A, Findlater K, et al.

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Differentiation between primary lateral de paralysie spinale ascendante chronique tion of the pyramidal tracts. J Nerv Ment sclerosis and amyotrophic lateral sclero- a pridominance unilaterale. Rev Neurol Dis 1903;30:385-97. sis: examination of symptoms and signs at 1927;1:585-98. 20. Turner MR, Gerhard A, Al-Chalabi A, et al. disease onset and during follow-up. Arch 16. Decourt J. Un cas d'hemiplegie spinale Mills’ and other isolated upper motor neu- Neurol 2007;64:232-6. ascendante chronique. Rev Neurol 1930;2: rone syndromes: in vivo study with 11C- 12. Gordon PH, Cheng B, Katz IB, et al. The 557-60. (R)-PK11195 PET. J Neurol Neurosurg natural history of primary lateral sclerosis. 17. Lhermitte J, Albessar V. L'hemiplegie Psychiatry 2005;76:871–874. Neurology 2006;66:647-53. ascendante progressive a evolution pro- 21. Lachaud S, Soriani MH, Delmont E, Budai 13. Le Forestier N, Maisonobe T, Piquard A, et longee. Gazette des Hopitaux (Paris) M, Desnuelle C, Lebrun C. Syndrome de al. Does primary lateral sclerosis exist? A 1934;11:185-90. Mills: une entité clinique rare. Rev Neurol study of 20 patients and a review of the lit- 18. Cossa P, Lombard P, Martin P. Sur deux cas 2007;163:335-40. erature. Brain 2001;124:1989-1999. de syndrome pyramidal lentement pro- 22. Dalla Volta G, Magoni M, Vangi D, Vignolo 14. Gastaut J-L, Bartolomei F. Mills’ syndrome: gressif et secondairement bilateralise. LA. Role of MRI in the diagnosis of Mills ascending (or descending) progressive Syndrome de Mills? Rev Neurol 1951; syndrome. Ital J Neurol Sci 1989;10:519-21. hemiplegia: a hemiplegic form of primary 84:327-30. 23. Doran M, Enevoldson TP, Ghadiali EJ, lateral sclerosis? J Neurol Neurosurg 19. Mills CK, Spiller WG. A case of progressive- Larner AJ. Mills syndrome with dementia: Psychiatry 1994;57:1280-81. ly developing hemiplegia later becoming broadening the phenotype of FTD/MND. J 15. Guillain G, Thevenard D, Decourt J. Un cas triplegia resulting from primary degenera- Neurol 2005;252:846-7.

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