Dystonia

INDEX

 

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.

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 (brief seizures with cyanosis, increased tone and jerks of the limbs, which remit by two years of age).

 

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 
20 attacks per day (1/month to 100/day)
80% of patients reported tens to hundreds of attacks per day1

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 trigger of attacks1

May be present
Long
10 minutes to 4 hours
Infrequent, typically weekly1
(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

 

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.

GLUT-1 patients usually show CSF glucose and lactate levels below the 10th percentile. Lactate levels are typically also low, and 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).

Figure 1. Algorithm for investigation of PED

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

 

 

Video 1. Paroxysmal kinesigenic dyskinesias in a professional runner. 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

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.

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
  Epilepsy Movement Disorders Migraine
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
PNKD/ MR-1 mutations     Migraine
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).

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)

 

Functional paroxysmal dyskinesia:

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

8.          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

9.          Méneret A, Roze E. Paroxysmal movement disorders: An update. Rev Neurol (Paris). 2016;172(8-9):433-445. doi:10.1016/j.neurol.2016.07.005

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