B. Ho , MD New England Medical Center , Boston , MA , USA
S.H. Mehta , MD, PhD (*) • K. D. Sethi , MD, FRCP (UK) Department of Neurology , Medical College of Georgia , 1120 15th Street , Augusta , GA 30912 , USA e-mail: [email protected]
This chapter contains videos segment which can be found at the URL: http://www.springerimages.com/Suchowersky
Video Segment Content
Case 1: Paroxysmal Kinesigenic Dyskinesia.This young man has dyskinesia precipitated by getting off the chair. Notice the dys-tonic features and the involvement of the face. Case 2: Paroxysmal Kinesigenic Dyskinesia.This 25 year old has PKD brought out by getting up off a chair. Case 3: Paroxysmal Kinesigenic Dyskinesia with Hemidystonia.This man develops hemidystonia, brought out by running a short distance. Case 4: Nonkinesigenic Dyskinesia PNKD.This little boy is writing and trashing on bed, an example of PKND. Case 5: Paroxysmal Exertional Dyskinesia.This man develops hemidystonia at 2 mins running on a treadmill. He has Paroxysmal Exertional Dyskinesia (PED) precipitated by prolonged exercise, manifesting as hemidystonia. This suggests a central mechanism. Case 6: Secondary Paroxysmal Dyskinesia, due to Multiple Sclerosis.This middle aged man develops right hemidystonia following hyperventilation. This paroxysmal dystonia is as initial manifestation of Multiple Sclerosis with hyperven-tilation precipitating the attack. Case 7: Secondary Paroxysmal Kinesigenic Dyskinesia, due to Hypoxia.This child with cerebral palsy has secondary PKD brought out by loud noise. Case 8: Secondary Dystonia, secondary to Orthostasis.This man develops right sided dystonia after getting up. He has orthostatic paroxys-mal dystonia secondary to severe bilateral inoperable carotid disease. Case 9: Secondary PKD.PKD due to a contralateral putaminal lacunar infarct.
Paroxysmal dyskinesias are a group of heterogenous disorders that are grouped together because of a common thread of sudden abnormal involuntary movements arising out of a background of normal motor behavior. The abnormal movements can involve chorea, ballism, and dystonia either alone or in any combination [ 1 ] . As there is extreme variability in the type of dyskinesia observed, using precise names for the abnormal movements is often inaccurate and unhelpful. Therefore, the term paroxysmal dyskinesia is preferred, with classifi cation according to Demirkiran and Jankovic [ 2 ] .
These attacks are frequently unwitnessed by the physician, and one needs to rely on a lay description of the movements. Because of the brevity of attacks and their unusual nature, misdiagnoses are common, and patients are often mislabeled as psychogenic. The accompanying videotaped examples should help guide the reader to make the correct diagnosis.
Clinical Manifestations
Paroxysmal Kinesigenic Dyskinesia
Although physicians such as Gowers, Spiller, and Pitha described patients with involuntary movements induced by active and passive movements as early as 1938 [ 1 ] , the credit for coining the term paroxysmal kinesigenic choreoathetosis goes to Kertesz [ 3 ] .
Paroxysmal kinesigenic dyskinesia (PKD) is often inherited in an autosomal dominant fashion, but sporadic cases are not uncommon. In a review of 111 idio-pathic cases, 49 were familial. Eighty-nine were male, giving a male–female ratio of 4:1 [ 4 ] . The age of onset is typically between 5 and 15 years in familial cases, but
Case 10: Paroxysmal Kinesigenic segmental spinal myoclonus.This young man has myoclonic movements of left shoulder, due to a cervical cord glioma Case 11: Psychogenic Paroxysmal Dyskinesia.This young man develops spasms with sudden movement and clapping. Note the dark glasses and the fact that spasms are precipitated by shining the light in one eye and not the other! Case 12: Psychogenic Paroxysmal Dystonia.This African American young woman has episodes of dystonia primarily on right, spreading to the neck and left arm. This patient with paroxysmal dystonia due to MS that subsequently developed psychogenic spells.
1476 Paroxysmal Dyskinesias
sporadic cases have more variable age of onset. The attacks are usually precipitated by startle or a sudden movement after a period of rest. They may be limited to one side of the body or even one limb alone. In one review of 73 cases of PKD, 25 occurred on one side only, 12 occurred unilaterally on either side, 11 occurred uni-laterally or bilaterally, and 22 were always bilateral [ 5 ] . Attacks are often followed by a refractory period in which sudden movement fails to provoke another attack. The attacks can occur very frequently, up to 100 times per day, and their duration is short, lasting from seconds to minutes [ 4 ] .
Bruno et al. evaluated 121 individuals with idiopathic PKD from 73 families to establish strict diagnostic criteria for the disorder. The following criteria have been proposed [ 6 ] : (1) identifi able kinesigenic trigger for the attacks, (2) short duration of attacks (<1 min), (3) no loss of consciousness or pain during the attack, (4) exclu-sion of other organic diseases and normal neurologic examination in between attacks, (5) control of attacks with phenytoin or carbamazepine, if tried, and (6) age at onset between 1 and 20 years, if no family history of PKD.
Dystonia is the most common movement seen though chorea may be seen. Ballism is rarely associated with PKD, and interictal myoclonus has been reported in a patient [ 7 ] . Patients may report having abnormal sensations in the affected limbs either during or preceding an attack. In some attacks, the “aura” may not be followed by visible abnormal movements. The attacks decrease in frequency as patients enter adulthood [ 3 ] . Regardless of duration, these patients respond well to anticonvulsants (see section on “ Treatment ”).
Paroxysmal Nonkinesigenic Dyskinesia
In 1940, Mount and Reback described a family with long-lasting attacks of dystonia and choreoathetosis precipitated not by movement but by alcohol or coffee [ 8 ] . There were 28 affected members in this family with an autosomal dominant mode of inheritance. Prior to this large family, Sterling in 1924 had described paroxysmal dyskinesia not precipitated by movement [ 1 ] . In later years, Lance described similar cases as idiopathic and secondary “tonic seizures” which he subsequently recog-nized to be paroxysmal dystonic choreoathetosis [ 9 ] .
Paroxysmal nonkinesigenic dyskinesia (PNKD) is commonly inherited as an autosomal dominant trait with slight preponderance of males though without the striking male preponderance seen in PKD. The age of onset varies from early child-hood to the third decade. Attacks occur less frequently than in PKD but tend to last longer. The frequency of attacks varies from three per day to two per year, with the usual precipitating factors being fatigue, alcohol, caffeine, and emotional excitement. The attack may start with involuntary movements of one limb but then spread to involve all extremities and the face. These attacks last up to 3–4 h. During the attack, the patient may be unable to communicate but continues to breathe normally, and consciousness is preserved. Some families exhibit predominant dystonia, while oth-ers have predominant choreoathetosis [ 8 ] . The attacks are often relieved by sleep.
148 B. Ho et al.
PNKD has been reported in a patient with familial ataxia, and in one family, PNKD was accompanied by myokymia [ 1 ] . Some families also have exertional cramping. It is unclear whether this is a forme fruste of PNKD or paroxysmal exer-tion-induced dyskinesia (PED).
Paroxysmal Exertion-Induced Dyskinesia
Lance reported a family with attacks precipitated by prolonged exercise in 1977 [ 9 ] . His proposed classifi cation of paroxysmal dyskinesias, based on duration of the attacks, listed these in the intermediate category.
PED is often inherited in an autosomal dominant fashion, but sporadic cases have been described [ 1, 10 ] . The attacks are triggered by prolonged exercise, in contrast to the sudden movement that precipitates PKD [ 9 ] . Frequency varies from one per day to two per month, with the usual duration being 5–30 min. Clinically, the abnormal movements may be indistinguishable from PNKD, although the lower extremities tend to be more affected. Interestingly, exercise limited to an upper extremity may provoke an attack in the upper extremity alone.
Several case reports have suggested that PED can be the presenting symptom in patients with young onset or familial form Parkinson’s disease [ 11– 13 ] . PED has also been reported in combination with migraines, different forms of epilepsy, and dystonia. Kamm et al. report a German family with 4 affected members who exhibit the above-mentioned conditions in variable combinations [ 14 ] . Wali reported one patient who had paroxysmal hemidystonia precipitated by prolonged running and cold temperature [ 1 ] . PED may be a manifestation of dopa-responsive dystonia due to GTP cyclohydrolase mutation [ 15 ] .
Glut-1 defi ciency syndrome (OMIM 606777) is a disorder of brain energy metabolism caused by impaired glucose transport into the brain mediated by the facilitative glucose transporter Glut-1 [ 1 ] . Classically, patients present with infan-tile epilepsy, developmental delay, acquired microcephaly, cognitive impairment, and varying degrees of spasticity, ataxia, and dystonia. A variant phenotype is char-acterized by paroxysmal episodes of abnormal head and eye movements and by chronic choreoathetosis and dystonia. Recently, a new phenotype is characterized by PED [ 16, 17 ] . This may open doors to new treatments for this group of patients with PED. A patient with PED and interictal myoclonus and dystonia has been reported [ 18 ] .
Paroxysmal Hypnogenic Dyskinesia
The fi rst report of an episodic movement disorder occurring during sleep was that of a 31-year-old man with attacks of cramping of the leg associated with diplopia [ 19 ] . These were described as tonic seizures and attributed to multiple sclerosis.
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The term nocturnal or hypnogenic dystonia was introduced by Lugaresi and Cirignotta [ 20 ] . They divided the attacks into short-lasting and long-lasting attacks consisting of episodes of dystonia, chorea, or ballism occurring during non-REM sleep [ 20 ] . Most cases of paroxysmal hypnogenic dyskinesia (PHD) are now known to represent medial frontal lobe seizures [ 21 ] . However, rare patients may belong to the group of paroxysmal dyskinesia as these patients have daytime attacks as well.
Although this classifi cation is helpful, there are many patients who do not easily fi t into a category, and syndromes may overlap [ 22 ] . Undoubtedly, there are newer entities waiting to be described. With better understanding of the genetics, a more rational classifi cation may be developed in the future.
Secondary Causes of Paroxysmal Dyskinesias
The majority of cases of PKD, PNKD, and PED are hereditary, inherited in an auto-somal dominant fashion. Rarely, they may have autosomal recessive inheritance. However, it is important to be aware of the secondary causes that may result in episodic movement disorders (Table 6.1 ).
Table 6.1 Clinical features of paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), paroxysmal exertional dyskinesia (PED), and paroxysmal hypnogenic dyskinesia (PHD)
Feature PKD PNKD PED PHD
Inheritance Autosomal dominant or sporadic
Autosomal dominant or sporadic
Autosomal dominant or sporadic
Autosomal dominant or sporadic
Male–female 4:1 1:5:1 1:2 Short 20–50 s Long 5–30 min
Age at onset (years)
<1–40 <1–30 2–20 10–40
Attacks Duration <5 min 2 min to 4 h 5–30 min Short 20–50 s
The most common cause of secondary PKD is demyelinating disease [ 23 ] . Paroxysmal hemidystonia (tonic seizures) may be the presenting manifestation of multiple sclerosis or may occur later in established disease [ 24 ] . These attacks are most consistently precipitated by hyperventilation and can be extremely painful. These typically involve one side of the body with or without the face; bilateral involvement can occasionally be seen. Each attack lasts a few seconds to a few minutes, and multiple attacks may occur during the day. The attacks tend to subside spontaneously over many weeks in spite of continuing disease activity.
Delayed onset PKD has been described after perinatal hypoxic encephalopathy [ 25 ] . The age of onset was 12, and the attacks were precipitated by being bumped from behind and not by a sudden movement. These attacks were short-lasting (5–30 s) and occurred 5–20 times a day. PKD may occur after head trauma, even minor, and there may be a lag period of several months between the head injury and the involuntary movements [ 26 ] .
PKD has been reported due to a variety of metabolic disorders, including idio-pathic hypoparathyroidism [ 1 ] , familial idiopathic hypoparathyroidism, with or without basal ganglionic calcifi cations [ 27 ] hyperthyroidism [ 28 ] , and nonketotic hyperglycemia [ 29 ] . As neuroimaging has become more advanced, more cases of PKD are being attributed to cerebral infarcts, particularly in the putamen and thala-mus [ 30 ] . Both stimulus-sensitive and action-induced paroxysmal dyskinesias have been described in a patient with a posterior thalamic infarct. A patient with focal PKD involving the muscles supplied by the lower cranial nerves has been described and was attributed to an old medulla hemorrhage found on MRI [ 31 ] . A patient with orthostatic paroxysmal dystonia has been described [ 32 ] . This patient had severe bilateral carotid stenosis and developed transient hemidystonia upon standing pre-sumably due to hemodynamic changes.
Rare causes of secondary PKD include progressive supranuclear palsy and meth-ylphenidate therapy [ 1 ] . PKD rarely has been associated with cervical spinal cord lesions. A patient with paroxysmal kinesigenic spinal myoclonus due to cervical cord glioma has been reported. The attacks resembled PKD as these were precipi-tated by sudden movement but did not respond to anticonvulsants [ 33 ] . Central pontine myelinolysis may rarely cause PKD [ 34 ] . For a detailed review of second-ary paroxysmal dyskinesias, please see reference [ 35 ] .
Secondary Paroxysmal Nonkinesigenic Dyskinesia
Most disorders causing PKD have also been associated with PNKD, and in some reports, it is not clear whether the patient had PKD or PNKD. Many have a mixed type of dyskinesia [ 35 ] .
As in PKD, the most common cause of secondary PNKD is multiple sclerosis. Short-lasting (1–2 min) attacks of PNKD due to a solitary cervical cord lesion that was presumed to be demyelinating have been reported.
1516 Paroxysmal Dyskinesias
PNKD has been reported in hypoglycemia and in thyrotoxicosis [ 35 ] . Both PKD and PNKD have been reported in association with familial idiopathic hypoparathy-roidism [ 27 ] as well as idiopathic calcifi cation of the basal ganglia (Fahr’s disease) [ 36 ] . PNKD has been reported to occur in inherited biopterin synthesis defect, but was accompanied by other clinical problems [ 37 ] .
Both central and rarely peripheral traumas may result in PNKD. The attacks have been reported to occur as early as 20 min after injury and may be very brief [ 38 ] . Transient ischemic attacks sometimes manifest as PNKD and may herald a major stroke [ 39 ] .
Both PKD and PNKD have been reported in patients with HIV infection [ 40 ] . There is one report of hypoxic damage to the pallidum with PNKD precipitated by alcohol [ 41 ] . Other causes include migraine, antiphospholipid antibody syndrome, kernicterus, Chiari malformation, and cytomegalovirus encephalitis [ 35, 42 ] .
Secondary Paroxysmal Exercise-Induced Dyskinesia
Most reported cases demonstrate an autosomal dominant inheritance pattern, but there is one report of a post-traumatic PED [ 2 ] . One may consider PED associated with GLUT-1 defi ciency, dopa-responsive dystonia, or young onset PD as second-ary PED.
Secondary Paroxysmal Hypnogenic Dyskinesia
Very few cases of secondary PHD have been described, two with multiple sclerosis and one after trauma [ 43, 44 ] . Many patients with PHD have frontal lobe seizures due to a structural lesion.
Pathophysiology
Paroxysmal dyskinesias are attributed to dysfunction in the basal ganglia, but con-clusive evidence to support this is lacking. Because of its excellent response to anticonvulsants, PKD has been thought to refl ect striatal epileptogenic discharges. Some patients have abnormal baseline EEGs consistent with seizures [ 45 ] , but in most cases, EEGs are usually normal between spells, and artifacts obscure the EEG recording during an attack. Invasive monitoring of a girl with PKD has been reported [ 46 ] . This patient experienced attacks precipitated by movement, loud noise, and stress, and the EEG performed with depth electrodes showed ictal discharges in the supplemental sensorimotor cortex and the caudate nucleus on the ipsilateral side. The fi ndings suggested that in some patients with PKD, the cause of the involuntary movements may be an electrical discharge from the medial frontal lobe spreading to
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the caudate nucleus [ 46 ] . Other physiological investigations have shown impaired inhibition at the cortical and spinal level [ 47, 48 ] . This is supported by the fi nding of interictal myoclonus in some cases with PKD [ 7 ] .
In one case of PKD, single-photon emission computed tomography (SPECT) using 99mTc-HMPAO ictal SPECT revealed decrease of cerebral blood fl ow in the basal ganglia contralateral to the side of choreoathetotic movements [ 49 ] . The authors hypothesized that dysfunction of indirect pathway (negative feedback) may be the underlying mechanism of PKD.
In PNKD, an invasive video-electrographic study in one patient with severe symptoms demonstrated that the PNKD did not originate from the cortex, while a discharge was registered from the caudate nuclei (5,046). An 18FDG PET scan failed to show metabolic anomalies [ 50 ] . 18FDOPA and a 11 C raclopride PET scans revealed a marked reduction in the density of presynaptic dopa decarboxylase activ-ity in the striatum together with an increased density of postsynaptic dopamine D2 receptors [ 51 ] . These fi ndings suggest chronic upregulation of postsynaptic dopa receptors either because of an increase in the number or increase in affi nity. In another patient with PNKD, 11 C dihydrotetrabenazine (DTBZ) PET scan showed no alteration, suggesting a normal dopamine terminal density in the striatum [ 51 ] . Evidence implicating the basal ganglia in PNKD also comes from a case of post-traumatic paroxysmal dystonia in whom positron emission tomography revealed abnormalities in the basal ganglia metabolism [ 38 ] .
In an animal model of paroxysmal dystonia, EEG changes predominate in the caudate, putamen, and the globus pallidus, with a signifi cant decrease in the high-frequency beta2 range. Also, there was a tendency towards an increase in delta and theta activities. These changes were seen both before and after onset of dystonic attacks, indicating a permanent disturbance of neural activities in the basal ganglia of the dystonic animals [ 52 ] .
The pathophysiology of PED is unclear. However, the overlap with PNKD in some families and response to levodopa in others (in the case where the movement disorder precedes young onset PD) suggests that PED may be of basal ganglia ori-gin [ 10, 12, 13 ] . However, in some families, PED exists along with seizures suggest-ing an epileptic mechanism [ 53 ] .
Paroxysmal hemidystonia in demyelinating disease may refl ect ephaptic trans-mission in the plaques [ 54 ] . The site of the ephaptic transmission is unclear, but midbrain and thalamus have been suggested as possible locations [ 55 ] . In some cases, the demyelination is demonstrable exclusively or predominantly in the spinal cord.
As already described, PHD, especially of short duration, is a form of frontal lobe epilepsy in most cases. In a patient with PHD, subtraction ictal SPECT co-registered to MRI indicated a bilateral signifi cant hyperperfusion in the anterior part of the cingulate gyrus [ 56 ] . This suggests that, in some cases of PHD, the epileptic focus may lie in the cingulate gyrus. The existence of true nocturnal dystonic attacks is debatable, but there are some patients who have diurnal and nocturnal attacks that are hard to classify [ 22 ] .
1536 Paroxysmal Dyskinesias
Neurochemistry
The neurochemistry of these disorders is largely unknown. As previously mentioned, the response to levodopa in one case of PKD and another case of PED suggests basal ganglionic dopaminergic dysfunction [ 57 ] . Use of haloperidol in PKD gives incon-sistent results [ 58 ] . In a mutant hamster model of paroxysmal dystonia, pharmaco-logic modulation of the GABAergic function affected the dystonia [ 59 ] . In a genetic hamster model of paroxysmal dystonia, studies implicated abnormal function of the GABA-gated chloride ion channel [ 60 ] . An increase in the striatal dopamine was observed in vivo in the same model during the attacks of dyskinesia [ 61 ] .
Neuropathology
Only two autopsy reports are described in PKD. In one patient, slight asymmetry of the substantia nigra was seen [ 62 ] . The other reported some melanin pigment in mac-rophages of the locus coeruleus suggestive of neuronal loss [ 3 ] . There have been no consistent pathologic changes in the brain and the spinal cord in animal models [ 63 ] .
An autopsy report of a patient with PNKD revealed intense astrogliosis and loss of calbindin-positive neurons in the subcortical gray matter [ 40 ] .
Genetics
Genetic evidence has suggested that paroxysmal dyskinesias may belong to a grow-ing family of episodic disorders that are known to be due to dysfunction of ion channels (channelopathies) (Table 6.2 ). These disorders share similarities and can coexist in families with episodic ataxias [ 64 ] . Several paroxysmal neurological dis-orders are now being discovered to be due to gene mutations regulating ion channels which are intimately involved in maintaining normal neuronal excitability. Initially, episodic neuromuscular disorders like the periodic paralyses were found to be caused by mutations in voltage-gated sodium and calcium channels [ 1 ] . Subsequently, the two forms of inherited episodic ataxias (EA1 and EA2) were shown to be muta-tions of voltage-gated potassium [ 65 ] and calcium channels, respectively [ 66, 67 ] .
There is a certain resemblance between PKD and episodic ataxia type 1 (EA-1) associated with interictal myokymia. Like PKD, the attacks of EA-1 are frequently provoked by sudden movement; the ataxic attacks are short-lasting and can occur several times a day [ 68 ] . Acetazolamide reduces the attacks in some kindreds, and anticonvulsant drugs may reduce the myokymia and attacks in some patients [ 69 ] . There are similarities between the two conditions with regard to the age of onset and improvement in adulthood [ 69 ] . Some members of EA-1 families also have PKD, suggesting a similar pathophysiological mechanism.
154 B. Ho et al.
Genes for PKD have been localized to chromosome 16 [ 70– 72 ] . A locus for PKD (EKD1) was mapped to 16p11.2–q12.1 in eight Japanese families and in Afro-Caribbean family [ 70, 71 ] . Valente et al. have identifi ed a second PKD locus (EKD2), also on chromosome 16, but separate from the EKD1 locus [ 72 ] . An addi-tional British family has been identifi ed where the PKD locus did not map to the previously identifi ed PKD loci on chromosome 16, representing a new gene, EKD3 [ 73 ] . Another rare disorder consisting of writer’s cramp, PED, and rolandic epilepsy maps to the same area of chromosome 16 [ 74 ] . Thus, it seems that there is signifi -cant clinical and genetic heterogeneity in PKD.
There may also be a relationship between infantile convulsions and PKD. Originally described as infantile convulsions and paroxysmal dyskinesia (ICCA) syndrome [ 75, 76 ] and linked to chromosome 16, the condition was thought to be uncommon. Subsequently, benign familial infantile convulsions were linked to the same area of chromosome 16p suggesting allelism to the ICCA syndrome [ 77 ] . Co-segregation of benign infantile convulsions and paroxysmal kinesigenic choreoathetosis was then demonstrated [ 78 ] . It has become clear now that the association between benign infantile convulsions and PKD is the rule rather than the exception [ 79 ] .
The gene for familial PNKD has been linked to a locus on chromosome 2q [ 80– 83 ] . It is known as myofi brillogenesis regulator 1 (MR-1) gene [ 84 ] and encodes
Table 6.2 Paroxysmal dyskinesias – genetics
Disorder Gene localization Gene function References
PKD Chromosome 16P 11.2–q12.1
Unknown Tomita et al. [ 70 ] Bennet et al. [ 71 ] Valente et al. [ 72 ]
Autosomal dominant paroxysmal choreoathetosis and spasticity
Chromosome 1P Potassium channel Auberger et al. [ 89 ]
1556 Paroxysmal Dyskinesias
an enzyme in a cellular stress response pathway. The mutation causes an alanine-to-valine substitution [ 85 ] . Bioinformatic analysis has shown that the MR-1 gene is homologous to the hydroxyacylglutathione hydrolase (HAGH) gene. HAGH func-tions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages, which may explain why both coffee and alcohol reliably pre-cipitate attacks in PNKD [ 86 ] . Alcohol and caffeine precipitated attacks in 98% of patients with the MR-1 mutation [ 86 ] . PNKD was thought to be genetically homog-enous. However, there may be some genetic heterogeneity in PNKD, as Spacey et al. have described a Canadian PNKD family with 14 members who did not have mutations in the MR-1 gene. Affected family members presented with episodes of dystonia primarily affecting hands and feet symmetrically, but alcohol, caffeine, and excitement were not obvious triggers in this kindred. Linkage analysis in this pedi-gree identifi ed a novel gene locus (PNKD-2) at chromosome 2q31, between mark-ers D2S335 and D2S152. One of the interesting genes in this locus is the glutamate decarboxylase gene, which codes for glutamic acid decarboxylase. Glutamate decarboxylase is expressed in the mammalian brain and catalyzes the conversion of glutamic acid to g -aminobutyric acid (GABA), which is the main inhibitory neuro-peptide in the basal ganglia [ 87 ] . In a recent study, Bruno et al. conclude that patients with classic PNKD phenotype as described by Mount and Reback are more likely to have the MR-1 mutations while the “PNKD-like” families with atypical features may not have the MR-1 mutations as some of them may actually have PED [ 86 ] .
The exact location of genes responsible for PED is unknown. However, a pedi-gree in which 3 members in the same generation are affected by PED, rolandic epilepsy (RE), and writer’s cramp (WC) has been described [ 74 ] . Both the seizures and paroxysmal dystonia had a strong age-related expression that peaked during childhood, whereas the WC, also appearing in childhood, remained stable. Genome-wide linkage analysis performed under the assumption of recessive inher-itance mapped to chromosome 16. Although the syndrome is unique, its features present striking analogies with the ICCA syndrome, and the same gene may be responsible for both RE-PED-WC and ICCA. Different location and/or types of mutations within the gene are thought to explain the different presentations of these Mendelian disorders.
Some patients with GLUT-1 defi ciency may have PED as one of the features [ 16, 17 ] , and some may have PED and epilepsy [ 88 ] . A gene for autosomal dominant paroxysmal choreoathetosis associated with spasticity has been mapped to chromo-some 1 in the vicinity of potassium channel gene cluster [ 89 ] .
The gene for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) has been localized to chromosome 20q and is characterized as a mutation of the alpha 4 subunit of the neuronal acetylcholine receptor (CHRNA4) gene [ 90, 91 ] . Another family with ADNFLE has been linked to chromosome 15 in the area of another nicotinic acetylcholine receptor gene [ 92 ] .
As can be seen, the list of disorders due to channel dysfunction continues to grow. One hopes that the identifi cation of a distinct genetic loci in these disorders will lead to a new genetic classifi cation and to a better understanding of these disorders.
156 B. Ho et al.
Differential Diagnosis
Paroxysmal dyskinesias must be differentiated from dopa-responsive dystonia (DRD), seizures, pseudoseizures, and tics. DRD usually begins in childhood and is characterized by marked diurnal fl uctuations, with improvement in symptoms after sleep and progressive worsening during the day. However, discrete paroxysms do not occur. Seizures arising from the supplemental motor area may resemble dyski-nesias and sometimes are precipitated by movement. The idiopathic paroxysmal dyskinesias have to be distinguished from symptomatic ones, as indicated in the section on “ Clinical Manifestations .”
There are two conditions occurring in infancy and childhood that are worth men-tioning. The fi rst, benign paroxysmal torticollis of infancy is a familial condition which usually occurs in the fi rst few months of life. The attacks occur once every 2–3 weeks and last hours to days. The head and sometimes trunk tilt to one or the other side. The attacks cease at 1–5 years of age, and the course is benign. Secondly, some children with large hiatal hernias may contort their bodies and develop a head tilt after a large meal. This has been called Sandifer’s syndrome. The abnormal head tilt resolves after surgery and other treatment of hiatal hernia [ 1, 19 ] .
Sometimes, paroxysmal dyskinesias are psychogenic [ 2 ] . In fact, in one series, psychogenic patients represented a large percentage of cases [ 35 ] . A case with psy-chogenic paroxysmal dyskinesia superimposed on an organic paroxysmal dyskine-sia has been described [ 93 ] .
Diagnostic Workup
A thorough history and videotape documentation are the most important elements in diagnosing paroxysmal dyskinesias. A detailed family history should also be obtained. EEG monitoring may be helpful in ruling out seizures in ambiguous cases or when PHD is being considered. If the attacks are precipitated by hyperventilation, MRI of the head should be obtained to look for evidence of demyelinating disease. In elderly cases of new onset, a thorough workup looking for vascular or other structural dis-ease should be performed. A thorough metabolic workup is also recommended.
Prognosis
Prognosis depends on the type of paroxysmal dyskinesia. PKD even of prolonged duration responds well to standard anticonvulsants, and the attacks tend to diminish during adulthood. PNKD and PED have a variable prognosis. Even with repeated attacks, neurologic function always returns to normal. In secondary dyskinesias, the prognosis depends on the underlying disease. In multiple sclerosis, the attacks tend to run a self-limited course even with continued disease activity.
1576 Paroxysmal Dyskinesias
Treatment
Paroxysmal Kinesigenic Dyskinesia
PKD responds well to anticonvulsants, including phenytoin, valproate, carbam-azepine, and phenobarbital [ 1 ] . The effective dose is usually lower than the stan-dard anticonvulsant dosage. PKD responds particularly well to low-dose carbamazepine [ 94 ] . Newer anticonvulsants including lamotrigine have also been found to be benefi cial [ 95, 96 ] . Other options include anticholinergics, levodopa, fl unarizine, and tetrabenazine [ 2 ] . Haloperidol has also been used, but response is inconsistent at best.
Paroxysmal Nonkinesigenic Dyskinesia
Avoidance of precipitating factors, such as alcohol, caffeine, and stress, should be encouraged. Several medications including clonazepam, haloperidol, alternate-day oxazepam, and anticholinergics have been used, but none have demon-strated consistent effi cacy [ 1, 2, 94 ] . Alternate-day oxazepam has been reported to be effective, and sublingual lorazepam may help some patients with severe prolonged attacks [ 97 ] . Anticonvulsants are ineffective in most cases. In severe refractory cases, deep brain stimulation of the globus pallidus or thalamus has been shown to be effective [ 98, 99 ] .
Paroxysmal Exercise-Induced Dyskinesia
Avoidance of prolonged exercise may diminish the frequency of attacks. Drug therapy is often ineffective though levodopa has been reported to be effi cacious in some cases [ 10 ] . In one severe case, posteroventral pallidotomy ameliorated attacks of paroxysmal dystonia induced by exercise [ 100 ] . In cases with GLUT-I defi ciency, ketogenic diet may be helpful. However, some cases with fi xed defi cits in GLUT-1 defi ciency may develop paroxysmal attacks after a ketogenic diet often accompa-nied by improvements in the fi xed defi cits [ 16 ] .
Paroxysmal Hypnogenic Dyskinesia
Short-duration PHD responds to anticonvulsants, including carbamazepine and phenytoin. The longer-lasting attacks respond less well but may improve with halo-peridol or acetazolamide.
158 B. Ho et al.
Secondary Paroxysmal Dyskinesias
The paroxysmal dystonia associated with multiple sclerosis responds well to anti-convulsants. Acetazolamide is a useful alternative or adjunct to anticonvulsants [ 101 ] . The choreoathetosis secondary to head injury may respond to anticonvulsants or a combination of anticonvulsants and trihexyphenidyl [ 38 ] . In metabolic cases, the underlying abnormality such as hypoglycemia, hyperglycemia, or thyrotoxico-sis should be corrected. The PKD associated with hypoparathyroidism may resolve with treatment of hypocalcemia by vitamin D. Appropriate secondary stroke pre-vention and vascular risk factor modifi cation should be addressed in cases where the paroxysmal dyskinesia is thought to be due to transient ischemic attacks.
Conclusion
The paroxysmal dyskinesias are a complex group of disorders which can be classi-fi ed by clinical features such as duration and precipitating factors. Many are now known to be hereditary channelopathies, but secondary causes should be ruled out especially when the onset is in adulthood. Treatment involves avoidance of precipi-tating factors, medications, and treatment of underlying medical conditions and in recalcitrant cases surgery. The prognosis depends on the type of dyskinesia and the underlying etiology. In general, PKD shows the best therapeutic response. A careful history and examination including videotapes supplemented by laboratory investi-gations will often led to accurate diagnosis and treatment.
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