Epilepsy Res,, 5 (1990) 251-254 Elsevier EPIRES 00328

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Autonomic nervous system function in Baltic myoclonus epilepsy Reetta K/ilvi/iinen a, Tapani Ker/inen b, Juha Mustonen c, Esko L~insimies d and Paavo Johannes Riekkinen a aDepartmentof Neurology, and bDepartmentof Pharmacology and Toxicology, Universityof Kuopio, SF-70210Kuopio (Finland), and CDepartmentof Medicine, and dDepartmentof ClinicalPhysiology, Kuopio UniversityCentralHospital, SF-70210 Kuopio (Finland) (Received 4 December 1989; accepted 12 December 1989) Key words: Baltic myocionus epilepsy; Autonomic nervous system; Cardiovascular reflexes

Baltic myoclonus epilepsy (BME) is a neurodegenerative disease characterized by tonic-clonic seizures, myoclonus and a progressive course. The aim of the present study was to assess the clinical symptoms and signs of possible involvement of the autonomic nervous system (ANS) and objectively evaluate autonomically mediated cardiovascular reflexes in this syndrome. Fifteen patients with BME and 14 healthy control subjects were studied. Thirteen (87%) of the patients had symptoms suggesting ANS dysfunction. The most common symptoms were postural dizziness and sweating disturbances. The heart rate variation during deep breathing was lower in patients than in controls. The heart rate response and systolic blood pressure response during tilting were similar in both groups. Our results suggest a mild parasympathetic hypofunction and an intact sympathetic function in ambulatory patients with BME.

INTRODUCi'ION Disturbances of autonomic nervous system (ANS) function may occur in various degenerative central nervous system disorders such as Parkinson's disease, multiple system atrophy, Huntington's disease and amyotrophic lateral sclerosis u. Autonomic disturbances are known to occur during epileptic seizures ~6, but there are limited data on possible interictal ANS dysfunction in different epileptic syndromes. The most well known disorder is hyposexuality in male epileptics~6. Baltic myoclonus epilepsy (BME) 3'8 is a degenerative form of progressive myoclonus epilepsy. BME is clinically similar to Unverricht-Lundborg's disease, and characterized by tonic-clonic Correspondence to: Prof. Paavo J. Riekkinen, Department of Neurology, University of Kuopio, P.O. Box 6, SF-70210 Kuopio, Finland.

seizures, myoclonus, ataxia and a progressive course9. Neuropathological studies in BME have revealed degenerative changes in basal ganglia and cerebellum but no Lafora bodies6. Electroneuromyographic and morphological studies have also suggested an involvement of the peripheral nervous system e. Recently, prolonged central conduction times in visual and somatosensory evoked potentials have been demonstrated in patients with B M E 12'13. The basal cerebrospinal fluid levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been reported to be low in patients with BME, possibly reflecting a dysfunction of dopaminergic and serotonergic neurons 1°. In her systematic study in patients with BME, Koskiniemi et al.9 reported occasional urinary and fecal incontinence, temporary retention of urine and sweating and pupillary disturbances. There are, however, no systematic studies using objec-

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252 tive tests of ANS function in patients with BME. In the present study we evaluated clinical symptoms and signs of possible involvement of the ANS and also applied standardized tests of the autonomically mediated cardiovascular reflexes. SUBJECTS AND METHODS The study was carried out at the Departments of Neurology and Clinical Physiology of Kuopio University Central Hospital. The study was approved by the Ethics Committee of the University of Kuopio. Diagnosis of BME was based on established clinical criteriaS: (1) stimulus-sensitive myoclonic jerks, (2) age at onset between 6 and 15 years, (3) tonic-clonic seizures, (4) characteristic electroencephalogram, and (5) progressive course. Fifteen ambulatory patients were studied. Clinical data of the patients are presented in Table I. Eleven patients were male and 4 female, aged from 19 to 39 years (mean 29.1 years). Patients suffering from other disorders known to impair the autonomic nervous cystem (e.g., cardiovascular diseases, diabetes mellitus, thyroid diseases, uremia, alcohol


abuse) were excluded. All patients received antiepileptic drug (AED) polytherapy including sodium valproate (VPA), clon~epam (CZP) and phenobarbital (PB). Doses of VPA varied from 600 to 2700 mg/day (mean 1640 mg/day), doses of CZP from 4 to 10 mg/day (mean 7 mg/day) and doses of PB from 50 to 200 mg/Say (mean 95 mg). Fourteen healthy subjects aged from 20 to 40 years (mean 32.4 years) served as a control group. Every patient was clinically investigated by the first author. In addition to this, special attention was paid to symptoms and signs suggestive of ANS dysfunction. The clinical severity of autonomic failure was estimated by an autonomic nervous system disability scale (ADS) described by Turkka 15. ANS function was evaluated by the foliowing cardiovascular function tests: Heart rate variation during deep breathing The subject breathed deeply 6 times/min in the sitting position. The end of each expirium was marked manually on the EEG recording. The longest and shortest R - R intervals during each breathing cycle were selected from the list of R - R intervals and converted to beats/rain. The heart rate difference (mean maximum heart rate - mean minimum heart rate) was calculated 4.

Clinicaldata of the patients with Baltic myocionus epilepsy

M, male; F, female; VPA, sodium valproate; CZP, clonazepare; PB, phenobarbital. Patient m..

Age (years)


Duration Medication of illness (years)

13 21 9 16 11 21 21 16 16 25 17 29 26 16 14




2 3 4 5 6 7 8 9 10 11 12 13 14 15

27 19 29 27 33 31 28 26 37 30 36 37 28 24



Heart rate response to tilting The orthostatic test was performed using an orthostatic test table ~4. After 5 rain rest in the supine position, the subject was tilted in 2-4 sec into the upright position (80°) and remained so for 3 min. ECG was recorded for 60 sec after tilting. From the list of R - R intervals, the shortest R - R interval (usually about 15th (+5) beats from tilting) and then the longest R - R interval (usually 30th (+5) beats) were selected. The modified 30/15 ratio was calculated from the ratio of the longest R - R intervaP. Systolic blood pressure response to tilting Blood pressu:e was determined before tiltin~ and at the end of each mimlte during standing. Systolic blood pressure response was taken as the difference between the value at rest and the value recorded after standing for i min.

253 During deep breathing and the orthostatic test, ECG was recorded at a paper speed of 50 mm/see. The R - R intervals were measured manually by an x-y digitizer interfaced to a computer. The program produced a list of measured R - R intervals. From this list the R - R intervals of interest were selected. Blood pressure was measured by a sphygmomanometer. The statistical evaluation of the results was carried out using the Mann-Whitney U test. Twosided P values were calculated and considered to be statistically significant when P < 0.05. RESULTS Thirteen (87%) of the 15 patients had symptoms suggesting ANS dysfunction and 8 (53%) patients had at least 3 different symptoms (Table II). None of the control subjects had symptoms or signs suggesting abnormalities in ANS function. The results of the recordings of cardiovascular function tests are summarized in Table III. The heart rate variation during deep breathing remained lower in patients with BME than in controis (P < 0.05), but such a difference between patients and controls was not observed in heart rate or blood pressure responses during tilting. There was no correlation between the heart rate variation during deep breathing and the severity of the clinical symptoms and signs of ANS dysfunction estimated with the ADS.

TABLE II Symptoms and~or signs of autonomic nervous system dysfunr. tion of the patients with Baltic myocionus epilepsy The percentages exceed 100 due to the multiple symptomatology of the patients.

Postural dizziness Sweating disturbances Peripheral circulating disturbances Increased salivation Urinary dysfunction Sluggish pupillary reactions Trophic disturbances Tachycardia Bowel dysfunction

No. (15)


6 6 5 5 4 4 3 3 2

40 40 30 30 27 27 20 20 13

TABLE III Results of the cardiovascular reflexes in patients with Baltic myoclonus epilepsy and in controls (mean + S.E.M., range) Patients (n = 15)

Controls (n = 14)

P values

Heart rate variation during deep < 0.05 breathing 21.6 +- 1.5 28.3 + 2.6 (beats/min) (12.8... 30.0) ( 8 . 9 . . . 46.1) R - R variation NS during tilting 1.27 +- 0.04 1.16 +_0.04 (30/15 ratio) (1.33... 1.51) (1.05... 1.39) Change in systolic NS blood pressure -3 + 2 -3 - 1 during tilting (mmHg) ( - 2 2 . . . +6) ( - 1 0 . . . + 8)

DISCUSSION Non-invasive cardiovascular function tests are generally regarded as sensitive and reliable methods for confirming ANS dysfunction, and determining whether sympathetic or parasympathetic pathways, or both, are involved u. Sympathetic function can be evaluated by studying blood pressure response to standing or vertical tilting and by measuring the blood pressure increase during isometric exercise 5,n. Parasympathetic pathways mediate reflexes involved in heart rate response to standing and in heart rate variation with respiration (during deep breathing Or during Valsalva maneuver) 5,n. In this particular patient group it was not possible to use the isometric exercise test or the Valsalva maneuver because the stimulus-sensitive myoclonic jerks of the patients would have impaired the reproducibility of the tests. For the same reason the tilting table was used in orthostatic tests instead of get.. ting the patient to stand up. The majority of our patients had at least one symptom suggesting ANS dysfunction and about 50% of the patients had several symptoms. The high prevalence of symptomatology seems to be at variance with the findings of objective tests revealing only minor abnormalities. Dizziness may be caused by cerebellar and vestibular affision due to BME. All the patients received AED polyphar-

254 macy, and CZP is known to cause dizziness, hypersecretion and hypersalivation ~. On the other hand, tests of sweating or pupillary functions u were not applied in this pilot study. Pupillary disturbances could be expected on the basis of the observed disturbances of visual evoked potentials in B M E 7A2.

In our patients, the systolic blood pressure response during tilting was not significantly different from that of the controls, suggesting an intact function of the sympathetic pathways. The heart rate response to tilting was normal, but the heart rate variation during deep breathing was significantly smaller in patients than in controls. However,

REFERENCES 1 Dam, M., Side effects. In: M. Dam, S.I. Johannessen, B. Nilsson and M. Sillanp/i/i (Eds.), Epilepsy: Progress in Treatment, Wiley, Chichester, 1987, pp. 125-135. 2 Danner, R., Leino, E., Partanen, J. et al., Electroneuromyographical and morphological findings in progressive myoclonus epilepsy (PME), Acta Neurol. Scand., 66 (1982) 673-680. 3 Eldridge, R., Iivanainen, M., Stern, R. et al., 'Baltic' myoclonus epilepsy: hereditary disorder of childhood made worse by phenytoin, Lancet, ii (1983) 838-842. 4 Ewing, D.J., Cardiac autonomic neuropathy. In: R.J. Jarrett (Ed.), Diabetes and Heart Disease, Elsevier Science Publishers Amsterdam, 1984, pp. 99-132, 5 Ewing, D.J. and Clarke, B.F., Diagnosis and management of diabetic autonomic neuropathy, Br. Med, J., 285 (1982) 916-918. 6 Haitia, M., Kristensson, K. and Sourande~, P., Neuropathological studies in three Scandinavian cases of progressive myoclonus epilepsy, Acta Neuroi. Scand., 45 (1968) 63-77. 7 Hess, C.W., Meienberg, O., Muff, S. et al., Visual evoked response in myoclonus epilepsy with large pupils, Arch. Neurol., 42 (1985) 359-361. 8 Koskiniemi, M.L., Baltic myoclonus, in: S. Fahn, C.D. Marsd~:n and M.H. Van Woert (Eds.), .~tyoelonus. Advances in Neurology, Vol. 43, Raven Press, New York, 1986, pp. 57-64.

none of the patients had a pathological heart rate response and only one of th~ ~,atients had a borderline value. Thus our findings suggest a mild parasympathetic hypofunction in BME. In conclusion, our study with objective tests of autonomically mediated cardiovascular function suggests intact function of the sympathetic pathways and only mild parasympathetic hypofunction in ambulatory patients with BME. This finding may be an early sign of ANS dysfunction. Further studies in more severely affected patients, as well as objective assessment of sweating and pupillary function, are indicated.

9 Koskiniemi, M., Donner, M., Majuri, H. et al., Progressive myoclonus epilepsy. A clinical and histopathological study, Acta Neurol. Scand., 50 (1974) 307-332. 10 Leino, E., MacDonald, E., Airaksinen, M.M. and Riekkin~n, P.J., Homovanillic acid and 5-hydroxyindolacetic acid levels in cerebrospinal fluid of patients with progressive myoclonus epilepsy, Acta NeuroL Scand., 62 (1980) 45-54. 11 McLeod, J.G. and "luck, R.R., Disorders of the autonomic nervous system. Part 1, Pathophysiology and clinical features, Ann. NeuroL, 21 (1987) 419-430. 12 Mervaala, E., Partanen, J.V., Ker~inen, T. et al., Prolonged cortical somatosensory evoked potential latencies in progressive myoclonus epilepsy, J. Neurol. Sci., 64 (1984) 131-135. 13 Mervaala, E., Ker~inen, T., P~i~ikk6nen, A. et al., Visual evoked potentials, brainstem auditory evoked potentials and quantitative EEG in Baltic progressive myocionus epilepsy, Epilepsia, 27 (1986) 542-547. 14 Sundkvist, G., Lilja, B. and Almer, L.D., Abnormal diastolic blood pressure and heart rate reaction to tilting in diabetes mellitus, Diabetologia, 19 (1980) 433-438. 15 Turkka, J.T., Correlation of the severity of autonomic dysfunction to cardiovascular reflexes and to plasma noradrenaline levels in Parkinson's disease, Eur. J, Neurol., 26 (1987) 203-210. 16 Wannamaker, B.B., Autonomic nervous system and epilepsy, Epilepsia, 26, Suppl. 1 (1985) $31-$39.

Autonomic nervous system function in Baltic myoclonus epilepsy.

Baltic myoclonus epilepsy (BME) is a neurodegenerative disease characterized by tonic-clonic seizures, myoclonus and a progressive course. The aim of ...
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