Journal of Child Neurology

http://jcn.sagepub.com/

Baclofen in the Treatment of Polymyoclonus in a Patient With Unverricht-Lundborg Disease

Yasser Awaad and Irving Fish J Child Neurol 1995 10: 68 DOI: 10.1177/088307389501000118 The online version of this article can be found at: http://jcn.sagepub.com/content/10/1/68

Published by:
http://www.sagepublications.com

Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav Citations: http://jcn.sagepub.com/content/10/1/68.refs.html

Downloaded from jcn.sagepub.com by guest on August 16, 2010

68

position

or (2) circular or oval pendular oscillations (as in Pelizaeus-Merzbacher diseasel9 and multiple sclerosis2o,2). We suggest that spasmus nutans be considered not a diagnostic entity, but a manifestation of a brainstem disturbance with manifestations sometimes not readily appreciated because of the difficulty of examining a small child or until the disease evolves. Thorough, repeated clinical examination and brain

Baclofen in the Treatment of Polymyoclonus in a Patient With Unverricht-Lundborg Disease

imaging are appropriate. Iqbal N. Allarakhia, MD Department of Pediatrics (Pediatric Neurology) University of Michigan Medical Center Ann Arbor, Michigan Jonathan D. Trobe, MD Departments of Ophthalmology and Neurology WK Kellogg Eye Center University of Michigan Medical Center Ann Arbor, Michigan
Received Oct 20, 1993. Received revised Jan cation Feb 23, 1994.

Unverricht-Lundborg disease is characterized by progressive 1 It ataxia, polymyoclonus, seizures, and intellectual deterioration. was first described by Unverricht in 1891. Lundborg, Unverrichts student, reported 50 similar cases in 30 families in 1903.2 Valproic acid and/or clonazepam have been reported to be effective in ameliorating the polymyoclonus and seizures seen in Unverricht3-6 In our patient, however, these drugs were Lundborg disease. ineffective in modifying the polymyoclonus and ataxia.
Case Report
A.B. is
term
a 15-year-old right-handed girl who was born in Poland after a fullgestation followed by a normal spontaneous vaginal delivery. She walked at 14 months and spoke in phrases by 25 months. At 3 years of age, she had a generalized seizure with fever. She recovered spontaneously, and no treatment was prescribed. At 4 years of age, she developed an ataxic gait, which became progressively worse. By age 5 years, her parents had noted mental deterioration and slurred speech. Intention polymyoclonus was first noted at age 6 years. All of her symptoms deteriorated, so that by age 11 years she was wheelchair bound and was unable to feed herself. Her father had to pick her up to move her from place to place. She was withdrawn and depressed, and her speech had become totally unintelligible. The family emigrated to the United States in November 1992, when the patient was 15 years old. Two weeks later, on November 24th, she was admitted to Bellevue Hospital. On admission, she was taking ethosuximide 250 mg qid, vitamin B12, valproic acid 250 mg tid, and clonazepam 2 mg tid. She was having four or five generalized and myoclonic seizures per day. General physical examination was normal. There was no hepatomegaly. Neurologic examination revealed a depressed child strapped into a wheelchair. Although she made sounds, her speech was unintelligible, and she did not follow commands even when given by her parents. At rest, there was titubation and constant diffuse polymyoclonus made worse by intention. She was able to hold a pencil with a palmar grasp, and her drawing and handwriting were unintelligible (Figure lA). Hypertonia was present in all four extremities. Deep tendon reflexes were increased throughout. However, toes were bilaterally down-going. She had severe truncal and appendicular ataxia made worse

10, 1994. Accepted for publi-

References
1. 2. Katzman B, Lu LW, Tiwari RP: Spasmus nutans in identical twins. Ann Ophthalmol 1981;13:1193-1195. Gottlob

A, Catalano RA, et al: Signs distinguishing spas(with and without central nervous system lesions) from infantile nystagmus. Ophthalmology 1990;97:1166-1175. 3. Chrousos GA, Reingold DR, Chu FC, et al: Habitual head turning in spasmus nutans: An oculographic study. J Pediatr Ophthalmol Strabismus 1985;22:113-116. 4. Koenig SB, Naidid TP, Zaparackas Z: Optic glioma masquerading as spasmus nutans. J Pediatr Ophthalmol Strabismus 1982;19:20-24. 5. Albright AL, Sclabassi J, Slamovits TJ, et al: Spasmus nutans associated with optic gliomas in infants. J Pediatr 1984;105:778-780. 6. Gresty MA, Leech J, Sanders MD, et al: A study of head and eye

I,

Zubcov

mus

nutans

movement in spasmus nutans. Br J

7.

8. 9.
10.
11.

12. 13.
14.

15. 16.

Ophthalmol 1976;60:652-654. EWD, Cogan DG: Spasmus nutans. A clinical study of twenty cases followed two years or more since onset. Arch Ophthalmol 1954;52:442-446. King RA, Nelson LB, Wagner RS: Spasmus nutans. A benign clinical entity? Arch Ophthalmol 1986; 104:1501-1504. Weissmann BM, DellOsso LF, Abel LA, Leigh RJ: Spasmus nutans: A quantitative prospective study. Arch Ophthalmol 1987;105:525-528. Antony JH, Ouvrier RA, Wise G: Spasmus nutans: A mistaken identity. Arch Neurol 1980;37:373-375. Gottlob I, Zubcov AA, Wizov SS, Reinecke RD: Head nodding is compensatory in spasmus nutans. Ophthalmology 1992;99:1024-1031. White PT, Ross AT: Inanition syndrome in infants with anterior hypothalamic neoplasms. Neurology 1963;13:974-981. Garty B, Weitz R, Mimouni M, Bauman B: Spasmus nutans as a presenting sign of diencephalic syndrome. J Pediatr 1985;107:484. Sedwick LA, Burde RM, Hodges FJ: Leighs subacute necrotizing encephalomyelopathy manifesting as spasmus nutans. Arch Ophthalmol 1984;102:1046-1048. Bienfang DC: Opsoclonus in infancy. Arch Ophthalmol 1974;91:
Norton

with intention.

203-205.

Digre KB: Opsoclonus in adults: Report of three of the literature. Arch Neurol 1986;43:1165-1175.

cases

and review

17. 18.
19. 20.

Savino PJ, Glaser JS: Opsoclonus: Pattern of regression in a child with neuroblastoma. Br J Ophthalmol 1975;59:696-698. Ashe J, Hain TC, Zee DS, et al: Microsaccadic flutter. Brain

21.

1991;114:461-472. AI, Longridge NS, Dunn HG, et al: Vestibular studies in Pelizaeus-Merzbacher disease. J Otolaryngol 1983; 12:361-364. Aschoff JC, Conrad B, Kornhuber HH: Acquired pendular nystagmus with oscillopsia in multiple sclerosis: A sign of cerebellar nuclear disease. J Neurol Neurosurg Psychiatry 1974;37:570-577. Gresty MA, Ell JJ, Findley LJ: Acquired pendular nystagmus: Its characteristics, localizing value and pathophysiology. J Neurol Neurosurg Psychiatry 1982;45:431-439.
Mallinson

Work-up including complete blood count, sequential multiple analysis-7, Mug+, P04, liver function tests, lactic acid, analysis of cerebrospinal fluid (white blood cells, protein, glucose, lactate, and pyruvate), carnitine (total and free), vitamin E, serum a-tocopherol, rubeola immunoglobulin G, and blood and urine organic amino acids produced normal results. Skin biopsy for Lafora bodies and neuronal ceroid lipofuscinosis was normal. Electron microscopy showed normal mitochondria architecture. Studies for GMI, GM2, and a-(N)-neuraminidase were normal. Head computed tomographic scan with contrast, electromyogram, and brainstem auditory evoked responses were normal. Electroencephalogram showed diffuse slowing with occasional parasagittal spikes. Visual evoked response showed abnormal P100 waves bilaterally. Ethosuximide and vitamin B12 were discontinued, with no change in her clinical status. Her valproic acid level was 85 pg/mL on 250 mg tid. The valproic acid dosage was raised to 500 mg tid, with a blood level of 120 pg/mL and no change in her clinical status. In order to attempt to decrease hypertonia and spasticity, baclofen 40 mg/day was added and gradually increased to 150 mg/day. Polymyoclonus and ataxia were significantly decreased, as was the spasticity and hypertonia. This resulted in a remarkable improvement in her clinical condition, so that she is now able to stand alone, walk holding on with one hand, climb steps, and turn while walking. She can throw and catch a ball and go on a swing and move it without assistance. She can draw pictures (Figure 1B), write legibly (Figure 2), use scissors, and feed herself. Speech is now intelligible, with a higher than expected cognitive level. She is outgoing and happy. Seizure frequency has decreased from four or five per day to one per week. This improvement has been sustained for 16 months to date.

Downloaded from jcn.sagepub.com by guest on August 16, 2010

69

Figure
a

attempt

A, Pretreatment writing and drawing samples. The upper left corner (arrow) is an initials; the remainder of the picture is the response to the request to draw person. B, A drawing sample (snowman) 1 month after baclofen treatment.
1.
to trace her

Discussion The dramatic clinical improvement displayed by this patient after baclofen was introduced was a surprise to us. We were

hoping to modify the hypertonia but did not expect to improve the polymyoclonus, ataxia, and slurred speech. It is very difficult to distinguish polymyoclonus from ataxia and slurred speech. We believe that baclofen diminished the polymyoclonus, and this resulted in less ataxia and clearer speech. The pathogenesis of Unverricht-Lundborg disease is not clear. Neuropathologic studies have been unrevealing. Recently, Lahesjok et al discovered an abnormality on chromosome 21 band q22.3 in 13 Finnish families with Unverricht-Lundborg diserase. This important finding may provide insight into the abnormalities that result in the neurologic dysfunction in UnverrichtLundborg disease.
Baclofen is 4-amino-3-(4-chlorophenyl)-butanoic acid (Lioresal). The precise mechanism of action of baclofen is not fully known. It is capable of inhibiting both monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent terminals. These effects may also occur at supraspinal sites, and this may contribute to its clinical effect.
Baclofen also stimulates

y-aminobutyric acids (GABAB)

on

recep-

tors and mimics the effect of GABA metabolism in the central

postsynaptic cells. Animal studies have shown that baclofen can influence dopamine
nervous

system. Baclofen has been

nigrostriatal and mesolimbic dopaminergic neurons as well as substance P (a neuromodulator with excitatory effects on dopamine neurons). Thus, administration of baclofen may increase dopamine availability, which would decrease dopamine receptor hypersensitivity.8 GABAergic inhibitory information channels play an important role in the balance of excitation and inhibition pertaining to motor function. Consequently, GABA receptor agonists such as baclofen

shown to inhibit both

Figure

2.

writing sample

in Polish 1 month after treatment with

baclofen.

Downloaded from jcn.sagepub.com by guest on August 16, 2010

70

GABAergic inhibitory activity.9 Presynaptic GABAB receptors, capable of inhibiting release of a variety of neurotransmitters, have been found in many areas of
have been used to enhance

the central nervous system.9 Ohisalo et all and Airaksinen and Leinoll have shown a decrease in cerebrospinal fluid GABA in patients with Unverricht-Lundborg disease. It is possible that baclofen in this patient is working as a GABA mimetic substitute in a patient who is GABA deficient. It is not clear why some patients such as A.B. do not respond well to valproic acid and

clonazepam, which
to 60

are

GABAergic drugs.
causes

It is
an

interesting

to

note that baclofen often

sedation in

adult at about 40

A.B. has tolerated 150 mg/day without any sedaany other side effects, for that matter. In Smith et al,12 Jones and Lance summarized their experience with 113 patients

mg/day.

tion

or

epilepsy—Pitfalls in diagnosis and management. Scott Med J 1991;36:18-19. 5. Somerville ER, Olanow W: Valproic acid, treatment of myoclonus in dyssynergia cerebellaris myoclonica. Arch Neurol 1982;39:527-528. 6. Iivanainen M, Himberg JJ: Valproate and clonazepam in the treatment of severe progressive myoclonus epilepsy. Arch Neurol 1982;39:236-238. 7. Bartholini G: GABA receptor agonist: Pharmacological spectrum and therapeutic actions. Med Res Rev 1985;5:55-75. 8. Ryan DM, Blumenthal FS: Baclofen-induced dyskinesia. Arch Phys Med Rehabil 1993;74:766-767. 9. Siegfried RN, Jacobson L, Chabal C: Development of an acute withdrawal syndrome following the cessation of intrathecal baclofen in a patient with spasticity. Anesthesiology 1992;77:
1048-1050. 10. Ohisalo JJ, Murros K, Fredholm BB, et al: Concentration of gamma-aminobutyric acid and adenosine in the CSF in progressive myoclonus epilepsy without Laforas bodies. Arch Neurol

spasticity treated with baclofen for up to 6 years. Baclofen dosage ranged from 30 to 200 mg daily, with the mean varying
with

from 60 to 110 mg. Menon and Vivonial3

1983;40:623-625.

reported that the

muscimol-induced

11.

myoclonus may be considered as a valid animal model for clinical myoclonus. On this basis, they tested the influence of several drugs on muscimol-induced myoclonic jerks and found that baclofen was effective in blocking this symptom. Polymyoclonus occurs in a wide variety of clinical conditions, including postanoxic encephalopathy, Lafora body disease, and neuronal ceroid lipofuscinosis. The standard treatment for myoclonus has been valproic acid and clonazepam, but this treatment is sometimes minimally effective A study is now being undertaken by us using baclofen to see if this GABAmimetic drug is effective only in Unverricht-Lundborg disease or in other conditions with polymyoclonus as well.
Conclusion

Airaksinen EM, Leino E: Decrease of GABA in the cerebrospinal fluid of patients with progressive myoclonus epilepsy and its correlation with the decrease of 5HIAA and HVA. Acta Neurol Scand 1982;66:666-672.
Smith CR, LaRocca NG, Giesser BS, et al: High-dose oral baclofen: Experience in patients with multiple sclerosis. Neu-

12.

13.

14.

rology 1991;41:1829-1831. Menon MK, Vivonia CA: Serotonergic drugs, benzodiazepines and baclofen block muscimol-induced myoclonic jerks in a strain of mice. 1981;73:155-161. Eur J Pharmacol Coletti A, Mandelli A, Minoli G, et al: Post-anoxic action myoclonus (Lance-Adams syndrome) treated with levodopa and gabaergic drugs. J 1980;223:67-70. Neurol

know, this is the first report in which baclofen administered to a patient with Unverricht-Lundborg disease resulted in sustained improvement of symptoms. Further
As far
as we

Hypoxia-Induced CHAP Syndrome

choreoathetosis, oral-facial dyskinesias, affective changes, hypotonia, and pseudobulbar signs (CHAP) 1 to 7 days after profound hypothermia and complete circulatory arrest induced to enable congenital heart defect repair has been described with the mnemonic CHAP syndrome. 1 These patients generally improve with time, with resolution of most of the fmdings. Rarely, a similar syndrome, albeit with a graver prognosis, has been reported after attempted strangulation. 2-4 Delayed neurologic deterioration after carbon monoxide poisoning also is a
The onset of known

research is baclofen in

required

to elucidate the mechanism of action of

patients with Unverricht-Lundborg disease. We feel that the results in this case are sufficiently promising to warrant a study using baclofen in two types of patients: those with Unverricht-Lundborg disease and those with polymyoclonus due to other etiologies. Yasser Awaad, MD, MSc Irving Fish, MD Department of Neurology New York University Medical Center New York, New York
Received Dec 21, 1993. Received revised April 13, 1994. Accepted for

4-6 entity.

We report a patient who demonstrated all of the elements of the CHAP syndrome, with onset on day 6 after a hypoxic
event

secondary

to a

respiratory

arrest induced

by injudicious

administration of morphine sulfate.

publication April 18, 1994. Presented in part at the XVth BC, Canada, September 1993.

World

Congress

of Neurology,

Vancouver,

Report of a Case
A previously healthy 32-kg right-handed 11-year-old Caucasian boy experienced a flulike illness, with complaints of sore throat, nausea, vomiting, and intense bilateral lower leg pain. Three days later, he was found by his mother unresponsive to stimulation, making gurgling sounds, but with good color. She drove him to the emergency room, arriving within 10 minutes, whereupon she noted cessation of respirations. He was emergently intubated and hyperventilated. After undergoing an evaluation, including a lumbar puncture, and receiving dextrose 50 and naloxone hydrochloride, it was discovered that he had ingested 60 mg of morphine sulfate contin apparently in an attempt to alleviate the myalgias. An arterial blood gas measurement obtained 3 minutes after intubation

References
Lahesjok AE, Koslaniemi M, Pandolfo M, et al: Linkage studies in progressive myoclonus epilepsy: Unverricht-Lundborg and Laforas diseases. Neurology 1992;42:1545-1550. 2. Lance JW: Myoclonus. Clin Pharmacol 1986;9:S11-S18. 3. Dreifuss FE: Treatment of seizure disorders and myoclonus. Psychosomatics 1985;26:30-37. 4. McKee PJW, McGinn G, Larkin JG, Brodie MJ: Myoclonic
1.

Downloaded from jcn.sagepub.com by guest on August 16, 2010