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In 1990, Ikeda et al described the entity of cortical tremor for the first time in the Western literature108.  They reported two patients who had rare seizures and who had developed fine tremor in the 4th and 7th decades. Diagnosis

Since 1990, a number of similar conditions have been described from Japan, typically characterized by a benign clinical course, with rare seizures, normal cerebellar function, absence of dementia and and associated with tremor109.  The tremor can be demonstrated to be of cortical origin, and represents a manifestation of cortical reflex myoclonus.

These conditions include:

  1. “Cortical tremor” (reported by Ikeda in 1990108)
  2. “Benign adult familial myoclonus epilepsy (BAFME)” (reported by Kuwano in 1996 110 )
  3. “Familial cortical myoclonic tremor” (reported by Terada in 1997109)
  4. “Familial cortical tremor with epilepsy” (FCTE) (reported by Okuma in 1997) 111
  5.  “Familial benign myoclonus epilepsy of adult onset” (reported by Okino in 1997112)
  6. “Familial adult myoclonic epilepsy (FAME)” (reported by Plaster in 1999)

In addition, similar conditions have been described in European families, namely ADCME with complex partial and generalized seizures and Familial Cortical Tremor, Epilepsy and Mental Retardation8;113. Inheritance

In Ikeda’s report, one of the patients had six siblings, of whom two had a similar tremor, indicating a possible AD condition108.  Terada et al described three pedigrees with AD inheritance109 and Okuma reported on a further Japanese family in which five members in three generations had a similar condition, and three further families in which the disorder was present in two successive generations111.  Kuwano reported five families, with age of onset between 18 and 50 years with AD inheritance110.  Plaster et al reported that AD inheritance was a criterion for FAME, and that penetrance was unusually high5 Myoclonus and Cortical Tremor

Wilkins et al had previously published on a group of patients in an article entitled ‘Primary generalised epileptic myoclonus: a frequent manifestation of minipolymyoclonus of central origin”114.  However, since the distribution and latency of the recorded premovement discharge, Ikeda et al coined the term “cortical tremor” although the movement resembled polyminimyoclonus.  The tremor was fine and shivering-like, brought out by outstretched posture and accentuated by action108 

In Okino’s report of 1997, rare seizures occurred, usually preceded by a worsening of myoclonic movements.  Examination showed “fine myoclonus in the distal portion of the upper limbs”in one patient, whose 81 year old mother was reported to have “marked generalized myoclonus” after a seizure112.  Okuma described “tremulous shivering-like movements” with posture-holding111. Clinical Manifestations

Table 2 reporting radiological findings and Table 3 reporting results of linkage analysis are found on page 51 and 52 respectively.  Table 17 concerning progression of disease and Table 19 concerning clinical features are available on page 205 and 211 respectively.

Ikeda’s initial report described two patients who had rare seizures and who had developed fine tremor in the 4th and 7th decades.  Seizures occurred twice in the older patient and the younger one had “several seizures every 1 to 2 years, especially when tired or tense”.  The tremor generalized prior to the seizure in both cases.  There were no cerebellar signs in either patient.  In one of the patients, “the involuntary movement was so severe that intensive medication was required to prevent generalized convulsion  (sic)”108.


In familial benign myoclonus epilepsy of adult onset, three families with onset of illness between the third and fifth decades were reported112.  The illness was characterised by jerks in arms and eyelids, which were exacerbated by movement.  There was no dementia, cerebellar ataxia or other characteristic signs of PME.  However, one 64 year old patient had slowly progressive generalized myoclonus, and had suffered seizures several times over the two decades prior to admission.  At admission, he was mildly drowsy with generalized myoclonus. 


BAFME has also been associated with night-blindness and abnormalities on electroretinography.  Manabe reported a family in which a 34-year-old proband developed night-blindness at the age of 13 and tremulous finger movements three years later115.  On examination the only abnormal finding was that of fine tremor in the fingers and myoclonus in the arms and legs at rest.  In particular, the reflexes were normal and there was no dementia present.  MRI scan was normal.  The proband’s mother had myoclonus of the arms and legs when tired from the age of 30, and generalized seizures from age 33.  The proband’s sister had myoclonus in the arms and legs, and fine tremulous movements in the fingers115.


In 1997, there was a report by Terada et al, originating from the same group which had originally coined the term “cortical tremor”, and now termed “Familial Cortical Myoclonic Tremor”109.  The patients had ‘tremulous involuntary movements’ which were rhythmic and seen in both the upper and lower limbs, and were exacerbated by posture and action.  They had been previously diagnosed as having familial essential tremor.  In six patients from three families, tremor commenced at a mean of 37 years and gradually progressed.  Three patients had episodes of loss of consciousness, but these were extremely rare, “on one to three occasions throughout the clinical course”.  One patient had akinesia, rigidity and gait disturbance with a limited response to dopamine replacement, but otherwise the neurological examination was normal.  Terada et al proposed the following criteria for the condition109.

  1. AD inheritance.
  2. Adult onset.
  3. Slowly progressive, but mild clinical course.
  4. Relatively rhythmic small jerks predominantly involving the distal limbs, markedly enhanced during movement.
  5. Infrequent attacks of loss of consciousness.
  6. No other neruological findings (no dementia or ataxia).
  7. Electrophysiology of :
    1. Generalized EEG spikes, with photoparoxysmal response.
    2. Giant SEPs.
    3. Enhanced C-reflex.
    4. Cortical spikes on jerk locked averaging (JLA).
    5. Preservation of normal bereitschaftpotential (BP).


Okuma described “Familial cortical tremor with epilepsy” in which the clinical features were “tremulous, shivering-like movements” and rare seizures111.  On standing the proband had rhythmic oscillations of the legs resembling orthostatic tremor.  He had a seizure three decades previously at the age of 25.  All of the four other members of the family who were described had a normal neurological examination with fine tremor of the fingers with posture holding.  CT and MRI of the brain were normal in the proband and his daughter.  Seizure onset occurred in the proband’s mother at 32 years, and in his daughter at 20, and in his son at age 32.


In a second report by Okuma et al, three additional families with seven affecteds were described116.  The proband had a seizure at the age of 20 and had tremulous finger movements from that time.  At the age of 39, she was on anticonvulsants which controlled the seizures, and when these were stopped myoclonus reappeared.  The tremor was not progressive and there was no evidence of corticospinal or cerebellar dysfunction.


The entity of FAME was reported by Uyama in 1996117.  There were four families, with 27 affected members presenting over three generations with high penetrance.  The following characteristics were noted 5:

  1. Adult onset at a mean age of 37.5 years.
  2. The course was benign, without associated ataxia or dementia.
  3. The condition had been only reported in Japan.
  4. The clinical features of FAME were myoclonic jerks in the arms and legs, tremulous finger movements and rare generalized tonic-clonic seizures (GTCS).
  5. Myoclonic jerks could be precipitated by fatigue, insomnia and photic stimuli.
  6. The EEG showed generalized spikes and polyspikes.


In 1999, the FAME locus was mapped to chromosome 8q245 by Plaster et al.  BAFME was mapped to the same locus, termed the FAME 1 locus (8q23.3-q24.11) by Mikami et al. who used microsatellite markers to demonstrate a maximum multipoint LOD score of 5.42 in the interval between the markers D8S555 and D8S17796.  The authors of the latter report pointed out the following characteristics:

  1. Autosomal dominant inheritance, tremulous finger movements and myoclonus of extremities.
  2. Infrequent epileptic seizures.
  3. EEG showed polyspike and wave with marked photosensitivity.
  4. Features of cortical myoclonus were present, including enlarged SEPs, enhanced C reflexes and positive spikes preceding myoclonus.
  5. Benign nonprogressive course without cerebellar ataxia and dementia6.


Mikami et al described a family with three affected generations and 17 affecteds6.  The onset of tremulous movements in fingers or myoclonus of the extremities typically occurred at an average age of 30.5 years (range 18-45 years).  In half the patients myoclonus involved both arms and legs, and was restricted to the arms in the remainder.  Seizures occurred infrequently, often less than four times throughout the lifespan of the patient.  Two of the 17 patients did not have generalised seizures.  No evidence of cerebellar ataxia of dementia was seen over an observation period of more than a decade.  CT demonstrated mild atrophy of the cerebral cortex in three patients. 


Subsequently, a four-generation family with FAME was reported from Spain: ten living and three deceased family members had “involuntary rhythmic movements of the extremities”, the mean age of onset being 41 years7.  The movements were described as myoclonic, rather than tremulous.  Eight of the 13 had generalized tonic-seizures, the mean age of onset being 44.6 years.  EEG showed polyspike and wave discharges without photosensitivity, and electrophysiological findings were compatible with cortical myoclonus7.


Van Rootselaar described a family from the Netherlands with FCTE118.  There were 13 definite affecteds, and three probably affected.  The proband had finger twitching, tremor, and trembling of his legs, worsened by stress and after waking.  He had a kinesogenic tremor with superimposed myoclonus in his fingers and toes.  He had rare seizures.  Linkage was negative for the FAME 1 and 2 loci119.


A European family was described by Elia et al. with cortical tremor, epilepsy and mental retardation, although mental retardation was present in only one individual113.  The family had a six generation pedigree with seven affecteds and appears to have been transmitted only through the female line, suggesting a mitochondrial disorder.  Two individuals in the first generation only had finger tremor.  One patient had no seizures, and seizure onset was age five in two affecteds, and age 18 in another. Seizures were well controlled by Phenobarbital in two patients.  MRI scan showed mildly enlarged subarachnoid space and lateral ventricles in two patients, and was normal in a third.


In 2001, Guerrini et al described a family from Tuscany of 11 individuals over five generations characterized by similarities to FAME but also having complex partial seizures8. The condition had linkage to chromosome 2p11.1-q12.2, and linkage to the locus for FAME was excluded.  This condition was termed ADCME8.  The features of the condition were:

  1. Onset in adulthood.  The age of onset of myoclonus range from 12 - 50 years, with a mean of 23 years and typically slightly preceded or commenced at the same time as the first GTCS. 
  2. The course of the illness was not progressive.
  3. Distal, semi-continuous, rhythmic myoclonus resembling tremor of variable ampitude.  Myoclonus of the hands was present at rest, but exacerbated by maintenance of posture.  There were also isolated multifocal jerks of the arms proximally and intermittent myoclonus of eyelids. 
  4. Of the eight family members, two had only one or two isolated GTCS, and three had seizures in remission on treatment, in two for 20 years. One had treatment resistant GTCS, two had intractable complex partial seizures, and one had complex partial seizures that responded to treatment.
  5. Three patients had mild to moderate mental retardation and one borderline intellectual functioning, and in the remaining three patients intelligence was below average. 
  6. EEG abnormalities included features of primary generalized epilepsy as well as frontotemporal or focal temporal spike discharges.


Electrophysiological testing was compatible with myoclonus of cortical origin.  MRI imaging was normal.  This family had two phenotypes: a core syndrome of rhythmic myoclonus and GTCS, and a more severe phenotype associated with complex partial seizures.  It was proposed that this could have been the consequence of a gene causing widespread cortical hyperexcitability, but particularly involving the frontotemporal regions8.


Two further Italian families were described with linkage to 2p11.1-q12.29.  These families had cortical tremor, and seizures were present in 40 % of one family and 60 % of the other, but were rare (one to five attacks) in those affected.  There was no dementia present, and neurological examination was normal apart from the presence of tremor.  This locus has been termed the FAME 2 locus.


Subsequently, Striano et al reported a new BAFME pedigree, with possible linkage to the FAME 2 locus, since lod scores only reached 1.5510.  Seven affecteds had cortical tremor and GTCS was present in six.  MRI of the brain was normal in three patients.  The authors proposed that the condition was found worldwide, but genetically heterogenous, with Japanese families linked to the FAME 1 locus and European ones to the FAME 2 locus10.  Similarly, Okuma and Mizuno pointed out that FAME, BAFME and familial cortical tremor were likely to be one entity120


FAME associated with migraine has been described in a five generation family from Turkey in which myoclonus started in the third or fourth decades121.  Generalised seizures were extremely uncommon, the only feature of note on examination was postural tremor of the hands, and both myoclonus and migraine were decreased by valproic acid121. Pathophysiology

Since BAFME responds to sodium valproate and diazepam, and since GABA receptors are the site of action of these drugs, linkage studies of the DNA polymorphisms of the GABA receptors, GABARb1, GABARb3 and GABARa6 were performed.  However, the gene for BAFME was not linked to a gene for the GABA receptors110.  Lack of neurodegeneration in FAME may suggest that the disorder is one of membrane excitability5. Special Investigations

Neuroradiological findings are summed up in Table 2.  Predominanly, both CT and MRI are normal in a wide range of reports.  Mild cerebellar and cerebral atrophy have been noted relatively infrequently.

Table 2.     Neuroradiological findings in FAME and related families.




Ikeda, 1990

Periventricular lucency

Moderate cerebral atrophy in patient aged 75.


Okino, 1997


Infarction in cerebellar hemisphere (patient 1).

Normal (patient 3).

Multiple lacunar infarctions (patient 4).

Okuma, 1997

Normal (2)


Okuma, 1998



Plaster, 1999



Elia, 1998


Mild enlarged subarachnoid space and lateral ventricles in two.  Normal in one.

Mikami, 1999

Mild atrophy in three


Guerrini, 2001


Normal (six)

Labauge, 2002


Normal (five)

Van Rootselaar, 2002


Slight cerebellar atrophy (two)

Normal (two)

De Falco, 2003


Normal (nine)

Van Rootselaar, 2004

Atrophy, particularly cerebellum


Manabe, 2002



Striano, 2004



Saka, 2000



Guerrini, 2001


Normal (six)

The EEG shows generalized spike and wave discharges109;112. and photosensitivity is often present109;110;116.  Recordings suggested origin of the movement in the sensorimotor area, possibly in hyperexcitable motor cortex108 and results of  electrophysiological testing appear to be uniformly compatible with cortical reflex myoclonus108;109;112;116.  Electrophysiological features of the European family with mental retardation were similar to those found in the families reported from Japan, including photosensitivity on EEG113. Pathology

In the Japanese literature, normal findings were reported in three patients with myoclonus and epilepsy, some of whom had “myoclonic tremor” (122cited in 111).

Van Rootselaar reported on a case of FCTE in which there was extensive mineralization of vessel walls and neurons in the globus pallidus.  The cerebellum showed Purkinje cell loss with Bergmann gliosis, atrophy of the molecular layer and abnormal Purkinje cell morphology.  Gliosis of the cerebellar white matter and cell loss and gliosis of the dentate nucleus were present123. Genetics

Linkage analysis of known studies is presented in Table 3.

Table 3.     Linkage analysis  in FAME and related families.



2p11.1-q12.2 FAME 2

8q24 FAME 1

Plaster, 1999




Mikami, 1999




Guerrini, 2001




De Falco, 2003




Labauge, 2002

Southern Spain



Van Rootselaar 2002; Bouwer, 2002




Striano, 2004



(Lod score 1.55)

- Management

Myoclonus, including finger tremor, and seizures were effectively treated with a combination of clonazepam and valproic acid109;116.         

  108.   Ikeda A, Kakigi R, Funai N, Neshige R, Kuroda Y, Shibasaki H. Cortical tremor: a variant of cortical reflex myoclonus. Neurology 1990;40:1561-5.

  109.   Terada K, Ikeda A, Mima T, Kimura M, Nagahama Y, Kamioka Y, Murone I, Kimura J, Shibasaki H. Familial cortical myoclonic tremor as a unique form of cortical reflex myoclonus. Movement Disorders 1997;12:370-7.

  110.   Kuwano A, Takakubo F, Morimoto Y, Uyama E, Uchino M, Ando M, Yasuda T, Terao A, Hayama T, Kobayashi R, Kondo I. Benign adult familial myoclonus epilepsy (BAFME): an autosomal dominant form not linked to the dentatorubral pallidoluysian atrophy (DRPLA) gene. Journal of Medical Genetics 1996;33:80-1.

  111.   Okuma, Y., Shimo, Y., Hatori, K., Hattori, T., Tanaka, S., and Mizuno, Y. Familial Cortical Tremor with Epilepsy. Parkinsonism and Related Disorders 3(2), 83-87. 1997.
Ref Type: Journal (Full)

  112.   Okino S. Familial benign myoclonus epilepsy of adult onset: a previously unrecognized myoclonic disorder. J.Neurol.Sci. 1997;145:113-8.

  113.   Elia M, Musumeci SA, Ferri R, Scuderi C, Del Gracco S, Bottitta M, Michelucci R, Tassinari CA. Familial cortical tremor, epilepsy, and mental retardation: a distinct clinical entity? Archives of Neurology 1998;55:1569-73.

  114.   Wilkins DE, Hallett M, Erba G. Primary generalised epileptic myoclonus: a frequent manifestation of minipolymyoclonus of central origin. Journal of Neurology, Neurosurgery & Psychiatry 1985;48:506-16.

  115.   Manabe Y, Narai H, Warita H, Hayashi T, Shiro Y, Sakai K, Kashihara K, Shoji M, Abe K. Benign adult familial myoclonic epilepsy (BAFME) with night blindness. Seizure. 2002;11:266-8.

  116.   Okuma Y, Shimo Y, Shimura H, Hatori K, Hattori T, Tanaka S, Kondo T, Mizuno Y. Familial cortical tremor with epilepsy: an under-recognized familial tremor. [Review] [10 refs]. Clinical Neurology & Neurosurgery 1998;100:75-8.

  117.   Uyama, E., Tokunaga, M, Murakami, T, Kuwano, A., Kondo, I., and Uchino, M. Familial Adult Myoclonus Epilepsy: A New Phenotype of Autosomal Dominant Myoclonus Epilepsy. Annals of Neurology 40, 505. 1996.
Ref Type: Abstract

  118.   van Rootselaar F, Callenbach PM, Hottenga JJ, Vermeulen FL, Speelman HD, Brouwer OF, Tijssen MA. A Dutch family with 'familial cortical tremor with epilepsy'. Clinical characteristics and exclusion of linkage to chromosome 8q23.3-q24.1. J Neurol 2002;249:829-34.

  119.   Bouwer OF, Callenbach, P. M., and van Rootselaar, A. F. A Dutch family with 'Familial Cortical Tremor with Epilepsy': exclusion of linkage to chromosomes 8q and 2p. Epilepsia 43(Suppl 8), 128. 2002.
Ref Type: Abstract

  120.   Okuma Y, Mizuno Y. Absence of linkage to 8q24 in a European family with familial adult myoclonic epilepsy (FAME). Neurology 2002;59:1665-6.

  121.   Saka E, Saygi S. Familial adult onset myoclonic epilepsy associated with migraine. Seizure. 2000;9:344-6.

  122.   Inazuki, G., Naito, H., and Ohama, E. 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 ). Sheishin-shinkeigaku 92, 1-21. 1992.
Ref Type: Journal (Full)

  123.   van Rootselaar AF, Aronica E, Jansen Steur EN, Rozemuller-Kwakkel JM, de Vos RA, Tijssen MA. Familial cortical tremor with epilepsy and cerebellar pathological findings. Mov Disord. 2004;19:213-7.