Primary progressive myoclonus of aging

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

1658

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


Patient did not wantmedication startedbecause of potentialadverse reactions

6/78/M Right face and Jaw 5 yrs MRI; Normal limits forage


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


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


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.



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.



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



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.

REFERENCES

1. Marsden CD, Hallett M, Fahn S. The nosology and pathophysiol-ogy of myoclonus. In Marsden, CD, Fahn, S, editors. Movementdisorders. London: Butterworths; 1982. p 196–248.

2. Caviness JN, Brown P. Myoclonus: current concepts and recentadvances. Lancet Neurol 2004;3:598–607.

3. Caviness JN, Adler CH, Beach TG, Wetjen KJ, Caselli RJ. Smallamplitude cortical myoclonus in Parkinson’s disease: physiologyand clinical observations. Mov Disord 2002;17:657–662.

4. American Psychiatric Association. Diagnostic and statistical man-ual of mental disorders, 4th ed. Washington, DC: American Psy-chiatric Association; 1994.

5. Shibasaki H. Electrophysiological studies of myoclonus. AAEMminimonograph #30. Muscle Nerve 2000;23:321–335.

6. Rinne JO, LeeMS, Thompson PD, Marsden CD. Corticobasal degen-eration: a clinical study of 36 cases. Brain 1994;117:1183–1196.

7. Thompson PD, Day BL, Rothwell JC, Brown P, Britton TC,Marsden CD. The myoclonus in corticobasal degeneration. Brain1994;117:1197–1207.

8. Maltete D, Guyant-Marechal L, Mihout B, Hannequin D. Move-ment disorders and Creutzfeldt-Jakob disease: a review. Parkin-sonism Relat Disord 2006;12:65–71.

9. Graff-Radford N, Woodruff B. Frontotemporal dementia. Contin-uum 2004;10:58–80.

10. Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK, de laMonte S, Norenberg MD, Schneck SA. Diffuse Lewy body dis-ease and progressive dementia. Neurology 1988;38:1520–1528.

11. Caviness JN, Adler CH, Caselli RJ, Hernandez J. Electrophysiol-ogy of myoclonus in dementia with Lewy bodies. Neurology2003;60:523–524.

12. Hallett M, Wilkins DE. Myoclonus in Alzheimer’s disease andminipolymyoclonus. Adv Neurol 1986;43:399–405.

13. Golaz J, Bouras C, Hof PR. Motor cortex involvement in prese-nile dementia: report of a case. J Geriatr Psychiatry Neurol 1992;5:85–92.

14. Chand P, Grafman J, Dickson D, Ishizawa K, Litvan I. Alzhei-mer’s disease presenting as corticobasal syndrome. Mov Disord2006;21:2018–2022.

15. Iijima M, Ishino H, Seno H, Inagaki T, Ebara T, Yamashita K.An autospy case of Alzheimer disease with myoclonus and peri-odic spikes on EEG. Jpn J Psychiatry Neurol 1994;48:615–621.

16. Farlow MR. Alzheimer’s disease. Continuum 2007;13:39–68.17. Glass GA, Ahlskog JE, Matsumoto JY. Orthostatic myoclonus: a

contributor to gait decline in selected elderly. Neurology 2007;68:1826–1830.

18. Magaudda A, Gelisse P, Genton P. Antimyoclonic effect of leve-tiracetam in 13 patients with Unverricht-Lundborg disease: clini-cal observations. Epilepsia 2004;45:678–681.



Primary progressive myoclonus of aging

Documents

Transcript of Primary progressive myoclonus of aging