Research Articles
Primary Progressive Myoclonus of Aging
Maria Alvarez, MD1 and John N. Caviness, MD2*
1Department of Neurology, Wilford Hall Medical Center, San Antonio, Texas, USA2Parkinson’s Disease and Other Movement Disorders Center, Mayo Clinic, Scottsdale, Arizona, USA
Abstract: Myoclonus in older individuals usually occurs inthe context of associated neurologic features which allow thediagnosis of the underlying disorder. We encountered 7patients with a newly recognized myoclonus syndrome; weuse the term primary progressive myoclonus of aging(PPMA) for this syndrome. Our purpose was to characterizethe clinical and electrophysiological properties of this syn-drome. Our database was searched for the presence of ‘‘myo-clonus’’ in the physical examination. Medical records andlaboratory data were retrospectively reviewed, including elec-trophysiology data. We applied our criteria for PPMA: (1)asymmetric symptomatic action myoclonus, (2) ‡65 years ofage, (3) cortical myoclonus physiology, (4) no dementia, (5)no associated features of defined neurodegenerative disorders,
and (6) no secondary cause found. Seven patients fulfilledcriteria. Age at presentation ranged from 70 to 87 years.Mean duration from myoclonus onset to last follow-up was2.9 years. Electrophysiology showed positive-negative back-averaged transients, consistent with cortical myoclonus. Nopatient demonstrated dementia. Brain imaging in all cases wasunremarkable. PPMA is a unique syndrome with characteristicfindings that differentiate it from dementias and defined neuro-degenerative syndromes. It is important to distinguish primaryPPMA from other syndromes seen in older individuals to avoiddiagnostic confusion. Some cases showed a response to lev-etiracetam. � 2008Movement Disorder SocietyKey words: myoclonus; neurodegeneration; cortex; senso-
rimotor cortex
Myoclonus refers to sudden, brief, lightening-like
jerks caused by muscle contraction or inhibition.1 Its
clinical significance is that the muscle jerking causes
disruption of voluntary movements, and thereby inter-
feres with activities of daily living. Myoclonus can be
seen in a wide variety of disorders. By using clinical
and neurophysiological classification schemes com-
bined with a directed evaluation, it is usually possible
to determine an etiology for myoclonus.2
In older individuals, symptomatic or secondary myo-
clonus is usually accompanied by other notable neurol-
ogy such as dementia, ataxia, or parkinsonism.1,2 Over
the last 10 years in our clinical practice, we have
observed older individuals who primarily presented
with a chronic progressive myoclonus and who did not
possess other features that reached criteria for estab-
lished diagnoses. Our purpose was to retrospectively
review these myoclonus cases and characterized this
syndrome clinically and by their electrophysiology
study results. We term this syndrome ‘‘primary pro-
gressive myoclonus of aging (PPMA).’’
PATIENTS AND METHODS
The Mayo Clinic Arizona Movement Disorders
Tracking System was searched for ‘‘myoclonus’’ as an
exam finding from 1997, when the database was estab-
lished, to 2006. The Mayo Foundation IRB approval
only allowed the review of existent clinical informa-
tion, including movement neurophysiology testing with
electrophysiology methods. In total, 196 myoclonus
cases were discovered. Based on our previous
experience, cases were selected that had the following
criteria:
1. Asymmetric symptomatic action myoclonus.
2. ‡65 years of age.
*Correspondence to: Dr. John N. Caviness, Parkinson’s Diseaseand Other Movement Disorders Center, 13400 East Shea Blvd.,Scottsdale, AZ 85259. E-mail: [email protected]
Potential conflict of interest: None reported.Received 6 March 2008; Accepted 27 March 2008Published online 15 August 2008 in Wiley InterScience (www.
interscience.wiley.com). DOI: 10.1002/mds.22085
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Movement DisordersVol. 23, No. 12, 2008, pp. 1658–1664� 2008 Movement Disorder Society
3. Cortical myoclonus confirmed through combined
electroencephalography (EEG)-electromyography
(EMG) electrophysiology with back-averaging. The
techniques used have been described elsewhere.3
Briefly, in our movement disorders laboratory, digi-
tal recordings are made during simultaneous EEG
and surface EMG of limbs and face. All electrodes
are Ag/AgCl; EEG electrodes are placed at standard
10 to 20 positions and bipolar surface EMG electro-
des are placed 2 to 4 cm apart over the muscle bel-
lies of 8 muscles in each arm (pectoralis major, del-
toid, biceps, triceps, wrist flexors, wrist extensors,
abductor pollicis brevis, and abductor digiti minimi)
and 4 muscles in each leg (hamstrings, quadriceps,
anterior tibialis, and medial gastrocneimeus). Sam-
pling occurs at 1,000 Hz with a 1 to 200 Hz band-
pass using the Neuroscan System (Compumedics
Neuroscan, El Paso, TX). Standard recordings are
conducted at rest, postural activation, kinetic activa-
tion, standing, handwriting, reflex testing, and any
other maneuver that may exacerbate the patient’s
movement problem. Off-line analysis allows careful
examination of EEG-EMG polygraphy as well as
both forward and back-averaging to stereotyped
events such as myoclonus EMG discharges. Median
nerve somatosensory evoked potentials and long-la-
tency EMG reflexes at rest are recorded.
4. No dementia by DSM-IV criteria.4
5. No associated features of defined neurodegenerative
disorders including Parkinsonism, ataxia, or deficits
of focal cortical cognitive function.
6. No secondary cause found by thorough evaluation
of medication list, neuroimaging, family history of
central nervous system disease, and laboratory meas-
ures including metabolic and inflammatory testing.
RESULTS
The database search yielded 7 cases (3.6%) that ful-
filled criteria. All cases were evaluated clinically and
with electrophysiology by one of the authors (JNC).
Every case in our series had myoclonus as their
primary source of physical disability. Every case was
ambulatory and not concerned with other medical
problems at the time of presentation. Clinical charac-
teristics and evaluation data are provided in Table 1.
Sample case vignettes are provided for Cases 1 and 3.
Case 1: 87-year-old woman presented with involun-
tary ‘‘leg shaking’’ for 3 months affecting her walking
and balance. The ‘‘shaking’’ was initially subtle, sub-
sided for a couple of weeks and then reappeared again
and was progressive. Treatment with valproic acid was
ineffective. She complained of repetitive jerking at rest
and with muscle activation. There were no complaints
about cognition or other aspects of motor control. She
had a past medical history of hypertension for which
she took lisinopril and metoprolol as her only medica-
tions. Her family history was unremarkable for move-
ment disorders but she had a sister with amyotrophic
lateral sclerosis. Her examination revealed multifocal
myoclonus of the legs while at rest, and worsening of
the myoclonus during postural activation of the legs or
with standing. No reflex sensitivity was observed. No
other remarkable findings including Parkinsonism or
apraxia. CT head was interpreted as being unremark-
able for her age. Neuropsychological testing showed
no signs of generalized cognitive impairment. A thor-
ough evaluation for metabolic, inflammatory, toxic,
and other symptomatic causes of myoclonus was unre-
markable. EEG showed no epileptiform discharges.
Movement neurophysiology testing showed myoclonus
EMG discharges that were greatest in the left leg
(Fig. 1, Top). A premyoclonus EEG transient back-
averaged from left quadriceps was maximal at Cz
(Fig. 1, Bottom). After being titrated to levetiracetam
750 mg BID, she reported 25% improvement. Patient
did not wish to increase the dosage or take additional
medication because of possible drowsiness.
Case 3: 70-year-old white man presented with pro-
gressive myoclonus. For 2 years, he complained of
gradual onset of involuntary right arm and leg jerks.
Patient had treatment trials with gabapentin, metopro-
lol, valproic acid, tizanadine, and oxcarbazepine with
no benefit. He had no complaints about cognition or
other aspects of motor control. He had no major medi-
cal illnesses in the past. His family history was unre-
markable for movement disorders or neurological
illness. He was on clonazepam 2.5 mg daily. During
examination, there was a very rare jerk at rest, but
with sustained postural activation or an intention ma-
neuver, there was moderate myoclonus in both upper
and lower extremities, right greater than left. There
was touch sensitivity to the myoclonus in both upper
and lower extremities. There were no other abnormal
movements seen such as tremor, apraxia, dystonia, or
Parkinsonism. Neuropsychological testing showed no
signs of generalized cognitive impairment. A thorough
evaluation for metabolic, inflammatory, toxic, and
other symptomatic causes of myoclonus was unremark-
able. EEG showed no epileptiform discharges. Move-
ment neurophysiology testing while the patient was at
rest showed occasional myoclonus EMG discharges.
With the arms outstretched, finger-to-nose maneuver,
or writing, there were marked exacerbations of these
1659PRIMARY PROGRESSIVE MYOCLONUS
Movement Disorders, Vol. 23, No. 12, 2008
discharges, right greater than left (Fig. 2, Top). The
EMG discharges in the arms and hands had reflex
sensitivity to touch, reflex hammer stimulation, or thumb
stretch. Back-averaging of right wrist extensor myoclo-
nus EMG discharges revealed a premyoclonus EEG tran-
sient (Fig. 2, Bottom). After being titrated up to 1,500 mg
BID of levetiracetam in addition to clonazepam, patient
reported substantial improvement of his symptoms.
Electrophysiology Evaluation of Myoclonus
In all cases, the myoclonus was associated with very
brief (<50 ms) surface EMG discharges (Figs. 1 and 2).
Although agonist only bursts could be seen, all individu-
als commonly demonstrated EMG co-contraction of
agonist and antagonists during myoclonus. Routine EEG
recordings were uniformly unremarkable. No pathologi-
cal slow waves were seen in the EEG. Background EEG
rhythms were never below 8 Hz (Table 1). No gross
EEG changes correlated with myoclonic jerking. In ev-
ery case, back-averaging of myoclonus EMG discharges
in the EEG-EMG polygraphy recordings from the most
affected body region yielded a focal positive-negative
premyoclonus EEG transient in the appropriate somato-
topic distribution (Figs. 1 and 2). Latencies from the
positive EEG transient peak to the beginning of the aver-
aged myoclonus EMG discharge were short and
depended on the body part involved. Two cases, 3 and 7,
demonstrated reflex sensitivity by touch of their myoclo-
nus and Case 3 had an enlarged somatosensory-evoked
potential and enhanced long latency EMG reflexes.
Neuropsychological Assessment
Four of the cases had normal mini-mental status ex-
amination and no concerns of cognitive impairment
TABLE 1. Clinical and evaluation data on cases with primary progressive myoclonus of aging
Case/age/sex
Mostaffectedarea
Duration: Onsetto last follow-up Brain imaging
EEG back-ground (Hz) Mental status testing
Medication (%improvements areapproximate)
1/87/F Left leg 1 yr CT; normal limits forage
8.0 Normal mini-mentalstatus exam
Valproic acid; not effectiveLevetiracetam 750 mgBID; 25% improvementby patient report
2/76/M Right arm 3 yrs MRI; normal limits forage
9.0 Amnestic MCI byneuro-psychbattery
Levetiracetam titrationrecommended; no follow-up report
3/70/M Right arm 2 yrs MRI; mild small vesseldisease. Normal limitsfor age
9.0 Normal neuro-psychbattery
Gabapentin; not effectiveMetoprolol: not effectiveTizanadine; not effectiveOxcarbazepine; noteffective Levetiracetam1,500 mg BID; 50%improvement by patientreport and repeat exam.Additional clonazepam1 mg TID; >75% betterby patient report
4/83/M Left arm 2-1/2 yrs MRI; mild small vesseldisease. Normal limitsfor age
10 Normal neuro-psychbattery
Levetiracetam 500 mg BID;75% improvement bypatient report and repeatexam
5/84/M Right arm 4 yrs MRI; mild small vesseldisease. Normal limitsfor age
9.0 Normal mini-mentalstatus exam
Patient did not wantmedication startedbecause of potentialadverse reactions
6/78/M Right face and Jaw 5 yrs MRI; Normal limits forage
9.5 Normal mini-mentalstatus exam
Clorazepate dipotassium 7.5mg once daily; 25%improvement by patientreport. Patient did notwant other medicationstarted because ofpotential adverse reactions
7/74/F Right arm 3-1/2 yrs MRI; Normal limits forage
8.0 Normal mini-mentalstatus exam
Levetiracetam 500 mg BID;50% improvement bypatient report
F, female; M, male; MCI, mild cognitive impairment; MMSE, mini-mental status examination.
1660 M. ALVAREZ AND J.N. CAVINESS
Movement Disorders, Vol. 23, No. 12, 2008
were found on history or examination. Three cases had
memory concerns and formal neuropsychological test-
ing showed normal findings in two and significant iso-
lated memory impairment (Amnestic MCI) in Case 2.
Brain Neuroimaging
Brain MRI in 6 cases and CT in 1 case were all inter-
preted by neuroradiologists as unremarkable for age.
Blood, Urine, and Cerebrospinal Fluid Examination
In all cases, electrolytes (including bismuth), liver
and kidney function tests, B12, folate, paraneoplastic
panel, glucose, thyroid testing, and serum antibody
tests for autoimmune inflammatory, and urinary heavy
metals (mercury, lead, arsenic, cadmium) were normal.
Anti-gliadin and anti-endomysial antibodies were tested
in all cases except 6 and were normal. Cases 2 and 3
FIG. 1. Myoclonus electrophysiology testing of Case 1. Top: Surface EMG polygraphy shows brief myoclonus EMG discharges in L > R legs.Bottom: EEG-EMG back-averaging shows premyoclonus EEG transient at Cz.
1661PRIMARY PROGRESSIVE MYOCLONUS
Movement Disorders, Vol. 23, No. 12, 2008
had cerebrospinal fluid examination and the results
were normal.
DISCUSSION
Our cases demonstrate characteristic findings: (1)
asymmetric action myoclonus, (2) slow onset and
progressive history in individuals over age 65, (3) no
neurological or medical etiology identified despite
extensive evaluation, (4) cortical origin demonstrated
by EEG-EMG back-averaging that reveals a focal posi-
tive-negative cortical transient in the appropriate soma-
totopic location contralateral to the analyzed limb. We
use the term ‘‘PPMA’’ for this syndrome. Its insidious
onset with chronic progression in older individuals is
characteristic for this syndrome. It was striking that
these cases had a primary presentation of progressive
myoclonus without a symptomatic (secondary) cause
FIG. 2. Myoclonus electrophysiology testing of Case 2. Top: Surface EMG polygraphy shows brief myoclonus EMG discharges in R > L arms.Bottom: EEG-EMG back-averaging shows premyoclonus EEG transient at C3.
1662 M. ALVAREZ AND J.N. CAVINESS
Movement Disorders, Vol. 23, No. 12, 2008
being identified. Moreover, associated features such as
dementia, Parkinsonism, ataxia, and apraxia were not
associated to allow the diagnosis of a known disorder.
The interval between myoclonus symptom onset and
last follow-up had a mean of 2.9 years, range 1 to 5
years. Thus, for these cases, there had been sufficient
time to allow associative features to develop. Although
uncommon, it is important to distinguish PPMA from
defined neurodegenerative syndromes to avoid diagnos-
tic confusion.
The focal and/or asymmetric predisposition of the
action myoclonus was very characteristic among these
cases. The most affected locations ranged from face/
jaw to arms to lower extremities. In all but Case 7,
surface EMG in the less affected limbs still showed
myoclonus EMG discharges, but these discharges were
smaller and appeared at less frequent intervals than at
the most symptomatic region. Often, the patients would
not even consider these less involved areas to be
affected at all. This suggests that the pathology causing
the myoclonus is more diffuse then indicated by the
distribution of the patient’s symptoms, and that the
myoclonus must reach a certain amplitude and fre-
quency to reach a symptomatic threshold. Reflex sensi-
tivity of the clinical myoclonus and surface EMG dis-
charges was only seen in only 2 of our 7 cases. The
focal EEG positive-negative back-averaged premyoclo-
nus potential, brief <50 ms duration myoclonus EMG
discharges, and co-contraction of agonist with antago-
nist and other contiguous muscles all firmly establish
this myoclonus as being of sensorimotor cortex origin.5
Despite the presence of cortical action myoclonus,
seizures were not present in any of these cases. The
routine EEG showed normal background alpha rhythms
and no excessive intermittent slow waves.
These cases are distinct from defined neurodegenera-
tive syndromes. Absence of other findings such as ri-
gidity, Parkinsonism, and apraxia at presentation or af-
ter a multiple year symptomatic myoclonus history
argued against corticobasal syndrome (CBS), although
CBS was a prime diagnostic consideration for these
cases.6 Despite a possible cortical origin, a back-aver-
aged EEG correlate has never been documented in
CBS, in contrast to the cortical EEG correlate found in
all of our cases described here.7 Myoclonus is the most
frequent movement disorder in Creutzfeldt-Jakob dis-
ease (CJD).8 However, CJD typically presents with
mental status changes, abnormal EEG, and shows
relentless progression to death. The lack of dementia
and behavior abnormalities in our patients combined
with a multi-year myoclonus history make CJD an
unlikely diagnosis. Myoclonus is rare in frontotemporal
dementia (FTD).9 In addition, no frontal or temporal
behavior manifestations were present in our cases.
Dementia with Lewy bodies (DLB) can have cortical
origin myoclonus with a cortical EEG back-averaged
correlate, but a lack of dementia and other behavior
abnormalities does not allow a DLB diagnosis.10,11
Myoclonus is common in Alzheimer’s disease (AD).
Myoclonus if present usually manifests itself in small
multifocal distal jerks.12 The myoclonus electrophysiol-
ogy in AD has been described to have widespread cort-
ical negativity that is much different than the focal
positive-negative wave seen in our patients. Moreover,
the myoclonus of AD has never been reported with the
premyoclonus cortical transient characteristics seen in
our cases. Occasionally, AD can be associated with
prominent myoclonus and marked AD pathology
involvement of the sensorimotor cortex.13 These cases
can be difficult to distinguish from CBS and CJD.14,15
However, these reported AD cases demonstrated fron-
tal or parietal lobe behavior syndromes or dementia.
One of our cases did have memory complaints and a
pattern of amnestic mild cognitive impairment found
on neuropsychological testing. The other cases had
unremarkable mini-mental status exams and/or neuro-
psychological testing. As a result, our cases fall consid-
erably short of the criteria for AD.16 Our cases had an
average duration of symptoms documented with fol-
low-up of 2.9 years. Thus, it is important to note that
dementia or other signs discussed above did not evolve
during this time.
Recently, the term ‘‘orthostatic myoclonus’’ was
coined to describe leg action myoclonus associated
with gait dysfunction in older individuals.17 The
authors characterized orthostatic myoclonus as a symp-
tom, and a secondary cause is seen in most cases.
Some of the patients described in that report had no
identifiable etiology. The authors did not perform EEG
back-averaging of orthostatic myoclonus, so it is not
known whether premyoclonus cortical transients would
be found as in our cases. Nevertheless it is possible
that Case 1 is similar to their idiopathic cases if a typi-
cal cortical transient is eventually found for orthostatic
myoclonus. However, none of our cases reported gait
initiation difficulties or freezing, as did some of those
reported to have orthostatic myoclonus.
We have established a cortical origin for PPMA.
However, further study is needed to reveal the underly-
ing nature and cause of this unique syndrome. Longitu-
dinal follow-up and autopsy examination would help
clarify the pathology and pathophysiology substrate of
PPMA. Follow-up of such cases should include the
consideration of repeating tests if warranted by the
1663PRIMARY PROGRESSIVE MYOCLONUS
Movement Disorders, Vol. 23, No. 12, 2008
clinical circumstances. Although it is possible that the
mechanism of PPMA is neurodegenerative, this awaits
pathological confirmation. For now, only symptomatic
treatment of the myoclonus can be offered once the di-
agnosis is made. Our cases were tried on many differ-
ent medications. Some cases showed a response to lev-
etiracetam. Three of the four cases that had follow-up
on levetiracetam reported a 50% or greater response.
No other medication was associated with a 50% or
greater effect. Although these treatment trials were not
controlled, a trial of levetiracetam should be consid-
ered in these patients. Levetiracetam is known to be
effective for cortical myoclonus.18
Acknowledgments: Mayo Clinic provided funding for thisproject.
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