Whole-Body Tremulousness: Title and subTitle BreakIsolated Generalized Polymyoclonus FREE

In our routine movement disorders clinical practice, occasionally patients have been referred with a diagnosis of an atypical generalized tremor syndrome that is ultimately recognized as repetitive low-amplitude myoclonus (polymyoclonus). Generalized polymyoclonus may resemble tremor but is distinguished by the absence of true periodicity, which can be confirmed using surface electromyography (EMG). Although this resemblance may occur in the context of a toxic-metabolic encephalopathy or a neurodegenerative condition, the accompanying clinical features of these disorders facilitate recognition. However, when generalized polymyoclonus develops as an isolated syndrome, the absence of clinical context and the resemblance to tremor may be diagnostically challenging. The distinction is important because the symptomatic treatments differ and adult-onset generalized myoclonus is typically acquired and may have an autoimmune basis, including paraneoplastic, or may be drug induced.¹ Herein we describe a series of adult patients with a syndrome of generalized repetitive myoclonus, most with recent onset (duration ≤ 2 years), confirmed by means of surface EMG. Tremor, tremulousness, or gait disorder was the typical referral diagnosis.

We sought to capture data on adult patients with a syndrome of acquired myoclonus affecting the whole body and developing in the absence of obvious systemic illness or other neurologic disease. The specific clinical inclusion criteria were as follows: (1) a syndrome of generalized repetitive myoclonus confirmed by surface EMG; (2) other neurologic features minimal or absent, except for impaired gait, balance, and dexterity directly attributable to the myoclonus; (3) absence of major organ failure; and (4) age at onset older than 21 years. The surface EMG criteria were 2-fold: (1) documentation of muscle burst durations less than 50 milliseconds and (2) absence of periodicity (tremor is, by definition, periodic).

We ascertained these cases by searching the Mayo Movement Neurophysiology Laboratory computerized database and medical records linkage system (1998-2006). Patients with focal, segmental, epileptic, or propriospinal myoclonus were excluded, as were those with coexisting movement disorders (dystonia, tremor, or chorea). The neurophysiologic features were described and myoclonus was documented by movement disorders neurophysiology staff in all cases. From this original cohort the medical records were then reviewed to exclude patients not meeting the previously described criteria. Thus, patients with myoclonus occurring in the context of neurodegenerative disease, encephalopathy, epilepsy, or obvious toxic-metabolic disease were excluded. We retained patients with minor or incidental neurologic findings in the study.

We identified 19 patients who met the previously mentioned criteria of isolated generalized polymyoclonus; 10 were men (Table 1). The mean age at symptom onset was 55 years (range, 22-77 years), and the mean duration of symptoms at the time of presentation was 21.3 months (range, 4-120 months). Myoclonus was not a referral diagnosis in any of the 19 patients, all of whom had been seen by a neurologist before review at Mayo Clinic. The chief complaints from the patients were tremors or tremulousness (10 patients), shaking (3 patients), jerks (3 patients), and balance or dexterity problems (3 patients). A family history of myoclonus or dystonia or amelioration of symptoms with alcohol use was not recorded in any case.

All 19 patients were examined by a Mayo staff neurologist. A movement disorders specialist examined all but 2 patients before the neurophysiologic assessment; 13 had their condition evaluated by at least 1 of us. Myoclonus (sudden, brief, shocklike, involuntary movements) was identified on clinical examination in 13 patients, with 4 others being characterized as having myoclonus and/or tremor; however, tremor was the diagnosis in 2 patients. In all of the patients, the observed tremulous movements affected all 4 limbs and were repetitive (generalized polymyoclonus), with upper limb predominance found in 2 patients. Cranial involvement was documented in 3 patients, and it was sufficient enough to cause dysarthria in 2. Opsoclonus or palatal myoclonus/palatal tremor was not present in any of the patients. In 14 of the 19 patients, gait and stance were impaired by the ongoing generalized polymyoclonus. This ranged from subjective unsteadiness alone to severe gait instability; 1 patient experienced myoclonic knee buckling, observed by the physician. In 2 patients, the physician commented that the myoclonic jerks in the lower limbs during standing were better appreciated by palpation than inspection. Minor or incidental features noted on examination were findings suggestive of small-fiber neuropathy (patient 3), mild cognitive impairment (patient 7), and reduced arm swing on ambulation (patient 15).

Surface EMG recordings revealed electrophysiologic evidence of generalized polymyoclonus in all of the patients characterized by repetitive muscle burst durations of less than 50 milliseconds and without evidence of periodicity (unlike tremor) (Figure). Myoclonus was observed at rest in 11 patients and with posture and action in all of the patients. Routine electroencephalography was performed in 12 patients, demonstrating epileptiform discharges in patients 7 and 17, neither of whom had a history of seizures.

A definite cause was established for the generalized polymyoclonus in 3 patients. Metastatic breast cancer was found in patients 8 and 14, discovered only after the cancer search was triggered by recognition of myoclonus. Patient 1 experienced resolution of generalized myoclonus after stopping use of the selective serotonin reuptake inhibitor (SSRI) fluoxetine hydrochloride, which implicated this as the cause.

Serologic evidence of neurologic autoimmunity was assessed in 15 patients and was detected and etiologically implicated in 4 patients (Table 2): patient 8 with breast cancer had antibodies to ganglionic acetylcholine receptor (AChR) (0.04 nmol/L; reference value, ≤0.02 nmol/L), patients 7 and 16 had CRMP-5 autoantibodies (recombinant Western blot assay), and patient 17 had neuronal voltage-gated potassium channel antibodies (0.79 nmol/L; reference value, ≤ 0.02 nmol/L). Cancer was not found in the latter 3 patients, but because of the known association with small cell lung carcinoma (patient 17 was a smoker), continued cancer surveillance was advised. Of the 9 patients whose cerebrospinal fluid was tested, only patient 13 had an abnormality (protein level, 12 g/dL). In all but 1 patient (patient 13), the possibility of neurologic autoimmunity related to an occult cancer was considered, and a serologic and oncologic evaluation was either noninformative or advised to be undertaken. However, follow-up was 1 month or less in all but 7 of the 19 patients. The available follow-up data are given in Table 2.

No definite etiology was identified in the 13 remaining patients. However, 1 or more medications known to cause myoclonus were being administered long-term to 6 of these patients. The potentially offending drugs were narcotics (patients 4, 5, 6, 13, and 18), SSRIs (patients 3, 4, and 6), and a serotonin-norepinephrine reuptake inhibitor (patient 18). Patients 4 and 6 (both with chronic pain syndrome) and 18 (with bipolar affective disorder) chose to continue taking the potentially causative medications. The potential for a drug-induced disorder was not recognized in patients 3, 5, or 13 at the time of evaluation, and, therefore, drug cessation was not considered. Because these 6 patients continued taking these medications, causation could not be proved.

Patient 14 had surgical treatment and radiotherapy to her chest wall metastatic lesion. Her myoclonus gradually resolved during a few months with effective treatment of her breast cancer, and 5 years later she remains in cancer remission without myoclonus. Patient 17 experienced initial symptomatic improvement after a course of plasma exchange but subsequently relapsed. An empirical 5-day course of intravenous methylprednisolone sodium succinate did not improve symptoms in patient 11. Symptomatic treatment for myoclonus was undertaken in 6 patients, 5 of whom had adequate follow-up. The myoclonus was markedly improved with clonazepam use alone (patient 6), treatment with clonazepam combined with gabapentin (patient 9), or levetiracetam monotherapy (patients 14 and 15). Patient 8 did not improve with clonazepam treatment.

The phenotype of adult-onset, isolated, diffuse (whole-body) tremulousness should raise the suspicion of generalized polymyoclonus. If confirmed (and especially if subacute or acute), this should generate a differential diagnosis to include 3 potentially treatable conditions: occult cancer, idiopathic neurologic autoimmunity, and adverse effect of medication.

Although this syndrome seems uncommon (19 patients in 9 years), we included only patients in whom myoclonus had been assessed and confirmed in the Mayo Movement Neurophysiology Laboratory. Given the difficulty recognizing this clinical entity, numerous other cases may have been overlooked by the staff, similar to the physicians who referred these patients (as exemplified by patients 6 and 15).

In this series, generalized polymyoclonus was consistently unrecognized and mistaken for tremor. Clinical clues include the following. First, tremor syndromes rarely involve the entire body, and certainly not subacutely or acutely. An exception is tremor related to toxic-metabolic or drug etiologies; however, such patients typically have systemic clues, are encephalopathic, or are taking drugs known to cause generalized tremor, such as lithium or valproic acid. Second, it is rare for tremor to degrade gait and stance, with the primary exception being orthostatic tremor. Third, the nonperiodicity of the movements on close inspection would exclude tremor because, by definition, tremor is perfectly periodic (rhythmic). Such nonperiodicity may not be obvious in the present context because the myoclonic jerks were of low amplitude and rapidly repetitive. Thus, clinical suspicion and focused observation of an outstretched arm with fingers extended will often reveal the irregular twitches that raise the suspicion of myoclonus.

The physicians who ultimately made the diagnosis in this series relied on neurophysiologic analyses to confirm myoclonus. The neurophysiologic technique we used is relatively straightforward using equipment available in all EMG laboratories, placing pairs of surface electrodes approximately 3 cm apart on the skin overlying the most active muscles. Thus, surface EMG recordings documented muscle burst durations of less than 50 milliseconds, which is consistent with myoclonus (Figure). The surface EMG recordings also displayed the irregularly repeating pattern, unlike the perfect periodicity of tremor. Hence, neurophysiologic confirmation can be made by practicing neurologists in the absence of sophisticated equipment.

The exact neuroanatomical origin of myoclonus in these patients is unknown. Myoclonus originates in the central nervous system by definition (although it may be triggered by peripheral stimuli). Exact localization in the central nervous system requires special studies and equipment that are not routinely available in most clinical practices (eg, jerk-locked, back-averaged electroencephalographic-EMG polygraphic recordings), unlike the surface EMG used to confirm myoclonus. However, the crucial step is recognition of myoclonus; hence, we emphasize that the electrophysiologic techniques available in routine neurologic practices are sufficient for that purpose.

In contrast to these patients, myoclonus is often a component of a broader syndrome rather than an isolated phenomenon. Thus, generalized myoclonus may occasionally occur in neurodegenerative disorders, such as Alzheimer disease,² Parkinson disease,³ inborn errors of metabolism, primary epilepsy syndromes,⁴ and toxic-metabolic encephalopathies. The myoclonus seen in some of these disorders has been primarily limited to small-amplitude jerks of the distal limbs (predominantly fingers), termed minipolymyoclonus.^{2 ,5} Similar to the present patients, these nonperiodic repetitive twitches of minipolymyoclonus may resemble tremor. However, our patients' phenotypes differ in terms of the prominence and generalized distribution of the myoclonus.

The known association of myoclonus with malignancy prompted a search for cancer, which led to the identification of occult metastatic breast carcinoma in 2 patients, 1 of whom (patient 8) had ganglionic AChR antibodies, but without adequate follow-up to know the outcome of treatment. Ganglionic AChR antibodies have previously been reported with solid tumors and dysautonomia.⁶ In patient 14, the myoclonus resolved after effective treatment of the cancer with surgery and radiotherapy. Three patients in whom cancer was not found had neuronal antibodies specific for CRMP-5 or voltage-gated potassium channels. CRMP-5 IgG is most commonly associated with small cell lung carcinoma.⁷ Patient 17 had neuron-specific voltage-gated potassium channel autoantibodies and initially responded well to plasma exchange. This antibody has previously been described in association with peripheral nerve hyperexcitability, epilepsy, and limbic encephalitis and may be associated with thymoma, small cell lung carcinoma, or other solid tumors.⁸

Certain commonly prescribed drugs may cause this myoclonic phenotype in the absence of other signs of toxicity; these drugs include tricyclic antidepressants⁹ , SSRIs and a serotonin-norepinephrine reuptake inhibitor,¹⁰ narcotics, and a combination of these drugs.¹¹ Whereas a drug-induced disorder was definitively proved only in patient 1, 6 other patients were taking 1 or a combination of these medications. Three patients elected to continue taking the potentially causative agents, whereas follow-up was inadequate in the other 3 patients. Thus, in patients with this myoclonic syndrome, review of medications should be one of the first diagnostic maneuvers. Other drugs have been implicated as rare causes of myoclonus, including lithium,¹² certain anticonvulsants (lamotrigine,¹³ carbamazepine,¹⁴ and topiramate¹⁵ ), cephalosporin antibiotics,¹⁶ amantadine,¹⁷ and verapamil.¹⁸

Myoclonus is also important to recognize because symptomatic drug treatment is often effective and differs from that used for tremor. Thus, 4 of the 6 patients improved markedly after treatment with clonazepam, levetiracetam, or gabapentin. Although gabapentin may be used to treat myoclonus, it has paradoxically caused myoclonus in the setting of renal failure.¹⁹

In summary, the phenotype of whole-body tremulousness should suggest consideration of the syndrome of generalized polymyoclonus, which can be easily confirmed using surface EMG available in routine neurologic practice. Recognition is important because it is symptomatically treatable and may be a clue to a treatable autoimmune etiology (paraneoplastic or idiopathic) or a drug effect.

Correspondence: Andrew McKeon, MB, MRCPI, Department of Neurology, Gonda 8 South, Mayo Clinic, 200 First St SW, Rochester, MN 55902 (mckeon.andrew@mayo.edu).

Accepted for Publication: January 27, 2007.

Author Contributions: All the authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: McKeon, Pittock, Glass, Lennon, and Ahlskog. Acquisition of data: McKeon, Pittock, Glass, Josephs, Bower, Lennon, and Ahlskog. Analysis and interpretation of data: McKeon, Pittock, Glass, and Ahlskog. Drafting of the manuscript: McKeon, Lennon, and Ahlskog. Critical revision of the manuscript for important intellectual content: Pittock, Glass, Josephs, Bower, Lennon, and Ahlskog. Study supervision: Pittock, Josephs, Bower, Lennon, and Ahlskog.

Financial Disclosure: None reported.