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Myotonie dystrophy: A quantification of some clinical aspects of the classical form J.P. ter Bruggen MYOTONIC DYSTROPHY: A QUANTIFICATION OF SOME CLINICAL ASPECTS OF THE CLASSICAL FORM J.P. ter Bruggen MYOTONIC DYSTROPHY: A QUANTIFICATION OF SOME CLINICAL ASPECTS OF THE CLASSICAL FORM A clinical and neurophysiological investigation (met een samenvatting in het Nederlands) Een wetenschappelijke proeve op het gebied van de Medische Wetenschappen PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Katholieke Universiteit Nijmegen, volgens besluit van het College van Decanen, in het openbaar te verdedigen op vrijdag 16 september 1994 des namiddags te 1.30 uur precies door Jan Pieter ter Bruggen geboren op 11 december 1954 te Meppel Thesis ICG Printing Dordrecht promotor: Prof. Dr. F.J.M. Gabreëls co-promotores: Dr. C.J. Höweler (University of Limburg) Dr. C.C. Tijssen (St. Elisabeth Hospital, Tilburg) Dr B.A.M. Maassen This investigation was performed on the departments of neurology and ophthalmology of the St. Elisabeth and Maria Hospitals, Tilburg, the Netherlands; the IKNC of the University of Nijmegen, the Netherlands. Additional investigations took place on the departments of clinical neurophysiology of the St. Elisabeth Hospital, Tilburg, the Netherlands, FC Donders Institute of Ophthalmology, Utrecht, the Netherlands and Canisius Hospital, Nijmegen the Netherlands. The publication of this thesis was supported by De Wever Hospital Heerlen, Bosch Medicentrum, Carolus-Liduina Hospital, Smith Kline and French, DAGRA, UCB, CIBA-Geigy, Norwich Eaton, SANOFI, Eh/Lilly, MSD, Anens Kapperfonds, Glaxo, Bayer, Duphar, Katwijk, Boehnnger-Ingelheim, Syntex, Allergan, Schering- Plough, Byk, Nycomed and Toennies CIP-GEGEVENS KONINKLIJKE BIBLIOTHEEK, DEN HAAG ter Bruggen, Jan Pieter A quantification of some clinical aspects of the classical form/ Jan Pieter ter Bruggen - proefschrift Nijmegen - met samenvatting in het Nederlands ISBN 90-9007185-7 Trefw myotonic atrophy \ dystrophy picture frontpage Statue of the Cyclads (2000 ВС) If one selfishly sees a thing as if it were everything, independent of the one and many, then one is in the darkness of ignorance. Anonymus, Bhagavad Gita ca. 1000 ВС Scientific work is investigating throughout some minor aspects in detail, which finally fit in a universal theory. Stephen J. Gould, Wonderful Life 1989 The main results from this thesis are reported in the following papers: - ter Bruggen J.P., Bastiaensen L.A.K., Tijssen CC, Gielen G. Disorders of eye movement in myotonic dystrophy. Brain 1990Д13: 463-473. - ter Bruggen J.P., Tijssen C.C., Brunner H.G., van Oost Β.Α., Bastiaensen L.A.K. Eye movement disorder: an early expression of the myotonic dystrophy gene? Muscle and Nerve 1992; 15: 358-361. - ter Bruggen J.P., van Meel G.J., Paridaens A.D.A., van Norren D., Tijssen C.C. Foveal photopigment kinetics-abnormality: an early sign in myotonic dystrophy? Br J Ophthalmol 1992; 76: 594-597 - Verhagen W.I.M., ter Bruggen J.P., Huygen P.L.M. Oculomotor, auditory and vestibular responses in myotonic dystrophy. Arch Neurol 1992; 49: 954-960 - ter Bruggen J.P, Tijssen C.C. Myotonic dystrophy: the natural history of eye movement disorders. Neuro-ophthalmology: 1993: 13:2: 85-88. - ter Bruggen J.P., van Ditzhuijsen Th.J., Gabreëls F.J.M. Myotonic dystrophy: functional bedside validation of silent dysphagia (submitted). - Maasen B.A.M., ter Bruggen J.P., Nanninga-Korver Α., van Spaendonck K.P.M., Weyn-Banningh E.W.A., Gabreëls F.J.M. Quantitative assessment of speech-motor programming and execution in mildly affected early-adult and adult myotonic dystrophy (submitted). - van Spaendonck K.P.M., ter Bruggen J.P., Weyn-Banningh E.W.A, Maasen B.A.M., van de Biezenbos J.B.M., Gabreëls F.J.M. Cognitive function in early adult and adult onset myotonic dystrophy with mild symptoms: neuropsychological and motor evidence (submitted). CONTENTS INTRODUCTION XI AIM AND OUTLINE OF THE STUDY XV CHAPTER 1 SELECTIVE REVIEW OF LITERATURE 1 CHAPTER 2 NEURO-OPHTHALMOLOGY 2.1 Disorders of eye movement in myotonic dystrophy. 27 2.2 Eye movement disorder: an early expression of the 39 myotonic dystrophy gene? 2.3 Myotonic dystrophy: the natural history of eye 47 movement disorders. 2.4 Foveal photopigment kinetics-abnormality: an early 53 sign of myotonic dystrophy? CHAPTER 3 NEURO-OTOLOGY 3.1 Oculomotor, auditory and vestibular responses in 63 myotonic dystrophy. CHAPTER 4 BULBAR DYSFUNCTION 4.1 Myotonic dystrophy: functional bedside validation of 79 silent dysphagia. 4.2 Quantitative assessment of speech-motor programming 87 and execution in mildly affected, early-adult and adult myotonic dystrophy. CHAPTER 5 NEUROPSYCHOLOGY 5.1 Cognitive function in early adult and adult onset 97 myotonic dystrophy with mild symptoms: neuropsychological and motor evidence. CHAPTER 6 GENERAL DISCUSSION AND EPILOGUE 109 6.1 SUMMARY & SAMENVATTING 119 REFERENCE LIST 129 DANKWOORD 145 VII ABBREVIATIONS BRS: bulbar rating scale CPP: crystals in the cortex posterior CTG: cytosin-thymin-guanin CAPK: cAMP dependent protein-kinase CMR02: cerebral metabolic rate of oxygen CVLT: Calnifornia Verbal Learning Test DC: dustlike crystals EDS: excessive daytime sleepiness EL: educational level EMR: eye movement registration EOG: electro-oculography EOM: extra-ocular muscles ERP: event related potentials FWL: focal white matter lesion ICD: inter commisurai distance IL: iridescent lucencies IWD: interwave delay LL-index: liplength-index LPS: light peak substance MDRS: muscular disability rating scale MRR: maximum repetition rate MSP: maximum sound prolongation MT-PK gene: myotonin protein kinase gene mutated in MyD MyD: myotonic dystrophy OH: ocular hypotonia OKN: optokinetic nystagmus PCC: polychromatic crystals PTA: pure tone audiogram RPE: retinal pigment epithelium SI or S-index: snout-index SP: smooth pursuit ST: swallowing test SWCT: Stroop Word Colour Test TMT: Trailmaking Test VFT: Verbal Fluency Test Vmax: maximum velocity of the visually guided saccades VOR: vestibulo-ocular-reflex WAIS: Wechsler Adult Intelligence Scale WCST: Wisconsin Card Sorting Test IX INTRODUCTION Myotonic dystrophy (MyD) has been recognized as a disease entity for approximately a century. In the same year Batten and Gibb (1909) and Steinert (1909) independently reported a series of patients with progressive muscular atrophy and weakness of facial and distal limb muscles, who were unable to relax the hand muscles after a forceful contraction (myotonia). During the following decennia, the involvement of multiple organ-systems was defined: cardiac conduction defects, smooth muscle involvement, hypersomnia, reduced intelligence and a lack of initiative in the early onset cases. These were accompanied by cataracts, abnormal glucose response, increased anaesthetic risk and in males, typical premature baldness and testicular atrophy (Harper, 1989). Since 1992, a diagnostic accuracy nearing 100% can be reached by a combination of clinical examination and DNA techniques (Reardon et al., 1992; Mahadevan et al., 1992; Brunner, thesis, 1993; Wieringa, 1994). At present, despite significant effort, there remains no treatment that will alter the natural history of muscular dystrophy (Harper, 1989). The early contributions by Fleischer (1918) and Vogt (1921) described in detail the inheritance pattern, using the typical multi-coloured cataract as a marker for MyD. Fleischer (1918) suggested that MyD is a hereditary illness, the severity of which depends on the age of onset and increases in successive generations. The disease may be transmitted for many generations without obvious symptoms, with the possible exception of cataract. This peculiar autosomal dominant inheritance pattern was confirmed by others in several other countries (Thomasen, 1948; Bell, 1947; Klein, 1958; Höweler, 1986, 1989). In Bell's review (1947), most studies revealed a remarkable trait: the disease presented earlier with increasing severity in subsequent generations (antici­ pation). This assumption was ignored by Penrose (1948) but confirmed by Klein (1985) and finally led to a reluctant acceptance of the anticipation theory by Höweler and associates, as shown in their work (1986, 1989). Three main clinical forms of MyD were recognized by Dyken (1969) and Dyken and Harper (1973): a 'congenital' adult and late onset form. This clinical classification was expanded by Höweler (1986) and more recently by Koch (1991), who divided their adult onset cases into two subgroups, these are, early adult and late adult (see Table 1). The late onset form of MyD is characterized by a very mild symptomatology: cataract is commonly the only feature, but in some cases a mild facial weakness and myotonia may be present. The 'congenital' form is the most severe, with at birth severe hypotonia, insufficient respiration and impaired swallowing (Harper, 1975; Hageman, 1993). Some of the cases may have talipes or arthrogryposis. Those surviving the neonatal period show mild to moderate mental retardation and later, develop the same pattern of muscular weakness as the adult onset form. This form, also termed the classical form of MyD has its onset in adolescence or in early or later adulthood. The majority of patients