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Keywords:

  • Cortical tremor;
  • Myoclonus;
  • EEG;
  • Evolution;
  • Prognosis

Summary

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
  8. Supporting Information

Purpose: To investigate for the first time the natural history and long-term evolution of “familial cortical tremor, myoclonus, and epilepsy.”

Methods: We evaluated the clinical, electrophysiologic, and treatment data of 14 patients from three families linked to 2p11.1–q12.2. A simplified scale was used to score myoclonus severity. Electroencephalography (EEG) studies were reviewed for the evaluation of background activity, paroxysmal abnormalities, and photoparoxysmal response. Data were organized for age groups. Correlation and logistic regression analysis were performed.

Key Findings: Patients’ mean age was 47.8 ± 22.0 years (range 20–86 years). Mean age at disease onset was 20.2 ± 7.8 years (range 11–40 years); mean follow-up duration was 14.0 ± 5.8 years (range 7–28 years). Evaluation at different age groups revealed a gradual, progressive worsening of the myoclonus in 10 patients (71.4%). Two subjects aged >80 years showed myoclonus interfering with autonomous walking. Myoclonus severity was correlated with disease duration (p < 0.001) and patients’ age (p = 0.001). Six patients (42.8%) experienced seizures, usually between the second and sixth decades of life. Evaluation of EEG long-term evolution revealed progressive slowing of background activity in parallel with the gradual worsening of myoclonus. In contrast, paroxysmal activity and photosensitivity were particularly evident during the intermediate phases of the disease. In addition, psychiatric and neuropsychological dysfunction occurred in more than one third of the patients.

Significance: We provide data for a slight age-dependent progression and the presence of neuropsychiatric and neuropsychological dysfunction in this unique syndrome, for which the definition of familial or autosomal dominant cortical tremor, myoclonus, and epilepsy (FCTME/ADCME) seems to be, therefore, more appropriate.

Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME/FCTME; OMIM:607876) or benign adult myoclonic epilepsy (BAFME/FAME; OMIM:601068) is characterized by familial occurrence of postural and action-induced shivering movement of the hands mimicking essential tremor, but showing the electrophysiologic findings of cortical reflex myoclonus (Ikeda et al., 1990; Striano et al., 2005a; Uyama et al., 2005). In addition, patients may have myoclonus of upper limbs and tonic–clonic seizures, often precipitated by sleep deprivation or photic stimulation (Ikeda et al., 1990; de Falco et al., 2003; Striano et al., 2005a). The genetic background of this condition is heterogeneous. In fact, Japanese families are linked to 8q24 and Italian to 2p11.1–q12.2 (Guerrini et al., 2001; Striano et al., 2005a; Uyama et al., 2005; Depienne et al., 2010). A third locus on 5p15.31–p15 has been recently identified in a single French family (Depienne et al., 2010). However, no causative genes have been identified so far.

The disease usually has a benign course, although drug-resistant partial seizures or slight mental retardation occurs in some cases (Guerrini et al., 2001; Depienne et al., 2010). Moreover, a worsening of cortical tremor and myoclonus is common in advanced age (Ikeda et al., 1990; de Falco et al., 2003; Striano et al., 2005a; Uyama et al., 2005). However, although the clinical picture of this syndrome is well defined, systematic studies on long-term evolution of this syndrome are still lacking.

Patients and Methods

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
  8. Supporting Information

Clinical evaluation

The local ethics committee approved the study and informed consent was signed by participants. All the patients had hand postural tremor and from myoclonus. We evaluated the clinical, electrophysiologic, and treatment data at the different ages of patients from three Italian pedigrees. These families share a common haplotype at 2p11.1–q12.2 (Madia et al., 2008) (Fig. S1) and have been described in detail elsewhere [family A (de Falco et al., 2003); family B (Striano et al., 2004); family C (Striano et al., 2005b)]. The same clinician (S.S.) reviewed the video recordings of the patients and scored the severity of myoclonus using a simplified scale (Table S1) (Magaudda et al., 2006).

Electrophysiologic studies

All available electroencephalography (EEG) recordings were independently reviewed by for the evaluation of background activity, the frequency of the posterior dominant rhythm, the paroxysmal abnormalities, and photoparoxysmal response. For the purpose of the study, the data were organized for different age groups (10–19; 20–39; 40–59; 60–79; ≥80 years). Somatosensory-evoked potentials (SEPs) and long latency reflex I (C-reflex), showing enlarged cortical responses consistent with cortical reflex myoclonus (Ikeda et al., 1990; Striano et al., 2005a), were obtained at least once in each patient.

Neuropsychological evaluation

Neuropsychological evaluation included Mini Mental State Examination, Wechsler Adult Intelligence Scale Revised (cognition); Digit Span, Rey’s 15 Words Immediate and Delayed Recall (verbal memory); Corsi’s Block Tapping Test, Rey’s Complex Figure (visual memory); Raven’s Progressive Matrices (abstract reasoning); Attentive Matrices (attention); Copy of Rey’s Complex Figure (visuospatial processing); and Token Test (language).

Statistical analysis

The relationship between parametric variables (i.e., patients’ age, disease duration, myoclonus severity, seizure frequency) was analyzed. Correlation (r) and regression (F-ratio) coefficients with p-value and 95% confidence interval (CI) were calculated by MedCalc 9.2 (MedCalc Software, Mariakerke, Belgium). The level of significance was set at p ≤ 0.01.

Results

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
  8. Supporting Information

Demographics and general data

Fourteen patients (nine men, five women; mean age: 47.8 ± 22.0 years, range 20–86; Table 1) were included. Mean age at disease onset was 20.2 ± 7.8 years (range 11–40 years); mean age at first evaluation was 33.6 ± 18.0 years (range 12–67 years). At the last evaluation, mean disease duration was 27.5 ± 19.8 years (range 8–66). Mean follow-up duration was 14.0 ± 5.8 years (range 7–28).

Table 1.   General data and evaluation of clinical features of the patients at different age groups
Family/IDSex/age (years)Age at onset (years)Age at first evaluation (years)Age at first treatment (years)Psychiatric comorbidityNeuropsychological findings (years)Current AEDsDisease duration (years)FW-up duration (years)Myoclonus score (years)Seizure frequency (years)
10–1920–3940–5960–79>8010–1920–3940–5960–79>80
  1. M, male; F, female; GAD, generalized anxiety disorder; D, depression; IQ, intelligence quotient; VVM, visual-verbal memory; VSP, visuospatial performance; L, language; GTCS, generalized tonic–clonic seizures; VPA, valproate; CNZ, clonazepam; LEV, levetiracetam; ZNS, zonisamide; CLB, clobazam; PB, phenobarbital.

A/1M/201212NoneNormal (12)None881200
A/2F/50113818GAD, DNormal (43)VPA, LEV391212030
A/3F/42202025GADNormal (33)VPA, CLN, LEV22221200
A/4M/86205858Low scores VVM, VSP (75)PB, LEV66282340210
A/5F/80406767GAD, DLow scores VVM, VSP (73)LEV, CLN401323000
B/lM/47163030IQ: 79; low scores VVM, VSP, L (30)VPA311712032
B/2M/45253030GAD, DNormal (30)VPA, CLB20152332
B/3F/80185940GAD, DLow scores VVM, VSP (72)VPA, LEV6218  23400000
C/1F/261818NoneNormal (18)None881100
C/2M/27182020Normal (20)ZNS9712000
C/3M/61184830GADNormal (55)VPA, CLN, LEV4313330030
C/4M/22131316Normal (18)LEV9101100
C/5M/51323535Low scores VSP (35)LEV, VPA19161220
C/6M/33232323Normal (23)LEV101010

Cortical tremor and myoclonus

Evaluation at different age groups (Table 1) revealed a gradual, progressive worsening of myoclonus in 10 (71.4%) of 14 patients. In fact, myoclonus was of minor severity at the beginning of the disease—with no interference with daily living (score 1)—but resulted in a variable degree (score 2 or 3) of functional impairment of fine movements, handwriting, signing, or speech in the following years. Two subjects aged >80 years showed myoclonus interfering with autonomous walking (score 4). None of the patients were wheelchair-bound or bedridden (score 5). Myoclonus severity was strongly correlated with disease duration (r = 0.84; F ratio = 31.0; p < 0.001) and patients’ age (r = 0.80; F ratio = 21.9; p = 0.001) (Fig. 1A,B). Overall, the severity of the disease seemed to be milder in patients with later onset of the symptom. However, the severity of myoclonus could differ between members of the same family at the same age.

image

Figure 1.   Regression analysis showing that myoclonus severity was correlated with disease duration (r = 0.84; F ratio = 31.0; p < 0.001) (A) and patients’ age (r = 0.80; F ratio = 21.9; p = 0.001) (B) but not with seizure frequency (C) (r = 0.28; F ratio = 1.03; p = 0.33). Graphic representation of patients’ EEG background activity (posterior dominant rhythm) showing gradual and progressive slowing over time (D).

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Epilepsy

Six patients (42.8%) experienced tonic–clonic seizures, commonly precipitated by sleep-deprivation or photic stimulation. Seizures were overall rare (from 1 to 5 episodes) and usually occurred between the second and sixth decades of life. There was no correlation between myoclonus severity and seizure frequency (r = 0.28; F ratio = 1.03; p = 0.33; Fig. 1B). Patient C/3 manifested a life-threatening status epilepticus following gabapentin therapy (Striano et al., 2007). No individual experienced seizures after age 80 years.

Psychiatric features

In adulthood, six subjects (42.8%) had moderate generalized anxiety disorder with excessive and disproportionate worry about everyday things, associated with mild depression in four cases (28.5%) (Table 1). None of them had psychosis or attempted suicide. Treatment with citalopram was required in two patients (A/2, B/3).

EEG findings

A total of 156 EEG studies (median 11, range 6–18) were reviewed. All patients had at least one awake or sleep EEG. The background activity was generally between 12 and 11 Hz before age 40 years (Table S2). However, a gradual and progressive slowing was evident over the years, independent from treatment (Figs 1C and 2). Eight patients (57.1%) showed paroxysmal activity (i.e., generalized polyspikes or polyspikes-waves) and five of them (57.1%) also displayed a photoparoxysmal response (type IV) (Waltz et al., 1992). None of the subjects showed focal paroxysmal activity. Overall, EEG abnormalities were more prominent between age groups 20–39 and 40–59 years and gradually disappeared during follow-up (Table S2; Fig. S2). Only patient C/3 still had an “active” EEG after age 60 years. There was no evident correlation between the occurrence of seizures and EEG abnormalities (Table S2).

image

Figure 2.   Free-draw Archimede’s spiral hands (left) and basal EEG of patient C/3 obtained at the age of 59 (A), 70 (B), and 80 years (C) showing worsening of myoclonus and progressive slowing of EEG background activity.

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Neuropsychological findings

At least one neuropsychological testing was available for all patients (mean age 38.3 ± 21.9 years, range 12–75), in eight cases obtained at the first evaluation (Table 1). Nine subjects (64.3%) showed normal neuropsychological testing. Five subjects (35.7%) displayed moderately impaired visuospatial processing associated with below average verbal and visual memory in four patients. In addition, one subject showed an intelligence quotient of 79 and poor language performance.

Treatment

Antiepileptic drugs (AEDs) were generally indicated for the treatment of cortical tremor. Mean age of initial treatment was 32.6 ± 15.6 years (range: 16–67 years). However, over the course of the disease, several changes were made and they were not reported as it was not the aim of the study. Treatment at the last follow-up is shown in Table 1. Two patients did not have any therapy. The remaining subjects were treated with 1–3 (mean 1.9 ± 0.7) AEDs. A significant clinical improvement was almost constantly observed with valproate (seven patients) used singly or in association with levetiracetam (five patients) or clonazepam (two patients). Two subjects were on monotherapy with either levetiracetam or zonisamide with partial benefit.

Discussion

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
  8. Supporting Information

The association of autosomal dominant cortical tremor, myoclonus, and epilepsy was first recognized in Japanese families and is now increasingly reported worldwide, even if named with different acronyms (e.g., BAFME, FAME, FCTME, ADCME) (Ikeda et al., 1990; Guerrini et al., 2001; Striano et al., 2005; Uyama et al., 2005). Despite being a well-delineated condition with remarkable features, it is not yet officially recognized from International League Against Epilepsy (ILAE), and its nosologic placement is still debated. Its clinical features (age of onset, seizure types, occurrence on awakening) are different from those of juvenile myoclonic epilepsy and other idiopathic generalized epilepsies. On the other hand, the lack of rapid cognitive decline and the less severe clinical course distinguishes this syndrome from progressive myoclonic epilepsies.

This is the first study reporting the natural history and long-term evolution of the syndrome. According to the homogeneous genetic background (common haplotype at 2p11.1–q12.2) (Madia et al., 2008), the core of the syndrome in our families included cortical tremor and myoclonus of the extremities, with age of onset highly variable (11–40 years) but usually starting within the second decade of life. Seizures, when present, are overall rare and often precipitated by sleep deprivation or photic stimulation (Striano et al., 2005a; Uyama et al., 2005; Gardella et al., 2006). Moreover, they usually occurred between the second and sixth decades of life and represent a minor feature. Therefore, epilepsy did not ever play a major role in patients’ disability level, which was instead determined by the intensity of myoclonus.

Myoclonus was of minor severity and did not interfere with daily living in the first years of the disease but did generally result in a significant functional impairment of fine movements in adult age, despite antiepileptic treatment. Moreover, in the majority of the patients we observed a slow but gradual and progressive worsening of the myoclonus, which was correlated with the duration of the disease. Indeed, this finding could be appreciated during a prolonged follow-up and resulted in walking impairment and need for help in everyday life for individuals aged >80 years. On the other hand, none of the patients were wheelchair-bound or bedridden.

Evaluation of the long-term evolution of EEG in our patients revealed mild progressive slowing of the background activity in parallel with the gradual worsening of myoclonus over the years. In contrast, paroxysmal activity and photosensitivity were particularly evident during the intermediate phases of the disease, and they tended to disappear becoming less frequent as the symptoms progressed.

Although long-term neuropsychological evaluation was not an aim of this study, one third of our patients displayed moderately impaired visuospatial processing and to a lesser extent, verbal and visual memory. This neuropsychological profile overlaps with that so far described in a single family (Suppa et al., 2009), confirming the “ventral pathway” involvement related to a temporal lobe dysfunction, at least in some affected individuals. However, only one patient had borderline intellectual functioning, consistent with the overall good neuropsychological outcome of this condition. Finally, we reported a relatively high frequency (>40% of the cases) of psychiatric features (i.e., generalized anxiety disorder and depression) in our patients, which have not been described previously in this syndrome. Although these manifestations were usually mild and required specific treatment only in some cases, we recommend neuropsychiatric assessment as part of the evaluation of these patients in adulthood.

The causative genes of this syndrome have not yet been identified and thus far its pathophysiology remains speculative. Both clinical and electrophysiologic features suggest a cortical hyperexcitability, which can be the result of enhanced intrinsic rhythmic activity of cortical generators (Brown et al., 1996) or decreased cortical inhibition caused by dysfunction of the cerebello-thalamo-cortical loop (Ikeda et al., 1990; Guerrini et al., 2001; Striano et al., 2005a). Recent brain magnetic resonance spectroscopy (MRS) (Striano et al., 2009) and functional magnetic resonance imaging (fMRI) studies (van Rootselaar et al., 2007) indicate that the cerebellum is the prominent site of neuronal dysfunction in these patients according to the few available postmortem histologic studies (van Rootselaar et al., 2004; Uyama et al., 2005). Overall, these findings are consistent with the slight age-dependent progression of the syndrome showed by the present study. Moreover, in our series, myoclonus severity correlated with disease duration but also with patients’ age, suggesting that the clinically evident progression of the disease reflects, at least in part, the effect of physiologic aging. This excessive cortical hyperexcitability may be the result of a disruption in γ-aminobutyric acid (GABA)ergic inhibition, which is thought to control neuronal excitability (Marco et al., 1996) and modulate abnormal oscillatory activities in the central motor networks (Valzania et al., 1999).

In conclusion, we provide data for a slight age-dependent progression and, alongside the already reported clinical features, the presence of additional neuropsychiatric and neuropsychological dysfunction in this unique syndrome. AED treatment is usually necessary to provide adequate control of the symptoms. Nevertheless, a progression of myoclonus and disability is seen over time. Therefore, we suggest avoiding the use of the terms “benign” or “adult” (BAFME/FAME) to identify these patients. On the other hand, the definition of familial or autosomal dominant cortical tremor, myoclonus, and epilepsy (FCTME/ADCME) seems to be more appropriate.

Disclosure

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
  8. Supporting Information

The authors report no conflicts of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
  8. Supporting Information

Supporting Information

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Disclosure
  7. References
  8. Supporting Information

Figure S1. Pedigrees and chromosome 2p11.1–q12.2 haplotypes of the three families (the plain bar indicates the segment shared by all families).

Figure S2. Graphical representation of EEG paroxysmal activity (A) and photoparoxysmal response (B) in the patients. EEG abnormalities were more prominent between age groups 20–39 and 40–59 years and gradually disappeared during the follow-up.

Table S1. Simplified myoclonus rating scale used in this study (from Magaudda et  al., 2006).

Table S2. EEG characteristics of the patients at different age groups.

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EPI_3017_sm_FigS1.tif2180KSupporting info item
EPI_3017_sm_FigS2.tif711KSupporting info item
EPI_3017_sm_TableS1.pdf52KSupporting info item
EPI_3017_sm_TableS2.pdf85KSupporting info item

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