- Email: [email protected]
Familial cortical tremor with epilepsy
Pnrkimm~im
6 Rrlnfd
( 1997 Published
Elsevier
Vol. 3, No. 2, pp 83-87,
Dieurdw
by Elsevier
Science Ltd
PII: s1353-8020(97100001-1
All nghts
l’rinted
lYY7
reserved
m Great Brltam
Familial Cortical Tremor with Epilepsy YASUYUKI OKUMAt, YASUSHI SHIMOt, KOZO HATORIt, SHIGEKI TANAKAt AND YOSHIKUNI MIZUNOS
TATSUYA HATTORIt,
Accepted 14 january 1997
We report here on a Japanese family in which five members in three generations developed non-progressive adult onset cortical tremor and epilepsy. Other than tremulous movements resembling essential tremor, the neurologic findings were unremarkable. Electrophysiologic studies revealed giant somatosensory evoked potentials (SEPsl, enhanced long latency reflexes K-reflex), and positive premovement cortical potentials, recorded by jerk-locked averaging, indicating cortical reflex myoclonus. The seizures were sporadic in nature and easily controlled by the anticonvulsants. The tremor also responded well to anticonvulsants such as clonazepam or sodium valproate, but not to @blockers. This dominantly inherited disorder should be considered in the differential diagnosis of essential tremor. 0 1997 Published by Elsevier Science Ltd Cortical tremor Cortical myoclonus
Myoclonus
epilepsy
locked averaging of cortical potentials. Surface EMGs were recorded from muscles in the upper and lower limbs, using surface electrodes placed over the muscle bellies 3 cm apart. The EMG was filtered with a bandpass of 10-5000 Hz. SEPs were obtained by stimulating the median nerve at the wrist or the posterior tibia1 nerve at the ankle with electric shocks at a rate of 2 Hz. The stimulus intensity was adjusted to 10% above the motor threshold. Recordings were made from the C4’ position (2 cm posterior to C4 in the International lo-20 system) for the median nerve stimulation, and Cz’ position (2 cm posterior to Cz) for the tibia1 nerve stimulation with linked-ears references. To record C-reflexes, surface electrodes were placed over the abductor pollicis brevis (APB) muscle for median nerve stimulation or on the abductor hallucis muscle for posterior tibia1 nerve stimulation. The filter setting for EEG was l-500 Hz. An SEP was judged as ‘giant’ when the amplitude difference between the N20 peak and the P25 peak was larger than 8.6 PV or that corresponding to P25 and N33 was larger than 8.4 PV [4]. Jerk-locked averaging of premovement EEG was performed using the method reported by Shibasaki rt al. [5]. The EMG bursts were recorded by surface electrodes placed over the wrist extensor muscles or the quadriceps femoris muscle. The EEG was recorded by the same electrode placement as used for the WI’s, and was averaged by a back-averaging program using the EMG burst onset pulse as a trigger. The analysis time was from 80 ms before to 20 ms after the EMG onset. 100 consecutive artifact-free EEG sweeps were averaged and analysed.
INTRODUCTION
Amongst the many causes of tremor, cortical tremor is a rare and newly identified pathophysiological entity which was first reported by Ikeda et al. [l]. The clinical features are: (1) fine shivering-like finger tremor resembling essential tremor; (2) relatively brief rhythmic EMG bursts at a rate of about 9 Hz on surface EMG; (3) response to anticonvulsants such as clonazepam, valproate, and primidone [ 1,2]. Electrophysiologic investigations indicate cortical reflex myoclonus [l-3]. This is defined as a type of myoclonus which is mediated in cerebral cortex [3], with electrophysiologic criteria including giant SEPs [4], enhanced long-loop reflexes (C-reflex), and positive premyoclonus cortical spikes recorded by the jerk-locked averaging method. In this paper, we describe a family presenting cortical tremor and epilepsy over three generations. METHODS
FOR ELECTROPHYSIOLOGIC
STUDIES
Electrophysiologic studies included surface electromyogram (EMG), SEPs with C-reflexes, and jerk-
tDepartment of Internal Medicine (Neurology), Urayasu Hospital of Juntendo University School of Medicine, 2-1-l Tomioka, Urayasu-city, Chiba 279, Japan. SDepartment of Neurology, Juntendo University School of Medicine, 2-1-l Tomioka, Urayasu-city, Chiba 279, Japan. Address correspondence to: Yasuyuki Okuma, Department of Neurology, Juntendo University School of Medicine, 2-l-l Hongo, Bunkyo, Tokyo 113, Japan. Tel.: 81-3-3813-3111; Fax: 813-56840476. 83
Y.OKUMA et n/.
84 CASE REPORTS Pf?fienf 1
The proband of this family (II-1 in Fig. 1) was a 55year-old Japanese man. At age 25, he had seizure with loss of consciousness, and since age 29 had noted postural tremulous movements of his fingers. He was treated with diphenylhydantoin which controlled the seizure disorder. The tremor was non-progressive. It was aggravated by emotional stress, and was decreased by taking alcohol. He was diagnosed as having essential tremor. In 1995 he had two tonic seizures with loss of consciousness. For two months prior to the present admission in March 1996 he had noted tremulous oscillations of his legs while standing. On admission, general physical findings were Neurologic examination revealed unremarkable. normal mental status and intact cranial nerves. Tremulous shivering-like movements were present in both hands in the outstretched posture. He had difficulty in holding a small cup filled with water. On standing, he rapidly developed rhythmic oscillations of both leg muscles resembling orthostatic tremor. The oscillation was decreased while walking. Muscle tone, strength, and deep tendon reflexes were normal. There were no pyramidal or cerebellar signs. Sensory examination was unremarkable. Laboratory studies including lactate and pyruvate levels in both serum and CSF, and lysosomal enzymes in the leukocytes were normal. Cranial CT and MRI were normal. EEG revealed multifocal spikes, spikeand-wave, and polyspike-and-wave complexes. Background activity consisted of alpha waves with a small amount of theta activity. Photic driving responses were markedly enhanced. On surface EMG recordings, rhythmic bursts of lo50 ms duration occurred at a frequency of 7-9 Hz in the forearm flexors and extensors of the outstretched arms (Fig. 2A). During finger to nose testing, faster and more synchronous EMG bursts appeared in the arm muscles (Fig. 2B). On standing, brief EMG bursts with
frequencies of 7-9 Hz were shown in the leg muscles (Fig. 2C). SEPs evoked by the median nerve stimulation showed giant potentials [4], and C-reflexes [6] appeared in the thenar muscles (Fig. 3A). Stimulation of the posterior tibia1 nerve at the ankle also elicited giant SEPs [7] and C-reflexes (Fig. 3B). Jerk-locked averaging disclosed a positive EEG peak 16 ms prior to the EMG burst in the wrist extensor muscle (Fig. 4A), and 18 ms preceding the quadriceps EMG burst (Fig. 48). These electrophysiologic findings fit what has been described for cortical tremor [1,2]. The orthostatic oscillation was eliminated by valproate and the hand tremor was markedly attenuated by valproate and clonazepam. Propranolol had no effect on either the hand or leg tremors. Patient 2 The first daughter of the proband (III-l) had her first generalized convulsive seizure at age 20. She had two more seizures with loss of consciousness while watching TV later in the same year, but the type of seizure
A Wrist flexors
4
Wrist extensors
1 sec.
B Biceps Triceps Wrist flexors Wrist extensors
1 sec.
I 500
pv
C Quadriceps Hamstrings
w
Tibialis anterior II
Gastrocnemius 1 5oopv 1 sec.
m 22
19
18
16
25
FIGURE 1. Pedigree of the family. Solid symbols indicate affected members. Numbers under the symbols show the ages of the patients.
FIGURE 2. Surface EMG recordings in patient 1. (A) Rhythmic bursts of lo-50 ms duration occurred at a frequency of 7-9 Hz in the for<>arm flexors and extensors of the outstretched arms. (B) During finger to nose testing, faster and more synchronous EMG bursts appeared in the arm muscles. (C) On standing, brief EMG bursts with frequency of 7-9 Hz were shown in the leg muscles.
FAMILIAL
CORTICAL
TREMOR
WITH EPILEPSY
85
C4’- AlA2
16.25 WV
C4’- AI A2
IlOPV APB
I 2mV
I 1 mV
10s
B Cz’-AI A2
Quad. d AH
mV FIGURE 4. Jerk-locked averaging in patient 1 disclosed a positive EEG peak 16 ms prior to the EMG burst in the wrist extensor muscle (A), and 18 ms preceding the quadriceps EMG burst (B).
C4’- AI A2
a giant SEP (N20-P25: 11 pV, P25-N33: there were no C-reflexes.
14 pV), but
Patient 4 APB
FIGURE 3. (A) SEPs evoked by median nerve stimulation in patient 1 showed giant potentials (N20-P25: 23 pV, P25-N33: 60 rV), and Creflexes appeared in the thenar muscles at the latency of 38 ms. C4’: 2 cm posterior to C4. APB: Abductor Pollicis Brevis. (B) Stimulation of the posterior tibia1 nerve at the ankle in patient 1 also elicited giant SEPs (N33-I’39: 11 pV, P39-N48: 20 pV) and C-reflexes at 75 ms. Cz’: 2 cm posterior to Cz. AH: Abductor Hallucis. (C) SEPs evoked by median nerve stimulation in patient 2 showed giant potentials (N20P25: 22 pV, P25-N33: 62 pV) and C-reflexes.
was not specified. She showed fine postural finger tremor, but otherwise was neurologically normal. EEG revealed generalized spike-and-wave and polyspikeand-wave complexes with photic stimulation, and some theta activity on a background of alpha activity (Fig. 5). Median nerve stimulation produced giant SEPs and C-reflexes (Fig. 3C). Cranial CT was unremarkable. Her seizures were well controlled with valproate and her finger tremor was also decreased. Patient 3 A younger sister of patient 2 (111-4) complained of fine postural finger tremor only when she was tired. Neurologic examination showed no abnormality. EEG showed focal sharp waves and generalized spike-andwave complexes. Median nerve stimulation evoked
The younger brother of the proband (11-2) had a convulsive seizure at age 32, and noted postural tremor of his hands around the same time. He was diagnosed as having essential tremor, but propranolol was not effective. His seizures were controlled by sodium valproate, and the postural tremor was also attenuated. He showed no other abnormal neurologic signs. He is able to work as an engineer even though he has some residual finger tremor. Patient 5 The mother of the proband (I-l) had a generalized convulsive seizure at age 32. She noted tremulous hand movements two years later. She was not demented or ataxic. Diazepam and valproate were effective for both the seizures and the hand tremor.
DISCUSSION
The clinical features and the electrophysiological characteristics of the postural or action tremor in our patients are consistent with cortical tremor [l], a variant of cortical reflex myoclonus [3]. Other than the cortical tremor, there were no abnormalities on neurological examination. The disabilities remained minimal if the patients took anticonvulsants regularly, and the disorder progressed very slowly, or not at all. Although our patients had cortical reflex myoclonus and epilepsy, this family can be differentiated from various forms of progressive myoclonus epilepsy
Y. OKUMA
86
et al.
FPI-A, FPZ-A2
Fs-AI F4-AZ CJ -AI Cc -AZ Ps-AI PC -A, 01 -AI Oz-AZ FI -AI Fe-AZ T, -Al T4
-AZ
Tc -AI T4 -AZ
”
. FIGURE
5. EEG recordings
in patient
Photicstim. 18Hz 4
2. (A) Some theta activity on a background of alpha activity. polyspike-and-wave complexes with photic stimulation.
@‘ME), such as Unverricht-Lundborg disease, Lafora disease, neuronal ceroid-lipofuscinoses, mitochondrial disorders, sialidosis, and dentatorubral-pallidoluysian atrophy by clinical and laboratory findings. Our patients had a much more ‘benign’ course than what usually occurs with the PME syndrome. There have been some reports on families similar to the one in our study. Otsuka et al. [8] described a family with cortical tremor spanning four generations. Their patients also had seizures, and both the seizures and tremulous movements responded well to valproate. Therefore, their patients would appear to be in the same category of disorder as ours. Inazuki et al. [9] reported 12 families in which members showed myoclonus and epilepsy. Some of their patients had ‘myoclonic tremor’, but no cerebellar or pyramidal signs. Autopsies were performed on 3 of these patients and the brains showed no pathologic abnormalities. They termed the disease familial essential myoclonus and epilepsy (FEME). Their patients seem quite similar to ours in terms of the dominant inheritance, absence of abnormal neurologic findings other than myoclonus or tremor, and very slow or no progression of the disease with a good response to anticonvulsants. Therefore, although they did not provide any electrophysiological evidence to suggest cortical reflex myoclonus, we assume that their patients had the same disorder as ours. Yasuda reported two similar families in which members showed tremulous finger movements and/or myoclonus after adolescence. He
(B) Generalized
l#c
=PJ
spike-and-wave
and
termed this ‘Benign adult onset familial myoclonic epilepsy (BAFME)’ [lo]. He suggested that the tremulous finger movements might be minipolymyoclonus [ll] or cortical tremor, but his patients showed cortical reflex myoclonus electrophysiologically, so the clinical manifestation may well have been a cortical tremor. To our knowledge, this disorder has been reported exclusively in Japan, and has been given different names by different authors. We believe that these reports all describe the same disorder and we propose that it should be identified as ‘familial cortical tremor with epilepsy’. Correct diagnosis of familial cortical tremor is important because not only the seizures but also the tremor are attenuated by anticonvulsants. Most patients were previously diagnosed as having essential tremor because of the characteristics of the tremor, positive familial history (autosomal dominant inheritance) and alcohol sensitivity. However, P-blockers did not demonstrate any beneficial effect in these patients. Infrequent seizures might often be overlooked or considered to be coincidental. Demonstration of cortical reflex myoclonus by electrophysiologic testing confirms the diagnosis [1,2]. Another interesting finding is that the proband of this family showed leg tremor during standing which resembled orthostatic tremor. Although the tremor frequency in this patient was lower than the typical primary orthostatic tremor (14-18 Hz) [12], the clinical features of the oscillation had some similarities to
FAMILIAL CORTICAL TREMOR WITH EPILEPSY
those of orthostatic tremor [12]. Since a giant SEP, a C-reflex following stimulation of the tibia1 nerve, and a myoclonus-related cortical spike preceding the quadriceps myoclonic EMG discharge were all present, it is reasonable to regard the leg tremor in this patient as a manifestation of cortical tremor. Attenuation of the leg tremor with valproate further supports this possibility. In summary, familial cortical tremor with epilepsy may not be a rare disorder. Recognition of the EEG abnormalities, or seizures associated with a postural tremor resembling essential tremor, together with a positive familial history, are essential for diagnosis. Correct diagnosis of this disorder will avoid unnecessary treatment with fl-blockers and will lead to successful treatment with anticonvulsants, particularly sodium valproate and clonazepam.
REFERENCES Ikeda A, Kakigi R, Funai N, Neshige R, Kuroda Y, Shibasaki H. Cortical tremor: A variant of cortical reflex myoclous. Neurology 1990; 40: 1561-1565. Toro C, Pascual-Leone A, Deuschl G, Tate E, Pranzatelli MR, Hallett M. Cortical tremor: A common manifestation of cortical reflex myoclonus. Neurology 1993; 43: 2346-2353. Hallett M, Chadwick D, Marsden CD. Cortical reflex myoclonus. Neurology 1979; 29: 1107-1125.
87
4. Shibasaki H, Yamashita Y, Tsuji S. Somatosensory evoked potentials. Diagnostic criteria and abnormalities in cerebral lesions. J Neural. Sci. 1977; 34: 427-439. 5. Shibasaki H, Yamashita Y, Neshige R, Tobimatsu S, Fukui R. Pathogenesis of giant somatosensory evoked postentials in progressive myoclonic epilepsy. Bruin 1985; 108: 225-240. 6. Sutton GG, Mayer RF. Focal reflex myoclnus. J. Neural. Neurosurg. Psychiatry 1974; 37: 207-217. 7. Kakigi R, Shibasaki H. Somatosensory evoked potentials following stimulation of the lower limb in corticcal reflex myoclonus. 1. Neural. Neurosurg. Psychiatry 1987; 50: 164-1646. 8. Otsuka M, Nakamura S, Yashima H, Ueki A, A familial case of cortical tremor. ] Movement Disorder and Disability 1995; 5; 99106 (in Japanese). 9. Inazuki G, Naito H, Ohama E, et al. A clinical study and neuropathological findings of a familial disease with myoclonus and epilepsy-The nosological place of a familial essential myoclonus and epilepsy (FEME). Seishin-shinkeigaku (in ]upanese) 1990; 92: l-21.
10. Yasuda T. Benign adult familial myoclonic epilepsy (BAFME). Kawasaki Med. J. 1991; 17: l-13. 11. Wilkins DE, Hallett M, Erba G. Primary generalized epileptic myoclonus: a frequent manifestation of minipolymyoclonus of central origin. J. Neural. Neurosurg. Psychiatry 1985; 48: 506-516. 12. Thompson PD, Rothwell JC, Day BL, Berardelli A, Dick JPR, Kachi T, Marsden CD. The physiology of orthostatic tremor. Arch. Neural. 1986; 43: 584587.
Acknowledgements-The authors wish to express their gratitude to Professor Hiroshi Shibasaki for reading the first draft of the manuscript. We also wish to thank Professor Robert G. Lee for commenting on the final version of the manuscript.
6 Rrlnfd
( 1997 Published
Elsevier
Vol. 3, No. 2, pp 83-87,
Dieurdw
by Elsevier
Science Ltd
PII: s1353-8020(97100001-1
All nghts
l’rinted
lYY7
reserved
m Great Brltam
Familial Cortical Tremor with Epilepsy YASUYUKI OKUMAt, YASUSHI SHIMOt, KOZO HATORIt, SHIGEKI TANAKAt AND YOSHIKUNI MIZUNOS
TATSUYA HATTORIt,
Accepted 14 january 1997
We report here on a Japanese family in which five members in three generations developed non-progressive adult onset cortical tremor and epilepsy. Other than tremulous movements resembling essential tremor, the neurologic findings were unremarkable. Electrophysiologic studies revealed giant somatosensory evoked potentials (SEPsl, enhanced long latency reflexes K-reflex), and positive premovement cortical potentials, recorded by jerk-locked averaging, indicating cortical reflex myoclonus. The seizures were sporadic in nature and easily controlled by the anticonvulsants. The tremor also responded well to anticonvulsants such as clonazepam or sodium valproate, but not to @blockers. This dominantly inherited disorder should be considered in the differential diagnosis of essential tremor. 0 1997 Published by Elsevier Science Ltd Cortical tremor Cortical myoclonus
Myoclonus
epilepsy
locked averaging of cortical potentials. Surface EMGs were recorded from muscles in the upper and lower limbs, using surface electrodes placed over the muscle bellies 3 cm apart. The EMG was filtered with a bandpass of 10-5000 Hz. SEPs were obtained by stimulating the median nerve at the wrist or the posterior tibia1 nerve at the ankle with electric shocks at a rate of 2 Hz. The stimulus intensity was adjusted to 10% above the motor threshold. Recordings were made from the C4’ position (2 cm posterior to C4 in the International lo-20 system) for the median nerve stimulation, and Cz’ position (2 cm posterior to Cz) for the tibia1 nerve stimulation with linked-ears references. To record C-reflexes, surface electrodes were placed over the abductor pollicis brevis (APB) muscle for median nerve stimulation or on the abductor hallucis muscle for posterior tibia1 nerve stimulation. The filter setting for EEG was l-500 Hz. An SEP was judged as ‘giant’ when the amplitude difference between the N20 peak and the P25 peak was larger than 8.6 PV or that corresponding to P25 and N33 was larger than 8.4 PV [4]. Jerk-locked averaging of premovement EEG was performed using the method reported by Shibasaki rt al. [5]. The EMG bursts were recorded by surface electrodes placed over the wrist extensor muscles or the quadriceps femoris muscle. The EEG was recorded by the same electrode placement as used for the WI’s, and was averaged by a back-averaging program using the EMG burst onset pulse as a trigger. The analysis time was from 80 ms before to 20 ms after the EMG onset. 100 consecutive artifact-free EEG sweeps were averaged and analysed.
INTRODUCTION
Amongst the many causes of tremor, cortical tremor is a rare and newly identified pathophysiological entity which was first reported by Ikeda et al. [l]. The clinical features are: (1) fine shivering-like finger tremor resembling essential tremor; (2) relatively brief rhythmic EMG bursts at a rate of about 9 Hz on surface EMG; (3) response to anticonvulsants such as clonazepam, valproate, and primidone [ 1,2]. Electrophysiologic investigations indicate cortical reflex myoclonus [l-3]. This is defined as a type of myoclonus which is mediated in cerebral cortex [3], with electrophysiologic criteria including giant SEPs [4], enhanced long-loop reflexes (C-reflex), and positive premyoclonus cortical spikes recorded by the jerk-locked averaging method. In this paper, we describe a family presenting cortical tremor and epilepsy over three generations. METHODS
FOR ELECTROPHYSIOLOGIC
STUDIES
Electrophysiologic studies included surface electromyogram (EMG), SEPs with C-reflexes, and jerk-
tDepartment of Internal Medicine (Neurology), Urayasu Hospital of Juntendo University School of Medicine, 2-1-l Tomioka, Urayasu-city, Chiba 279, Japan. SDepartment of Neurology, Juntendo University School of Medicine, 2-1-l Tomioka, Urayasu-city, Chiba 279, Japan. Address correspondence to: Yasuyuki Okuma, Department of Neurology, Juntendo University School of Medicine, 2-l-l Hongo, Bunkyo, Tokyo 113, Japan. Tel.: 81-3-3813-3111; Fax: 813-56840476. 83
Y.OKUMA et n/.
84 CASE REPORTS Pf?fienf 1
The proband of this family (II-1 in Fig. 1) was a 55year-old Japanese man. At age 25, he had seizure with loss of consciousness, and since age 29 had noted postural tremulous movements of his fingers. He was treated with diphenylhydantoin which controlled the seizure disorder. The tremor was non-progressive. It was aggravated by emotional stress, and was decreased by taking alcohol. He was diagnosed as having essential tremor. In 1995 he had two tonic seizures with loss of consciousness. For two months prior to the present admission in March 1996 he had noted tremulous oscillations of his legs while standing. On admission, general physical findings were Neurologic examination revealed unremarkable. normal mental status and intact cranial nerves. Tremulous shivering-like movements were present in both hands in the outstretched posture. He had difficulty in holding a small cup filled with water. On standing, he rapidly developed rhythmic oscillations of both leg muscles resembling orthostatic tremor. The oscillation was decreased while walking. Muscle tone, strength, and deep tendon reflexes were normal. There were no pyramidal or cerebellar signs. Sensory examination was unremarkable. Laboratory studies including lactate and pyruvate levels in both serum and CSF, and lysosomal enzymes in the leukocytes were normal. Cranial CT and MRI were normal. EEG revealed multifocal spikes, spikeand-wave, and polyspike-and-wave complexes. Background activity consisted of alpha waves with a small amount of theta activity. Photic driving responses were markedly enhanced. On surface EMG recordings, rhythmic bursts of lo50 ms duration occurred at a frequency of 7-9 Hz in the forearm flexors and extensors of the outstretched arms (Fig. 2A). During finger to nose testing, faster and more synchronous EMG bursts appeared in the arm muscles (Fig. 2B). On standing, brief EMG bursts with
frequencies of 7-9 Hz were shown in the leg muscles (Fig. 2C). SEPs evoked by the median nerve stimulation showed giant potentials [4], and C-reflexes [6] appeared in the thenar muscles (Fig. 3A). Stimulation of the posterior tibia1 nerve at the ankle also elicited giant SEPs [7] and C-reflexes (Fig. 3B). Jerk-locked averaging disclosed a positive EEG peak 16 ms prior to the EMG burst in the wrist extensor muscle (Fig. 4A), and 18 ms preceding the quadriceps EMG burst (Fig. 48). These electrophysiologic findings fit what has been described for cortical tremor [1,2]. The orthostatic oscillation was eliminated by valproate and the hand tremor was markedly attenuated by valproate and clonazepam. Propranolol had no effect on either the hand or leg tremors. Patient 2 The first daughter of the proband (III-l) had her first generalized convulsive seizure at age 20. She had two more seizures with loss of consciousness while watching TV later in the same year, but the type of seizure
A Wrist flexors
4
Wrist extensors
1 sec.
B Biceps Triceps Wrist flexors Wrist extensors
1 sec.
I 500
pv
C Quadriceps Hamstrings
w
Tibialis anterior II
Gastrocnemius 1 5oopv 1 sec.
m 22
19
18
16
25
FIGURE 1. Pedigree of the family. Solid symbols indicate affected members. Numbers under the symbols show the ages of the patients.
FIGURE 2. Surface EMG recordings in patient 1. (A) Rhythmic bursts of lo-50 ms duration occurred at a frequency of 7-9 Hz in the for<>arm flexors and extensors of the outstretched arms. (B) During finger to nose testing, faster and more synchronous EMG bursts appeared in the arm muscles. (C) On standing, brief EMG bursts with frequency of 7-9 Hz were shown in the leg muscles.
FAMILIAL
CORTICAL
TREMOR
WITH EPILEPSY
85
C4’- AlA2
16.25 WV
C4’- AI A2
IlOPV APB
I 2mV
I 1 mV
10s
B Cz’-AI A2
Quad. d AH
mV FIGURE 4. Jerk-locked averaging in patient 1 disclosed a positive EEG peak 16 ms prior to the EMG burst in the wrist extensor muscle (A), and 18 ms preceding the quadriceps EMG burst (B).
C4’- AI A2
a giant SEP (N20-P25: 11 pV, P25-N33: there were no C-reflexes.
14 pV), but
Patient 4 APB
FIGURE 3. (A) SEPs evoked by median nerve stimulation in patient 1 showed giant potentials (N20-P25: 23 pV, P25-N33: 60 rV), and Creflexes appeared in the thenar muscles at the latency of 38 ms. C4’: 2 cm posterior to C4. APB: Abductor Pollicis Brevis. (B) Stimulation of the posterior tibia1 nerve at the ankle in patient 1 also elicited giant SEPs (N33-I’39: 11 pV, P39-N48: 20 pV) and C-reflexes at 75 ms. Cz’: 2 cm posterior to Cz. AH: Abductor Hallucis. (C) SEPs evoked by median nerve stimulation in patient 2 showed giant potentials (N20P25: 22 pV, P25-N33: 62 pV) and C-reflexes.
was not specified. She showed fine postural finger tremor, but otherwise was neurologically normal. EEG revealed generalized spike-and-wave and polyspikeand-wave complexes with photic stimulation, and some theta activity on a background of alpha activity (Fig. 5). Median nerve stimulation produced giant SEPs and C-reflexes (Fig. 3C). Cranial CT was unremarkable. Her seizures were well controlled with valproate and her finger tremor was also decreased. Patient 3 A younger sister of patient 2 (111-4) complained of fine postural finger tremor only when she was tired. Neurologic examination showed no abnormality. EEG showed focal sharp waves and generalized spike-andwave complexes. Median nerve stimulation evoked
The younger brother of the proband (11-2) had a convulsive seizure at age 32, and noted postural tremor of his hands around the same time. He was diagnosed as having essential tremor, but propranolol was not effective. His seizures were controlled by sodium valproate, and the postural tremor was also attenuated. He showed no other abnormal neurologic signs. He is able to work as an engineer even though he has some residual finger tremor. Patient 5 The mother of the proband (I-l) had a generalized convulsive seizure at age 32. She noted tremulous hand movements two years later. She was not demented or ataxic. Diazepam and valproate were effective for both the seizures and the hand tremor.
DISCUSSION
The clinical features and the electrophysiological characteristics of the postural or action tremor in our patients are consistent with cortical tremor [l], a variant of cortical reflex myoclonus [3]. Other than the cortical tremor, there were no abnormalities on neurological examination. The disabilities remained minimal if the patients took anticonvulsants regularly, and the disorder progressed very slowly, or not at all. Although our patients had cortical reflex myoclonus and epilepsy, this family can be differentiated from various forms of progressive myoclonus epilepsy
Y. OKUMA
86
et al.
FPI-A, FPZ-A2
Fs-AI F4-AZ CJ -AI Cc -AZ Ps-AI PC -A, 01 -AI Oz-AZ FI -AI Fe-AZ T, -Al T4
-AZ
Tc -AI T4 -AZ
”
. FIGURE
5. EEG recordings
in patient
Photicstim. 18Hz 4
2. (A) Some theta activity on a background of alpha activity. polyspike-and-wave complexes with photic stimulation.
@‘ME), such as Unverricht-Lundborg disease, Lafora disease, neuronal ceroid-lipofuscinoses, mitochondrial disorders, sialidosis, and dentatorubral-pallidoluysian atrophy by clinical and laboratory findings. Our patients had a much more ‘benign’ course than what usually occurs with the PME syndrome. There have been some reports on families similar to the one in our study. Otsuka et al. [8] described a family with cortical tremor spanning four generations. Their patients also had seizures, and both the seizures and tremulous movements responded well to valproate. Therefore, their patients would appear to be in the same category of disorder as ours. Inazuki et al. [9] reported 12 families in which members showed myoclonus and epilepsy. Some of their patients had ‘myoclonic tremor’, but no cerebellar or pyramidal signs. Autopsies were performed on 3 of these patients and the brains showed no pathologic abnormalities. They termed the disease familial essential myoclonus and epilepsy (FEME). Their patients seem quite similar to ours in terms of the dominant inheritance, absence of abnormal neurologic findings other than myoclonus or tremor, and very slow or no progression of the disease with a good response to anticonvulsants. Therefore, although they did not provide any electrophysiological evidence to suggest cortical reflex myoclonus, we assume that their patients had the same disorder as ours. Yasuda reported two similar families in which members showed tremulous finger movements and/or myoclonus after adolescence. He
(B) Generalized
l#c
=PJ
spike-and-wave
and
termed this ‘Benign adult onset familial myoclonic epilepsy (BAFME)’ [lo]. He suggested that the tremulous finger movements might be minipolymyoclonus [ll] or cortical tremor, but his patients showed cortical reflex myoclonus electrophysiologically, so the clinical manifestation may well have been a cortical tremor. To our knowledge, this disorder has been reported exclusively in Japan, and has been given different names by different authors. We believe that these reports all describe the same disorder and we propose that it should be identified as ‘familial cortical tremor with epilepsy’. Correct diagnosis of familial cortical tremor is important because not only the seizures but also the tremor are attenuated by anticonvulsants. Most patients were previously diagnosed as having essential tremor because of the characteristics of the tremor, positive familial history (autosomal dominant inheritance) and alcohol sensitivity. However, P-blockers did not demonstrate any beneficial effect in these patients. Infrequent seizures might often be overlooked or considered to be coincidental. Demonstration of cortical reflex myoclonus by electrophysiologic testing confirms the diagnosis [1,2]. Another interesting finding is that the proband of this family showed leg tremor during standing which resembled orthostatic tremor. Although the tremor frequency in this patient was lower than the typical primary orthostatic tremor (14-18 Hz) [12], the clinical features of the oscillation had some similarities to
FAMILIAL CORTICAL TREMOR WITH EPILEPSY
those of orthostatic tremor [12]. Since a giant SEP, a C-reflex following stimulation of the tibia1 nerve, and a myoclonus-related cortical spike preceding the quadriceps myoclonic EMG discharge were all present, it is reasonable to regard the leg tremor in this patient as a manifestation of cortical tremor. Attenuation of the leg tremor with valproate further supports this possibility. In summary, familial cortical tremor with epilepsy may not be a rare disorder. Recognition of the EEG abnormalities, or seizures associated with a postural tremor resembling essential tremor, together with a positive familial history, are essential for diagnosis. Correct diagnosis of this disorder will avoid unnecessary treatment with fl-blockers and will lead to successful treatment with anticonvulsants, particularly sodium valproate and clonazepam.
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4. Shibasaki H, Yamashita Y, Tsuji S. Somatosensory evoked potentials. Diagnostic criteria and abnormalities in cerebral lesions. J Neural. Sci. 1977; 34: 427-439. 5. Shibasaki H, Yamashita Y, Neshige R, Tobimatsu S, Fukui R. Pathogenesis of giant somatosensory evoked postentials in progressive myoclonic epilepsy. Bruin 1985; 108: 225-240. 6. Sutton GG, Mayer RF. Focal reflex myoclnus. J. Neural. Neurosurg. Psychiatry 1974; 37: 207-217. 7. Kakigi R, Shibasaki H. Somatosensory evoked potentials following stimulation of the lower limb in corticcal reflex myoclonus. 1. Neural. Neurosurg. Psychiatry 1987; 50: 164-1646. 8. Otsuka M, Nakamura S, Yashima H, Ueki A, A familial case of cortical tremor. ] Movement Disorder and Disability 1995; 5; 99106 (in Japanese). 9. Inazuki G, Naito H, Ohama E, et al. A clinical study and neuropathological findings of a familial disease with myoclonus and epilepsy-The nosological place of a familial essential myoclonus and epilepsy (FEME). Seishin-shinkeigaku (in ]upanese) 1990; 92: l-21.
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Acknowledgements-The authors wish to express their gratitude to Professor Hiroshi Shibasaki for reading the first draft of the manuscript. We also wish to thank Professor Robert G. Lee for commenting on the final version of the manuscript.