Dystonia

INDEX

 

Differential of paroxysmal events

Paroxysmal dyskinesias are characterized by recurrent episodes of sudden involuntary movement disorders.

These disorders are commonly associated with other episodic symptoms, such as migraine and episodic ataxia. Although paroxysmal dyskinesias were thought to be channelopathies (and some are), none of the three genes which are associated with the bulk of these conditions actually encode ion channels.
 

Classification

Paroxysmal dyskinesias are classified according to the precipitating factors into three major subtypes:

  1. Paroxysmal Kinesigenic Dyskinesia (PKD)
  2. Paroxysmal Nonkinesigenic Dyskinesia (PNKD)
  3. Paroxysmal Exercise-Induced Dyskinesia (PED)

In addition, a further paroxysmal entity occurs, Paroxysmal Hypnogenic Dyskinesias (PHD) characterised by attacks occurring during sleep without identifiable trigger), and usually due to the condition of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in most cases1.

Clinical Features

All three forms can present with dystonic, choreic, or ballistic movements, or a mixture of those, and can involve one or more limbs, the trunk, and/or the face.

1. PKD (Paroxysmal Kinesigenic Dyskinesia)

PKD is the commonest type, and dystonia the commonest movement disorder.

Virtually all cases due to mutations in the PRRT2 gene have a clear kinesigenic trigger, although in up to 40%–50% of cases anxiety, stress, startle or prolonged exercise can also induce attacks2.
Very rarely (about 1%–2% of patients) there are no kinesigenic triggers. About half of the patients experience a sensory aura at the initial site of the attacks.

Genetics
PRRT2 mutations are common in patients with PKD and are significantly associated with an earlier age at onset and longer duration of attacks3.  PRRT2 mutations account for approximately 60% to 100% of patients with familial PKD and 10% to 50% of sporadic PKD cases. Inheritance follows an autosomal dominant pattern. In patients with homozygous or compound heterozygous mutations there is a more severe phenotype.MCG

About 25% of patients with PRRT2 related PKD have infantile convulsions4. In patients with Infantile Convulsions with Choreoathetosis (ICCA) syndrome, PKD starts after the onset of epilepsy (the seizures develop within the first two years of life), usually after age five, although some patients might have epileptic seizures at a later age.

After a peak in puberty, there is a tendency for the attack frequency to decrease, and the condition may completely remit in adulthood4.

Mutations in the PRRT2 gene are also associated with Benign Familial Infantile Seizures (BFIE) (brief seizures with cyanosis, increased tone and jerks of the limbs, which remit by two years of age). PKD, BFIE and ICCA are considered to represent a continuous disease spectrum.MCG

Table 1. Clinical features of the paroxysmal dyskinesias

 

  Trigger Aura Duration Frequency Movement Pain Age at Onset
1.PKD
Sudden movement/ startle ; modification of ongoing movement; anxiety, stress, or prolonged exercise.
Can be self-provoked.
Frequently present  Brief
Usually lasting < 1 minute and most commonly less than 10 seconds
20 attacks per day (1/month to 100/day)
80% of patients reported tens to hundreds of attacks per day4

Both chorea and dystonia, and tend to generalise. Ballism may be present.

No Childhood, very rarely later than 20 years of age
2.PNKD

Coffe, alcohol and stress.

Anxiety, excitement.
7% of cases reported prolonged exercise as triggers of attacks4.

May be present
Long
10 minutes to 4 hours
Infrequent, may be weekly4 or a few times a year.
(Rarely > 1 daily). May be attack free for months.
Both chorea and dystonia. Possible Childhood
3.PED Exercise
Hyperventilation
 

Intermediate:

5-30 minutes

Weekly Both chorea and dystonia.  May involve body part involved in exercise; legs typically involved. No Childhood-30 years
Video 1. Example of case of PKD

 

This patient was a 20‐year‐old man who had experienced 2 attacks of infantile convulsions at the age of 5 to 10 months and had involuntary dystonia, usually alternating between the left and right sides, since the age of 10. He would experience increased muscular tension in the lower limb of the affected side before an episode, and slowing down occasionally relieved the attack. The episodic attacks, mostly triggered by voluntary movement and emotional stress, but never by caffeine, occurred 10 to 30 times per day and usually involved the face and neck. Each attack lasted less than 20 seconds and was never associated with loss of consciousness.

(vv)PatientR.mp4(tt)

From: Tian WT, Huang XJ, Mao X, Liu Q, Liu XL, Zeng S, Guo XN, Shen JY, Xu YQ, Tang HD, Yin XM, Zhang M, Tang WG, Liu XR, Tang BS, Chen SD, Cao L. Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients. Mov Disord. 2018 Mar;33(3):459-467. 

 

Video 2. Example of case of PKD

(vv)PatientR.mp4(tt)
Patient RJ7712 was a 19‐year‐old woman who had involuntary dystonia affecting the right or both sides since the age of 15. The episodic attacks, mostly elicited by voluntary movements, occurred 10 to 20 times per day, with an approximate duration of 10 seconds Carbamazepine (50 mg/night) could satisfactorily control the attacks. She experienced an incomplete remission at the age of 19, with occasional aura attacks

From: Tian WT, Huang XJ, Mao X, Liu Q, Liu XL, Zeng S, Guo XN, Shen JY, Xu YQ, Tang HD, Yin XM, Zhang M, Tang WG, Liu XR, Tang BS, Chen SD, Cao L. Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 163 patients. Mov Disord. 2018 Mar;33(3):459-467. 

2. PNKD

There is always a dominant family history for similar attacks, no sporadic cases having been reported thus far.  Attacks are generalised in about 50% of the patients.

In a number of patients episodes became heterogeneous during the course of the disease, being more dystonic in the early phase, with more choreic components seen subsequently4.

Attacks can rarely be complicated by dysarthria, dysphagia, oculogyric crises, inability to move and may even be fatal.

The duration of the attacks is variable but typically last from several minutest to 1-2 hours.

Although several non-kinesigenic triggers (ie, stress, tiredness, sustained exercise) can be present, the attacks are characteristically brought on by coffee and/or alcohol intake.

3. PED

The majority of patients showed focal/unilateral involvement, and generalization of the attack is uncommon4.  lower-limb dystonia precipitated by sustained walking or running is the most common manifestation.   Most cases with PED are de novo, whereas only 10% have a positive family history.

Associated neurological disorders, seen in almost ¾ of patients include epilepsy, learning difficulties, ataxia, and pyramidal signs4.

Genetics
A mutation in the solute carrier family 2, member 1 (SLC2A1) gene is the most common cause of PED.  SLC2A1 encodes GLUT-1 which is the primary glucose transporter into erythrocytes, across the blood–brain barrier and into and out of astrocytes.  Patients usually show CSF glucose and lactate levels below the 10th percentile. Lactate levels are typically also low,  a CSF to blood glucose ratio at or below the 25th percentile, and CSF lactate levels are never elevated5. (Clincially, these patients have epilepsy, hypotonia, spasticity, ataxia, and developmental delay2).

Video 3. Example of PED

 

Segment 1. Recording of a running session. This segment shows involuntary bilateral hand twisting movements (white arrows) presenting at the end of the sprint of a short running path. The patient complains also facial grimace and leg tightness (not shown).
Segment 2.Neurological examination and provoking maneuver (running in place). This segment shows an unremarkable finger-tapping test in the beginning of the examination. The exercise provokes after 10 seconds the onset of bilateral hand dystonia with left clenched fist and right hand twisting posture. The finger tapping performances at the end of the segment are impaired by bradykinesia and dystonic jerks

(vv)Vid1PED.mp4(tt)

From: Marano M, Motolese F, Consoli F, De Luca A, Di Lazzaro V. Paroxysmal Dyskinesias in a PRRT2 Mutation Carrier. Tremor Other Hyperkinet Mov (N Y). 2018 Dec 3;8:616. doi: 10.7916/D8S488X0. PMID: 30622840; PMCID: PMC6315045.

Figure 1. Algorithm for investigation of PED.

Major differential includes Dopa-responsive dystonia and mutations in the parkin gene.  Note that currently a gene panel is likely to be most cost effective method of making the diagnosis. Typically, this should be obtained before imaging.

From: Erro R, Stamelou M, Ganos C, et al. The Clinical Syndrome of Paroxysmal Exercise-Induced Dystonia: Diagnostic Outcomes and an Algorithm. Mov Disord Clin Pract. 2014;1(1):57-61. doi:10.1002/mdc3.12007

 

4. PHD

Characterized by violent attacks of dystonic and tonic movements that occur during sleep and last for around 45 sec. In fact, PHD is almost always a form of frontal lobe epilepsy ‘autosomal-dominant nocturnal frontal lobe epilepsy’ (ADNFLE). Mutations have been found in CHRNA4, CHRNA2 and CHRNB2, which code for acetylcholine receptor subunits.

However, PRRT2 mutations have been recently identified in 2 out of 11 patients (18.2%) with PHD6.

 

Examination: See Table 1.

Age of onset: See Table 1.

Diagnosis & Special Investigations

The critical features on diagnosis are:

  1. Nature of the trigger (see Table 1),
  2. Presence of additional interictal neurological signs2

Table 1. Clinical features of the paroxysmal dyskinesias

 

 

Epilepsy

Movement Disorders

Migraine

1.PKD/PRRT2 mutations
  1. Infantile Convulsions with Choreoathetosis (ICCA)
  2. Infantile Convulsions (25% of patients)
  3. Benign Familial Infantile Epilepsy (BFIE)

Cerebellar Ataxia
Episodic Ataxia4
Paroxysmal Torticollis4

Also: PNKD and PED7

  1. Migraine
  2. Hemiplegic Migraine
2.PNKD/ MR-1 mutations

 

 
Migraine
3.PED/SLC2A1 Epilepsy Ataxia

Migraine

Note: Low frequency of PRRT2 mutations in Episodic Ataxia and Hemiplegic Migraine

Figure 2. Suggested algorithm to lead the genetic analyses.

*If SLC2A1 is negative, also consider PRRT-2, especially if PNKD attacks are brief.

**Only 20-25% of PED cases are positive for SLC2A1, suggesting that other genes are implicated.

From: Erro R, Sheerin UM, Bhatia KP. Paroxysmal dyskinesias revisited: A review of 500 genetically proven cases and a new classification. Mov Disord. 2014;29(9):1108-1116. doi:10.1002/mds.25933

 

Prognosis

PKD: The frequency of attacks usually decreases with advancing age after puberty and the syndrome can completely remit regardless of any treatments.

Differential Diagnosis

There are a wide range of disorders which are reported to produce paroxysmal movement disorders (see Table 2)2,7.

The classical neurological examples include:

In addition, propriospinal myoclonus is frequently paroxysmal8.

Table 2. Episodic movement disorders resembling paroxysmal dyskinesias2,7

 

Structural lesions of CNS: CNS and systemic immune disorders: Cerebrovascular disorders: Neurodegenerative disorders: CNS infections: Systemic metabolic disorders: Other disorders:
  • Multiple sclerosis
  • Stroke in basal ganglia or thalamus
  • Traumatic brain injury (onset of dyskinesias is often delayed by several months)
  • Primary CNS lymphoma
  • Brain tumours
  • Basal ganglia calcification
  • Voltage-gated potassium channel antibody encephalitis
  • Anti CASPR 2 encephalitis
  • Antiphospholipid syndrome, SLE
  • Poststreptococcal autoimmune neuropsychiatric syndrome
  • Celiac disease
  • Sjogren syndrome
  • Behcet’s disease
  • Hashimoto encephalopathy
  • Transient ischemic attacks
  • Severe carotid stenosis or occlusion,
  • Moya-Moya disease
  • Arteriovenous malformation
  • Progressive Supranuclear Palsy
  • Fahr disease,
  • Neuroacanthocytosis
  • Parkinson disease
  • Human Immunodeficiency Virus encephalitis
  • Subacute Sclerosing Panencephalitis
  • Cytomegalovirus encephalitis
  • Meningovascular syphilis
  • Hypocalcaemia
  • Hypoparathyroidism
  • Pseudohypoparathyroidism,
  • Hyperglycaemia, hypoglycaemia
  • Thyrotoxicosis
  • Wilson disease, kernicterus
  • Peripheral nerve injury
  • Perinatal hypoxic encephalopathy
  • Migraine aura
  • Cerebral palsy (often delayed-onset paroxysmal dyskinesia)

 

Paroxysmal attacks were initially reported in multiple sclerosis, but have since been described in neuromyelitis optica121.  These attacks are identical phenomenologically to PKD.
It remains a matter of speculation regarding the antomical origin of these events: the majority likely have brainstem involvement, but hemispheric and spinal origins likely also occur.
The attacks typically are stereotyped and have the following characteristics:

Short duration (seconds to minutes)
High frequency of attacks, up to 200/day.
Consciousness is unaffected and EEG is normal, suggesting a nonepileptic origin.
The location of the precipitating lesion remains unknown but clinical findings are compatible with a brain stem origin.
Good response to carbamazepine

Video 4. Paroxysmal dyskinesias associated with NMO spectrum disorder

45 year old man, seen in the emergency room with recent onset of apparent seizures involving the left side of the body.  History of hypertension and diabetes.
Stereotyped movements involving the left side of the body, including the face, and occurring currently throughout the day (20-30 times).
There was no associated loss of consciousness and no aura present. No history of epilepsy in the family. Not brought out, or worsened by movement. Resolved rapidly with phenytoin.
MRI show hyperintense signal in midbrain and pons on FLAIR images:


 

(vv)Pkd2.mp4(tt)

Similar events are described with infarction of the thalamus and of the midbrain (paroxysmal ataxia and dysarthria13):

Video 5. Paroxysmal dyskinesias associated with thalamic infarction

 

The patient has an unusual hemdystonic gait, attempting to suppress involuntary movements of the right leg with her arm.  Spontaneous dyskinesias of the right leg occur while sitting.  
Finger-nose and heel-shintesting showed marked cerebellar dysmetria and tremor, but precise movements of the right-hand were normal.  Elevation of the right leg resulted in ballistic jerks, with severe ataxia. The most remarkable feature of this presentation is the response to touch of the right arm and leg which led to complex movements with elements of jerks, dystonia, balance and stereotypies.

(vv)Tijssen.mp4(tt)

From: Nijssen PC, Tijssen CC. Stimulus-sensitive paroxysmal dyskinesias associated with a thalamic infarct. Mov Disord. 1992 Oct;7(4):364-6. 

 

Functional paroxysmal dyskinesia:

Suggestive features include:

  1. Late age on onset;  in one published series, the mean age at onset was 39 years, much later than that seen with other paroxysmal dyskinesias9
  2. Paroxysmal Tremor may be present7, as may a range of other signs of functional neurological disorders.
  3. The movements are highly variable, and duration is typically much longer than paroxysmal dyskinesias, of the order of hours to days.
  4. Consciousness may be altered
  5. Attack triggers, although present, are not typical for paroxysmal dyskinesias; notably, 1 in 5 patients had coexistent organic movement disorder (tic, dystonia, tremor).

Treatment

PKD

Carbamazepine is the first-line treatment option, being very effective at low doses (50- 100 mg) (in  98% of patients3)(50–600 md/day).  PRRT2-positive patients are more likely to respond11.

PNKD

Clonazepam is the first-line pharmacological option when lifestyle modifications (i.e., avoiding coffee and alcohol) are not efficacious.  Regardless of any treatment, there is a tendency for the attacks to reduce or remit in adulthood.

Acetazolamide, valproate and levetiracetam may be of benefit.

PED

PxD in the context of SLC2A1 cases have a positive but partial response to a ketogenic diet, which should be pursued to treat the underlying neuroglycopenia.

Anti-epileptics not typically useful.

 

 

 

 

 

 

 

 

References

 1.           Steinlein OK, Mulley JC, Propping P, et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 1995;11(2):201-203. doi:10.1038/ng1095-201

2.           Erro R, Bhatia KP. Unravelling of the paroxysmal dyskinesias. J Neurol Neurosurg Psychiatry. 2019;90(2):227-234. doi:10.1136/jnnp-2018-318932

3.           Huang X-J, Wang T, Wang J-L, et al. Paroxysmal kinesigenic dyskinesia: Clinical and genetic analyses of 110 patients. Neurology. 2015;85(18):1546-1553. doi:10.1212/WNL.0000000000002079

4.           Erro R, Sheerin UM, Bhatia KP. Paroxysmal dyskinesias revisited: A review of 500 genetically proven cases and a new classification. Mov Disord. 2014;29(9):1108-1116. doi:10.1002/mds.25933

5.           Leen WG, Wevers RA, Kamsteeg EJ, Scheffer H, Verbeek MM, Willemsen MA. Cerebrospinal fluid analysis in the workup of GLUT1 deficiency syndrome: A systematic review. JAMA Neurol. 2013;70(11):1440-1444. doi:10.1001/jamaneurol.2013.3090

6.           Liu XR, Huang D, Wang J, et al. Paroxysmal hypnogenic dyskinesia is associated with mutations in the PRRT2 gene. Neurol Genet. 2016;2(2). doi:10.1212/NXG.0000000000000066

7.           Méneret A, Roze E. Movement disorders Paroxysmal movement disorders: An update. Rev Neurol (Paris). 2018;172(8-9):1-13. doi:10.1016/j.neurol.2016.07.005

8.           Williams DR, Cowey M, Tuck K, Day B. Psychogenic propriospinal myoclonus. Mov Disord. 2008;23(9):1312-1313. doi:10.1002/mds.22072

9.           Ganos C, Aguirregomozcorta M, Batla A, et al. Psychogenic paroxysmal movement disorders--clinical features and diagnostic clues. Parkinsonism Relat Disord. 2014;20(1):41-46. doi:10.1016/j.parkreldis.2013.09.012

10.        Erro R, Stamelou M, Ganos C, et al. The Clinical Syndrome of Paroxysmal Exercise-Induced Dystonia: Diagnostic Outcomes and an Algorithm. Mov Disord Clin Pract. 2014;1(1):57-61. doi:10.1002/mdc3.12007

11.        Gardiner AR, Jaffer F, Dale RC, et al. The clinical and genetic heterogeneity of paroxysmal dyskinesias. Brain. 2015;138(12):3567-3580. doi:10.1093/brain/awv310

12.         Matsui M, Tomimoto H, Sano K, Hashikawa K, Fukuyama H, Shibasaki H. Paroxysmal dysarthria and ataxia after midbrain infarction. Neurology 2004; 63: 345–7.

13.         Eriksson M, Ben-Menachem E, Andersen O. Epileptic seizures, cranial neuralgias and paroxysmal symptoms in remitting and progressive multiple sclerosis. Mult Scler 2002; 8: 495–9.