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Paroxysmal Non-kinesigenic Dyskinesia

  • Zain GuduruEmail author
  • Kapil D. Sethi
Chapter
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Abstract

Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare disorder which typically begins in childhood. Attacks are characterized by a combination of dystonia and chorea, and they are usually triggered by alcohol, coffee, or strong emotion. Attacks can last from 5 min to 4 h. MR-1, which is now called PNKD gene, is the disease-causing gene in “primary” PNKD. Clonazepam appears to be the most successful treatment for PNKD. Deep brain stimulation of internal part of globus pallidus can be a treatment option in medication-resistant cases.

Keywords

Paroxysmal non-kinesigenic dyskinesia Paroxysmal dystonic choreoathetosis Primary paroxysmal non-kinesigenic dyskinesia Paroxysmal dyskinesia PNKD gene Myofibrillogenesis regulator-1 gene Deep brain stimulation Chorea Dystonia Athetosis Clonazepam 

Introduction

Paroxysmal non-kinesigenic dyskinesia (PNKD) is a rare movement disorder characterized by the recurrent attacks of dystonia, chorea, athetosis, ballism, or a combination. It can be idiopathic, genetic - and in both cases either sporadic or familial- or secondary due to a known etiology. The attacks usually range in duration from minutes to hours and are often precipitated by consuming alcohol, coffee, or tea, psychological stress or excitement, and fatigue. PNKD was earlier referred to as paroxysmal dystonic choreoathetosis (PDC), familial paroxysmal choreoathetosis [1]. Longer duration of attacks, smaller frequency of the attacks, and a host of different precipitants of the attacks differentiate it from paroxysmal kinesigenic dyskinesia (PKD). This chapter will focus on those forms formerly known as “primary” PNKD (i.e., idiopathic and/or genetically determined) where these attacks occur out of a background of normal motor behavior.

Epidemiology

PNKD is a rare disorder, occurring at an estimated prevalence of around one in a million people [2]. Familial cases of “primary” PNKD still greatly outnumber sporadic cases. Sporadic form may actually be underreported as it may be difficult to differentiate these attacks from a functional (psychogenic) etiology. When familial, PNKD is inherited as autosomal dominant trait, and the gene involved is myofibrillogenesis regulator-1 (MR-1), now called PNKD gene. More males than females are affected (1.4:1), although the preponderance is not as striking as PKD (M:F, 3–4:1). Age of onset can be from 1 to 20 years; mean age of onset is 12. Attacks tend to diminish with age [1]. In sporadic cases, age of onset tends to be higher [3].

History

Paroxysmal dyskinesia (PxD) was first reported in 1892 by Shuzo Kure in a 23-year-old Japanese man, who had frequent movement-induced paroxysmal attacks from the age of 10 years. At that time the diagnosis was referred to as atypical Thomsen’s disease [4]. Later, Gowers (1901) described a similar child, but he considered this movement disorder an epileptic phenomenon [5]. Wilson (1930) described a 5-year-old boy who had brief attacks of unilateral torsion and tonic spasm that lasted up to 3 min and were precipitated by fright or excitement, without loss of consciousness. Initially they were labeled as reflex epilepsy [6].

In 1940, Mount and Reback reported an index case who was a 23-year-old man with small (lasting 5–10 min) and long attacks (lasting up to 2 h) with retrocollis, eyes rolling, and abnormal movements of the face and hands. The onset of the attacks was in infancy. Twenty-seven other family members over five generations appeared to be similarly affected with an autosomal dominant pattern of inheritance. They labeled this condition familial paroxysmal choreoathetosis [7]. Forssman (1961) [8], Weber (1967) [9], Lance (1963) [10], and Richard and Barnett (1968) [11] reported similar large family cases series. Weber described families with this condition as familial paroxysmal dystonia. In 1967, Kertesz first differentiated the kinesigenic variant from that described by Mount and Reback, Forssman, and Lance, which were not aggravated by movement but by alcohol, caffeine, and fatigue [12]. Richard and Barnett coined the term paroxysmal dystonic choreoathetosis (PDC), which was later adopted by Lance in 1977. The classification of PxD was first proposed by Lance in 1977, based on the duration of the paroxysms, precipitating factors, and phenomenology of abnormal movements [13]. Later, this classification was replaced with the one proposed by Demirkiran and Jankovic, who used a generic term “dyskinesia” rather than dystonia, chorea, or choreoathetosis. Their major classification was based solely on precipitating factors of the attacks, and they further subclassified based on duration of attacks and etiology. Their observation supports the conclusion that the precipitant of an attack is the major contributor of the future course [14] (cfr. Chaps. 1 and 2). More recently, Erro and Bhatia reviewed 500 cases and proposed a new classification of genetically determined PxD based on two axes. Axis one encompasses clinical characteristics and axis two the genetic findings [15].

Genetics

The mode of inheritance in PNKD was recognized as autosomal dominant, with a high but incomplete penetrance [16]. Initial reports of PNKD were familial, with hereditary transmission being autosomal dominant. A linkage study on an Italian family with PNKD by Fink et al. in 1996 [17] first mapped the disease allele to chromosome 2q35, but the disease-causing gene (MR-1) was not identified until 2004 [18, 19], and it is now referred to as the PNKD gene. The encoded PNKD protein associates with membranes and is expressed in neurons where it enriches in pre- and postsynaptic preparations [19, 20]. The PNKD gene has at least three alternate splice forms, which encode proteins of 385, 361, and 142 amino acids. The long isoform of PNKD (PNKD-L) is specifically expressed in CNS, while the medium isoform (PNKD-M) and short isoform (PNKD-S) are ubiquitously expressed [19]. Two missense mutations (Ala to Val), located at amino acids 7 or 9 of PNKD-L and PNKD-S, were found in most patients, and a third mutation (Ala to Pro) at position 33 was reported in one family [21]. Both PNKD-L and PNKD-M have a putative catalytic domain that is homologous to hydroxyacylglutathione hydrolase (HAGH), a member of the zinc metallo-hydrolase enzyme family, which contains β-lactamase domains. HAGH functions in a pathway to detoxify methylglyoxal, a compound present in coffee and alcoholic beverages and produced as a by-product of oxidative stress [22]. This could explain the attacks provoked particularly by caffeine, alcohol, and stress [23]. Shen et al. [24] have shown that PNKD interacts with the synaptic active zone proteins RAB-interacting molecule (RIM) 1 and RIM 2 and modulated neurotransmitter release. The mutant protein is less effective at inhibiting exocytosis. Based on these findings, altered release of synaptic neurotransmitter vesicles and increased neuronal hyperexcitability have been postulated as the main disease mechanisms in PNKD. PNKD-positive PNKD is also categorized as DYT8 [25]. However, the authors of this chapter do not agree with the inclusion of paroxysmal dyskinesia in the classification of dystonia.

MR-1 (PNKD gene) negative sporadic and familial PNKD cases have also been reported (Table 4.1). Paroxysmal non-kinesigenic dyskinesia with or without generalized epilepsy (PNKD3) is an autosomal dominant neurologic disorder due to a pathogenic variant ion the KCNMA1 gene.
Table 4.1

PNKD (MR1) gene-negative sporadic and familial PNKD cases, reported in the literature

Case/Family

Gene mutation

Accompanying feature

Mutation DNA and amino acid

Reference #

One Family

PRRT2

Migraine

c.649C > T (p.Arg217X)

[26]

One case

PRRT2

PKD

c.649C > T (p.Arg217X)

[27]

Five cases

PRRT2

PKD

c.884G>A and c.649C > T

[28]

Four cases

PRRT2 (biallelic)

Seizures in all patients, PKD in one patient

c.649dupC/ c.649dupC

[29]

Two cases

PRRT2

Unknown

[30]

One family

Gene locus at 2q31

Migraine in three patients and seizures in two patients

[31]

One family

SLC2A1 gene on chromosome 1-encoding glucose transporter (GLUT-1)

Spastic paraparesis

[32]

One family

KCNMA1

A few had epilepsy

p.D434.G

[33]

Two unrelated children

KCNMA1

Developmental delay

p.E884K and p.N1053S

[34]

One case

KCNMA1

PKD

c.1534A>G (p.I512V)

[35]

Clinical Features

PNKD typically begins in childhood (mean age is 12 years), and only a few patients have the onset after 18 years of age. They are precipitated by consuming alcohol, coffee, or tea and also by psychological stress or excitement and by fatigue. Attacks may begin with premonitory symptoms (41% of MR-1 gene-positive cases) such as a sensation of tightness (80% of those) in one limb, involuntary movements of the mouth, or anxiety [36]. The attacks of PNKD consist of any combination of dystonic postures, chorea, athetosis, and ballism (Video 4.1). They can be unilateral – always on one side or on either side – or bilateral, and unilateral episodes can be followed by a bilateral one. They can affect a single region of the body or be generalized [1]. Attacks have never been associated with loss of consciousness or with seizures and never reported to occur during sleep. Sleep aborts the episodes. Speech is often affected, with inability to speak due to dystonia, but there is never any alteration of consciousness, and there is no pain during the episodes. Attacks may diminish spontaneously with age [3, 13]. Attacks lasts for minutes to hours, sometimes longer than a day. Usually they range from 5 min to 4 h. However, they are much more infrequent than PKD and occur a few times a day to only a few times a year [2, 7, 19]. There is no consistent correlation between duration and frequency. PNKD differs from PKD by longer duration of attacks, smaller frequency of the attacks, and different precipitants of the attacks (cfr. Chap.  3).

Patients with PNKD who do not carry a MR-1 (PNKD gene) mutation are more variable in their age of onset, provoking factors, and response to medication (Table 4.2). The clinical characteristics of PNKD with MR-1 (PNKD gene) mutations are more uniform. The MR-1 (PNKD gene) mutation-positive individuals have the precipitation of attacks by caffeine and alcohol in nearly 100% of instances. Sleep benefit (attack resolving if the patients went to sleep during their attacks) was a characteristic for PNKD previously reported and was found in patients both with and without the MR-1 (PNKD gene) mutations. The prevalence of migraine was high in the mutation carriers, reported in 47% of the patients [33]. In summary, the patients with MR-1 (PNKD gene) mutations have three distinguishing features: (1) onset of attacks in infancy or early childhood; (2) precipitation of attacks by caffeine and alcohol in nearly 100% of patients; and (3) a favorable response to benzodiazepines and sleep [19].
Table 4.2

Summary of clinical characteristics for MR-1 mutation-positive and mutation-negative patients in PNKD

 

MR-1 mutation positive

MR-1 mutation negative

Number of patients

49

22

   Male

27

14

   Female

22

14

Age at onset

4.0 ± 4.6

12.3 ± 10.8

Premonitory sensation

41%

63%

Precipitants

  

   Alcohol

98% (n = 44)

0% (n = 6)

   Caffeine

98%

38%

   Exercise

12%

68%

   Fatigue

12%

32%

   Emotional stress

82%

27%

   Sleep benefit

70%

36%

Attack phenomenology

  

   Dystonia

12%

36%

   Chorea

18%

   Combination of dystonia and chorea

88%

27%

   Ballism

18%

Typical attack duration (minimum and maximum)

10 min to 1 h

10 min to few hours

From Bruno et al. [36]. Reprinted with permission from Wolters Kluwer Health, Inc.

In sporadic cases, onset age tends to be even higher; many of the sporadic PNKD patients in fact have a functional (psychogenic) movement disorder [3]. Conversely, PNKD may be mistakenly diagnosed as a functional disorder as stated above.

Acquired PNKD might have interictal neurologic abnormalities reflecting the underlying disorder, as opposed to “primary” PNKD with normal neurologic examination between the paroxysms. Onset of symptoms of acquired PNKD has a wider range (2.5–79 years), with a peak in the twenties when caused by trauma and a mean age of 60 years when a result of vascular events [37] (cfr. Chap.  6).

KCNMA1 gene mutation-induced PNKD cases are characterized by absence seizures, generalized tonic-clonic seizures, and paroxysmal non-kinesigenic dyskinesia. Onset is usually in childhood. Patients may have seizures only, dyskinesia only, or both.

ADCY5-induced choreoathetosis can be jerky or twitchy, and trigger factors are drowsiness and intercurrent illness. Episodes mostly occur at the initiation of sleep (with prolonged sleep latency) or waking up from sleep. Initially the disorder can be episodic and progressively becomes constant. Usually the onset is in the infancy with delayed milestones. The movements can be initially episodic lasting for minutes to hours and even up to days during intercurrent illness. Interictal examination often shows hypotonia and movement disorders such as chorea. The exacerbating factors could often be identified, and they lacked the stereotyped trigger and duration of many paroxysmal movement disorders, leading to prefer the term episodic rather than paroxysmal (however, the dictionary meaning of episodic and paroxysmal is the same) [1]. A further important point differentiating ADCY5 gene mutations from PNKD gene mutation-positive PNKD is the presence of a normal neurological examination between episodes in the latter [38]. Onset in the first months of life and relation to sleep is unusual in paroxysmal movement disorders due to PRRT2, PNKD, and SLC2A1 mutations; thus, mutations in ADCY5 should be considered in the differential of paroxysmal movement disorders with a very early onset even in the absence of a detectable chronic movement disorder [39].

Investigations

CT head, MRI brain, and ictal and interictal EEGs are generally normal. However, an invasive video-electroencephalographic study by Lombroso [40] demonstrated discharge from the caudate nuclei, whereas cortical recordings were normal. We do not recommend invasive investigations in this setting. SPECT scans have revealed hyperperfusion of the right caudate and thalamus [41]. Reduced density of presynaptic aromatic amino acid decarboxylase activity in the striatum and increased density of postsynaptic dopamine D2 receptors could be demonstrated by 18F-DOPA and 11C-raclopride PET [41]. This was thought to reflect chronic upregulation of postsynaptic dopaminergic receptors. 18FDG and [11C] dihydrotetrabenazine (DTBZ) PET did not show any metabolic abnormalities or abnormal binding [42]. It has been suggested that dopaminergic abnormalities, if present, may be a result of altered regulation of dopamine release or of postsynaptic mechanisms, rather than of an altered density of nigrostriatal innervation. Animal models with PNKD have demonstrated dopamine dysregulation in the basal ganglia [43]. Lance [13] mentioned that autopsies performed on two patients with PNKD revealed no pathology. In acquired PNKD, abnormal EEG, MRI brain, and laboratory investigations may be noted.

Treatment

Avoidance of the precipitating factors such as alcohol or caffeine can be helpful. Unlike PKD, PNKD does not readily respond to anticonvulsants, and medical treatment is less rewarding. However, anticonvulsants should be tried in every case, and an occasional patient may respond to carbamazepine (200–400 mg/day). Clonazepam (0.25 mg BID), as introduced for PDC by Lance [13], appears to be the most successful agent, for both idiopathic and symptomatic PDC. Other drugs that have been tried including diazepam (2 mg, 2–3 times/day), haloperidol, alternate-day oxazepam [44], and anticholinergics such as benztropine and trihexyphenidyl (up to 20 mg total daily dose) and levetiracetam (500 mg BID) [45, 46], however, without consistent success. Van Rootselaar reported successful treatment of two children with PNKD from a large kindred with sublingual lorazepam. Benzodiazepines appeared to be of some benefit in one-third to three-fourths of patients with PNKD [2].

Deep brain stimulation (DBS) is also being explored as a potential therapeutic option in the treatment of medically refractory severe PNKD. Loher et al. [47] have assessed the effect of chronic stimulation of the ventrointermediate (Vim) thalamus for treatment of dystonic PNKD. Chronic stimulations through a stereotactically implanted monopolar electrode in the left Vim resulted in a decrease of the frequency, duration, and intensity of the dystonic paroxysmal movement disorder, and the benefit of stimulation was maintained over 4 years of follow-up. Long-term follow-up was reported after 9 years and showed mild loss of stimulation effect. The effect was regained when the target was changed to the GPi [48]. Yamada et al. [49] presented a case of unilateral posttraumatic PNKD with complete suppression of abnormal movements after implantation of GPi DBS, and Kaufman et al. [50] reported a difficult case with a generalized movement disorder with superimposed bilateral PNKD which, although with atypical elements, showed a significant reduction in the frequency and intensity of the episodic dystonic episodes. Riaan van Coller et al. [51] reported successful treatment with chronic stimulation of bilateral globus pallidus in two patients.

Botulinum toxin has been tried by some, but the generalized nature of the movement disorder limits its usefulness [37]. In acquired PNKD the treatment of the underlying etiology is the most important.

Conclusion

Paroxysmal non-kinesigenic dyskinesia is a rare disorder, and the attacks are often precipitated by consuming alcohol, coffee, or tea and also by psychological stress or excitement and by fatigue. Genetically determined or idiopathic PNKD have normal interictal examination. PNKD differs from PKD by longer duration of attacks, lower frequency of the attacks, and a host of different precipitants of the attacks. Clonazepam is the treatment of choice. Further research into the mechanisms and pathophysiology of disease [52] will help to elucidate novel therapies for treatment and disease modification.

Supplementary material

Video 4.1

A 7-year-old boy who developed episodic abnormal involuntary movements at the age of 3 years. These attacks occurred 2–3 times per week and were not brought on by sudden movement of startle or prolonged running. He develops generalized involuntary jerking and sometimes writhing movements that also involved his face. He remained alert during the episode, and the attacks lasted for 20 min to 6 h (MP4 85007 kb)

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Copyright information

© Springer Nature Switzerland AG 2021

Authors and Affiliations

  1. 1.Department of Neurology, Movement Disorders SectionUniversity of KentuckyLexingtonUSA
  2. 2.Department of Neurology, Movement Disorders SectionAugusta UniversityAugustaUSA

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