Paroxysmal movement disorders may be mistaken as seizure activity due to similar clinical characteristics and often overlapping treatment strategies. This chapter reviews the paroxysmal movement disorders, highlighting their key clinical features and emphasizing the differences between episodic movement and seizure disorders. Distinction between these disease entities may lead to more accurate and rapid diagnoses.

The paroxysmal dyskinesias are a heterogeneous group of disorders clinically characterized as acute episodes of hyperkinetic involuntary movements. These disorders are rare and can be misdiagnosed as seizures. The episodic nature of these conditions is the primary defining feature, as movements can range from dystonia to choreoathetosis to ballismus. To better understand the paroxysmal dyskinesias, they are often categorized into four main subgroupings: (1) paroxysmal kinesigenic dyskinesia (PKD), (2) paroxysmal nonkinesigenic dyskinesia (PNKD), (3) paroxysmal exertion-induced dyskinesia (PED), and paroxysmal hypnogenic dyskinesia (PHD). Table 21-1 summarizes some of the distinguishing characteristics of these groups.

Epidemiology

PKD is a rare condition, and its incidence in the general population is unknown. Symptoms usually manifest before age 20, although patients may present at later stages of adulthood. Older age of onset is associated with symptomatic (secondary) rather than idiopathic (familial and sporadic) etiology. There is a reported 4:1 male predominance.¹ In certain cases, PKD co-occurs with infantile convulsions. This rare syndrome is known as infantile convulsions with paroxysmal choreoathetosis (ICCA).²

Causes or Risk Factors

Typically, PKD is inherited in an autosomal dominant familial pattern, although some cases occur sporadically. The ICCA syndrome, also inherited in an autosomal dominant pattern, was mapped to chromosome 16 (16p11.2-q11.2). Aside from genetic sources, common symptomatic etiologies are multiple sclerosis, head trauma, and perinatal encephalopathy. Hypoparathyroidism, hyperthyroidism, and diabetes mellitus are less common sources of symptomatic PKD.

Typical Manifestations

PKD is provoked by a sudden movement, such as arising from a chair. However, cases similar in character may occur during exercise, from hyperventilation, or after a startle.¹ Movements may be preceded by an “auralike” limb sensation.³ Episodes of PKD are brief, lasting seconds to minutes. The movements are usually dystonic or choreoathetotic, involving the hemibody; the alternate hemibody may be involved in subsequent attacks. When the clinical presentation is bilateral, there is asymmetry of limb involvement. There is never loss or alteration of consciousness. Patients may have several attacks, even up to 100, per day. Stress, temperature, and menstruation may increase the frequency of the attacks, although the severity may decrease over time. Symptoms can produce falls as well as interfere with activities of daily living.

The preceding aura, attack duration, and motor manifestations, in addition to symptom responsiveness to antiepileptic drugs (AEDs), are features of PKD that resemble seizures. Observation of the clinical episode may help distinguish the disease from seizures; however, electroencephalography (EEG) is an important tool that can help differentiate the two, as EEG recordings will be normal in PKD.

Patients with the ICCA syndrome are relatively homogeneous in their clinical presentation. All have benign infantile seizures that remit after the first year of life. Typical seizures are brief with motor arrest, unilateral head and eye deviation, generalized hypertonia, cyanosis, and limb jerks. Seizures often occur in clusters. Partial seizures usually secondarily generalize. Ictal EEG may reveal a focal abnormality or multifocal abnormality, originating from various cerebral lobes.⁴ Some patients have seizure recurrence in later years. All manifest typical features of PKD, with symptoms beginning later in childhood or during early adolescence (Video 21-1, 21-2, and 21-3).

Treatment

Low doses of AEDs are recommended. Although phenytoin was one of the first medications used in treatment, carbamazepine is typically used as first-line therapy, starting at 5 mg/kg divided twice daily and titrated to efficacy. Other medications that have been used are older AEDs, such as phenobarbital, primidone, valproic acid, and clonazepam, as well as newer drugs, such as gabapentin, lamotrigine, and levatiracetam. A review of 121 patients with PKD reported that patients not taking phenytoin or carbamazepine at best received “moderate response” to alternative AEDs, and all eventually discontinued these therapies due to side effects or suboptimal response.⁵ Tetrabenazine, a monoamine-depleting medication, and acetazolamide, a carbonic anhydrase inhibitor, may also provide clinical benefit.

Epidemiology

PNKD is a rare condition. The mean age of onset is 12 years; however, there are case reports of symptom onset in adults. Attacks occur more often in boys and men, in a 2:1 male-to-female ratio.⁶

Causes or Risk Factors

Early descriptions of the disease suggest a familial origin; however, sporadic cases were described in later reports.⁷ Genetic analyses of some familial cases suggest the involvement of chromosomes 1, 2, and 16. Like PKD, the most common secondary cause of PNKD is multiple sclerosis.⁸ There is a broad spectrum of identified secondary etiologies ranging from metabolic abnormalities to mass lesions associated with PNKD. Perinatal encephalopathy and psychogenic causes are two of the more frequent secondary sources.⁹

Typical Manifestations

Fatigue, temperature extremes, caffeine use, and alcohol consumption are event triggers; sudden movements or startle do not induce episodes as they do in PKD. Similar to PKD, a sensory aura in a limb may precede the episode. Episode duration ranges from 5 minutes to 4 hours. Movements can vary along the hyperkinetic spectrum, but they are predominantly dystonic or choreoathetotic. Affected areas may be focal or generalized, unilateral or bilateral. Unilateral episodes may alternate sides on subsequent attacks. Speech can become involved secondary to dystonic movements of the face. Consciousness is maintained throughout the episode. Symptoms may abate with sleep. Compared to PKD, the frequency of PNKD attacks is significantly reduced, averaging no more than three attacks per day. Months may pass between attacks. Like PKD, symptoms sometimes improve with age; however, in most patients, episodes persist.

The presence of an aura, the episodic nature of events, the symptomatic distribution, and the patients’ responsiveness to benzodiazepines are suggestive of seizure. Maintenance of consciousness, episode duration, and the quality of movements are clinical features that may help differentiate PNKD from an epileptic event. An EEG is often useful to help distinguish the two entities, as patients with PNKD usually do not have epileptiform abnormalities. One report of PNKD found a caudate discharge in a patient placed with an invasive electrograph (Video 21-4).¹⁰

Treatment

Although AEDs are commonly used, PNKD is not exquisitely responsive to these medications. Clonazepam is the most effective of the drugs used to treat PNKD for both primary and secondary etiologies.¹¹ Other medications found to have some benefit are antimuscarinics,¹² carbonic anhydrase inhibitors (e.g., acetazolamide),^7,13 other benzodiazepines,¹⁴ and dopamine-blocking agents.¹⁵

Epidemiology

PED is a rare condition. The largest reported series included eight patients with sporadic disease.¹⁶ Onset occurs before the age of 30, and most reported cases have a childhood onset. There is no sex preference. A gene has yet to be identified; however, in a few reported cases where the pattern of inheritance appears autosomal dominant, there is genetic mapping to chromosome 16. There is one report of a family with autosomal recessive PED who also had rolandic epilepsy and writer’s cramp. This was linked to chromosome 16p12-11.2.¹⁷

Typical Manifestations

PED is sometimes considered a subdivision of PNKD. However, it is often discussed as a separate entity because of its unique clinical features. The triggers typically associated with PNKD do not seem to be influential in PED. Attacks of PED are precipitated by prolonged or strenuous exercise. Episodes are briefer than PNKD, lasting from 5 to 30 minutes. Movements are hyperkinetic and most often dystonic. Episodes commonly affect both legs, although a unilateral presentation as well as involvement in other locations can occur. This bilateral distribution with maintenance of consciousness may help to distinguish PED from epileptic events. Symptoms usually resolve in 10 to 15 minutes after exercise cessation. Most patients have up to five episodes per month. Ictal and interictal cerebral perfusion single-photon emission computed tomography (SPECT) studies in PED show decreased perfusion of the frontal cortex and basal ganglia, as well as increased cerebellar perfusion, during the attack. Cortical hyperperfusion, indicative of an epileptic origin, is not present in PED.¹⁸

Treatment

Given the generally poor response to medication, there is no recommended first-line therapy for PED. Acetazolamide, antimuscarinics, and benzodiazepines may offer some benefit.

Epidemiology

PHD is a rare condition. Symptoms present in childhood. There is no sex preference.

Typical Manifestations

PHD is defined by attacks of ballistic, dystonic, or choreiform movements that occur during non–rapid eye movement (REM) sleep. Signs of arousal are often present just prior to the onset of the attack. Attacks are usually brief, lasting <1 minute, although attacks of longer duration occur in a minority of patients.^19,20 Attack frequency is typically 4 or 5 times a year, although this may increase over time. Stress, fatigue, menses, and increased activity can lower the threshold for symptom onset in susceptible patients. Frontal lobe epilepsy may mimic PHD, and monitoring should be conducted to rule out an epileptogenic focus. Surface EEG may miss this diagnosis, requiring an admission to an epilepsy monitoring unit and possibly intracranial electrodes.^21,22

Treatments

PHD is responsive to anticonvulsants. Carbamazepine is often first-line therapy. Phenytoin and phenobarbital are used in some cases, and acetazolamide is another pharmaceutical alternative. Patients may require polytherapy.

Epidemiology

The episodic ataxias are rare conditions characterized by periods of incoordination and imbalance, often with associated progressive, chronic ataxia. Several syndromes are known, although only some genes have been identified. These include episodic ataxias 1, 2, 5, and 6. Episodic ataxia 2 (EA2) is the most common of the episodic ataxias. Episodic ataxia 1 (EA1) and EA2 generally present in childhood between the ages of 2 and 15, although EA2 can present in adults as well. Five additional episodic ataxias are described in the literature (EA3–EA7).^23–25 These ataxias have mostly been described in an individual or single family. Symptom onset is usually in childhood. Seizures sometimes co-occur with episodic ataxias. Focal epilepsy is associated with EA1²⁶ and EA6. Seizure types described in patients with EA2 include complex partial, absence, and generalized tonic-clonic seizures.^27,28 EA5 is associated with juvenile myoclonic epilepsy.

Causes or Risk Factors

EA1 maps to chromosome 12p13. In affected patients, missense mutations and in one reported case, a truncation mutation occur in KCNA1, a voltage-gated potassium channel gene.^29,30 EA2 maps to chromosome 19p13.^31–33 EA2 is usually caused by mutations that interrupt the reading frame of the calcium channel gene CACNA1A²⁷ EA5 is associated with mutations in CACNB4 on chromosome 2q22-q23, a gene that encodes the calcium channel β⁴ subunit. EA6 is associated with mutations in SLC1A3on chromosome 5p13, a gene that encodes the transporter protein responsible for glutamate uptake. The mutation associated with EA3 was mapped to chromosome locus 1q42,³⁴ and EA7 was mapped to chromosome 19p13. An aberrant gene has yet to be identified in these cases. Testing is commercially available for EA1 and EA2. The most updated information regarding available testing can be found at www.geneclinics.org.

Typical Manifestations

Clinical episodes in EA1 are sometimes triggered by startle or sudden movement, much like PKD. Exercise, fatigue, and excitement are also identified precipitants. Auras described as sensations of falling or weakness may precede the episode. During the attack, patients are usually ataxic, dysarthric, and have gaze-evoked nystagmus. There are variations in the clinical presentation. Unusual cases include a patient who had myokymia without ataxia³⁵ and a patient with severe neuromyotonia without episodic ataxia.³⁶ In the second patient, family members had more classic disease. Sometimes, choreiform or dystonic movements are associated with the event. Episodes are brief, lasting from seconds to minutes. They can occur up to 15 times per day. Periocular and hand myokymia are present interictally, sometimes detectable only through needle electromyogram (EMG) studies. Attacks often become milder with age.

EA2 is triggered by caffeine and alcohol consumption, exercise, fatigue, and stress. Ataxia typically lasts hours, although the duration can range from minutes to weeks. Vertigo, nausea, and vomiting are associated features present in more than half of all patients. In addition to cerebellar dysfunction, symptoms localizing to the brainstem or neocortex can sometimes be seen. More than half of these patients have a medical history of migraines; some have a history of basilar migraines. Familial hemiplegic migraine maps to the same gene as EA2, and symptoms may co-occur in affected individuals.²⁸ Interictally, gaze-evoked nystagmus is present, and approximately one third of patients have spontaneous nystagmus, which is typically downbeat.³⁷ Over time, patients sometimes develop persistent or progressive symptoms of ataxia.³⁸ When symptoms are progressive, magnetic resonance imaging (MRI) may show associated cerebellar atrophy. Diagnostic differentiation between EA1 and EA2 is possible when myokymia is present on needle EMG (EA1) or when baseline nystagmus or ataxia is present (EA2).³⁹

A sudden head movement can precipitate an attack in EA3. These ataxic events are associated with ocular motility problems producing diplopia. Vertigo and nausea are additional associated features. Symptoms last minutes to hours; the frequency of attacks varies from daily to yearly. Over time, symptoms invade into the interictal period and become constant.⁴⁰

There are no known precipitants of EA4, which was first described in 2001.⁴¹ Symptoms associated with the attack include ataxia, tinnitus, vertigo, blurry vision, headache, nausea, and balance difficulties. Attacks persist for 10 to 30 minutes. Interictal features include myokymia and ataxia.

EA5 patients have recurrent episodes of ataxia and vertigo, along with interictal nystagmus and dysarthria. These patients may develop juvenile myoclonic epilepsy.

EA6 was reported in one boy whose symptoms developed in infancy. Symptoms were described as 30-minute episodes of muscle tone loss; these episodes were preceded by fever. An EEG performed when he was 6 years old showed subclinical seizure activity in the left frontal temporal cortex and slowing on the right. Three years later, he developed partial seizures, described as rhythmic jerking of his left arm associated with 30 minutes of confusion. Additionally, he developed migraines and bouts of ataxia associated with left hemifield distortions. Ataxic episodes were followed by headache.⁴²

EA7 patients have periods of ataxia that can last hours to days. Episodes are associated with weakness and dysarthria. Exercise and excitement are triggers. Some of the distinguishing characteristics of the episodic ataxias are listed in Table 21-2.

Treatment

There are no controlled studies that address the efficacy of the medications used for treating episodic ataxias. Patients with EA1 can sometimes defer medications by learning to avoid abrupt movements. If medication is needed for prevention, acetazolamide (500–700

mg/day) is used as first-line therapy. Patients with EA1 do not always respond well to acetazolamide; if it is not effective, anticonvulsants such as carbamazepine and valproic acid sometimes are tried. Acetazolamide is much more effective for prevention in cases of EA2.²⁸ It is also used successfully in EA5 and, with moderate improvements, in EA4. EA3 is not responsive to acetazolamide. Of note, flunarizine and 4-aminopyridine are sometimes useful in the treatment of episodic ataxias.^43,44

Epidemiology

Myoclonus is a common movement disorder defined as sudden, brief, shocklike involuntary movements caused by muscular contraction (positive myoclonus) or inhibitions (negative myoclonus), typically originating from the central nervous system.⁴⁵ A record review by the Mayo Clinic of cases of myoclonus in Olmsted County, Minnesota, between 1976 and 1990 indicates that the average annual incidence of myoclonus is 1.3 cases per 100,000 person-years. Overall, there is no age or sex preference for myoclonus. Prevalence of myoclonus in 1990 was 8.6 cases per 100,000 in the population.⁴⁶ Myoclonus is associated with several epileptic syndromes in childhood.

Causes or Risk Factors

Myoclonic movements may stem from a cerebral neocortical region, the brainstem, the spinal cord, or, less commonly, from the peripheral nervous system. A psychogenic origin should be considered as well. There are several causes of myoclonus. In the Olmsted study mentioned above, symptomatic myoclonus was the most common cause, followed by epileptic and essential myoclonus.⁴⁶ The list of secondary causes for noncortical myoclonus is extensive, and a comprehensive review is not possible in this limited format. More commonly identified causes of secondary myoclonus are hypoxic brain injury, metabolic abnormalities (kidney and liver failure), drug effects (of opiates and serotonergic drugs), neurodegenerative diseases (e.g., multiple system atrophy and Huntington disease), and infectious sources (e.g., subacute sclerosing panencephalitis and Creutzfeldt-Jakob disease). The clinical distribution of myoclonus (focal, segmental, multifocal, and generalized) can help determine the physiological source of the movement.

Typical Manifestations

Myoclonus is a fast, brief, involuntary jerking movement that may be triggered by a visual, auditory, or somesthetic stimulus. When an external stimulus precipitates an event, it is referred to as reflex myoclonus. The jerks may be present at rest, or they may be triggered or aggravated by attempts to perform fine movements. The speed of the movement cannot be simulated voluntarily. Movements are not suppressible and are not associated with a psychological urge to move. Jerking may be rhythmic or arrhythmic and can involve one body region (focal) or multiple (multifocal, generalized). Symptoms can persist in sleep.

Myoclonus is often divided into broad categories based on etiology. Some myoclonus, including hiccups and sleep (hypnic) jerks, is normal and is termed physiological myoclonus. Essential myoclonus describes a nonprogressive syndrome presenting in the first 2 decades of life. Patients present with multifocal myoclonus and no other neurologic deficits; investigative studies are normal. Symptomatic generalized myoclonus is a term used for myoclonus caused by one of a multitude of etiologies producing generalized or multifocal disease. Psychogenic myoclonus is a variant of conversion disorder. Epileptic myoclonus defines the group of epilepsies where myoclonus is one of the epileptic syndrome’s seizure manifestations. Other seizure types are also generalized and may include tonic-clonic, atonic, or tonic seizures. It is a subcategory of cortical myoclonus. A full discussion on epileptic myoclonus is found in Chapter 16.

Most presentations of multifocal or generalized myoclonus have a cortical origin. In fact, a cortical origin is always a consideration when myoclonus is present, and an EEG may be helpful in localizing the source of myoclonus. Below is a discussion of a few distinct clinical presentations of myoclonus.

When myoclonus is localized to a focal or segmental region and is rhythmic, the question of status epilepticus partialis arises. If an EEG is normal, spinal segmental myoclonus should be considered. Spinal segmental myoclonus presents with a 0.5 to 3.0 Hz frequency and involves only the muscles innervated by a few spinal segments. Of note, a normal EEG does not exclude a cortical source. Focal seizures may not be captured on a routine EEG; focal slowing may be present.

Palatal myoclonus is a form of focal myoclonus localizing to a brainstem origin. It is categorized as essential or secondary palatal myoclonus. These two types of myoclonus are distinguished by the presence of ear clicking due to rhythmic contractions of the tensor veli palatini noted in the former of these two entities. Rhythmic palatal movements of 1.5 to 3.0 Hz are present in both types. Palatal movements may also have associated movements of the face, tongue, larynx, head, trunk, intercostal muscles, and diaphragm. Movements are bilateral and symmetric, occurring from 100 to 150 times per minute, and in some circumstances, persist during sleep.^47,48

Brainstem reticular myoclonus is an axial myoclonus that produces generalized axial muscle jerks originating in muscles innervated by the lower brainstem, then spreading bidirectionally up the brainstem and down the spinal cord. Multifocal or generalized myoclonus can also have a brainstem focus. These forms of myoclonus are seen in postanoxic states or during toxic-metabolic dysfunction.

The startle syndrome known as hyperekplexia also originates from the brainstem. This condition may be inherited or due to a secondary source, such as multiple sclerosis. Patients with hyperekplexia will manifest an excessive motor response to an unexpected auditory and occasionally visual or somesthetic stimuli. The startle is comprised of a jump involving a blink, contortion of the face, flexion of the neck and trunk, and abduction and flexion of the arm. Patients may fall during these events. In some hyperekplexic syndromes, such as the “jumping Frenchman of Maine,” stereotyped behaviors and vocalizations are seen. When neonates are hyperekplexic, they become hypertonic when handled and subsequently develop walking impairments. These neonates have excessive startles, which manifest in two ways: a simple brief startle jerk or an extended tonic startle spasm. There is no loss of consciousness during these events. An EEG will help distinguish between hyperekplexia and a startle-evoked epileptic seizure. In some cases, hyperekplexia is inherited in an autosomal dominant fashion. These cases are linked to a point mutation on chromosome 5q33-q35.

There are several components of the examination and diagnostic workup that can help differentiate cortical from subcortical myoclonus. Clinically, cortical myoclonus is more likely to present focally, in a distal limb, whereas subcortical myoclonus is more likely to be generalized and have both proximal and distal involvement. Activation in cortical myoclonus is rostrocaudal, whereas subcortical myoclonus may propagate both upward and downward. Muscle group involvement in cortical myoclonus tends to involve one synergistic group, whereas subcortical myoclonus can produce both agonist and antagonist contractions.⁴⁹ In cortical events, sensory evoked potentials are enhanced, and there are time-locked cortical correlates on EEGs.⁵⁰ However, sometimes the EEG correlates are visible only with averaging of several myoclonic episodes. On EMG evaluation, cortical myoclonus is associated with brief discharges (<50 ms), whereas longer discharges are noted in subcortical myoclonus.

Treatment

Several medications are helpful in the treatment of myoclonus. Clonazepam, a long-acting benzodiazepine, provides symptomatic relief, regardless of the pathophysiological source. It is first-line therapy for brainstem myoclonus, including palatal myoclonus and hyperekplexia.^51,52 Spinal and segmental myoclonus have the best response to clonazepam as well.^53,54 Clonazepam is used as adjunctive or second-line therapy in cortical myoclonus.

Valproic acid is often the drug of choice in cortical myoclonus and is useful in hyperekplexia. Other AEDs, such a primidone and levetiracetam, are beneficial in cortical myoclonus.⁵⁵ Of note, cortical myoclonus often responds best to polytherapy.⁵⁶ AEDs are useful in treating other types of myoclonus as well. Carbamazepine is used in palatal myoclonus.^57,58 Topiramate significantly improved a case of segmental myoclonus.⁵⁹

Other drugs aside from the antiepileptics may be helpful. Acetazolamide is often used successfully in cortical myoclonus. Anticholinergic medications are used in brainstem myoclonus, including palatal and essential myoclonus. Propranolol and other beta-blockers may improve essential myoclonus.^60,61 Tetrabenazine and baclofen are occasionally helpful in spinal and segmental myoclonus.⁶² Sumatriptan and other serotonergic medications may have a role in noncortical myoclonus.^63,64 Botulinum toxin can improve the ear clicking that occurs in palatal myoclonus.^65,66

Epidemiology

Dystonia is a movement disorder defined by sustained muscle contractions producing twisting and repetitive movements or abnormal postures. The incidence of dystonia in the general population is not known. Patients with dystonia are a heterogeneous group. Dystonia may be a primary condition with no additional neurologic signs or symptoms and no identifiable secondary source. Secondary dystonia includes a host of etiologies—monogenic, environmental, and complex—with pathology often involving the basal ganglia. Thus, the incidence and prevalence of dystonia in a population vary depending on both the type of dystonia and the population.

The annual incidence of primary dystonia in Rochester, Minnesota, is estimated as 0.2 per 100,000.⁶⁷ However, the incidence and prevalence rates for primary dystonia are higher in the Ashkenazi Jewish population.⁶⁸ A recent study estimated the incidence for idiopathic cervical dystonia in a Northern California community as 0.8 per 100,000.⁶⁹