Subhashie Wijemanne

Dopa-responsive dystonia[mdash]clinical and genetic heterogeneity

Dopa-responsive dystonia (DRD) encompasses a group of clinically and genetically heterogeneous disorders that typically manifest as limb-onset, diurnally fluctuating dystonia and exhibit a robust and sustained response to levodopa treatment. Autosomal dominant GTP cyclohydrolase 1 deficiency, also known as Segawa disease, is the most common and best-characterized condition that manifests as DRD, but a similar presentation can be seen with genetic abnormalities that lead to deficiencies in tyrosine hydroxylase, sepiapterin reductase or other enzymes that are involved in the biosynthesis of dopamine. In rare cases, DRD can result from conditions that do not affect the biosynthesis of dopamine; single case reports have shown that DRD can be a manifestation of hereditary spastic paraplegia type 11, spinocerebellar ataxia type 3 and ataxia telangiectasia. This heterogeneity of conditions that underlie DRD frequently leads to misdiagnosis, which delays the appropriate treatment with levodopa. Correct diagnosis at an early stage requires use of the appropriate diagnostic tests, which include a levodopa trial, genetic testing (including whole-exome sequencing), cerebrospinal fluid neurotransmitter analysis, the phenylalanine loading test, and enzyme activity measurements. The selection of tests for use depends on the clinical presentation and level of complexity. This Review presents the common and rarer causes of DRD and their clinical features, and considers the most appropriate approaches to ensure early diagnosis and treatment.

Restless legs syndrome: clinical presentation diagnosis and treatment

Restless legs syndrome (RLS) is a circadian disorder of sensory-motor integration that may be related to genetically determined dysregulation of iron transport across the blood-brain barrier. Dopamine agonists (DAs) have been considered the first-line therapy, but with the growing appreciation of problems associated with long-term treatment, particularly augmentation and impulse control disorder, alpha-2-delta drugs, such as gabapentin, are now considered the first line of treatment in patients with troublesome RLS. Opioids can be considered as an alternative therapy, particularly in patients with DA-related augmentation. In more severe cases, a combination therapy may be required. Intravenous iron therapy may be considered on those patients with refractory RLS.

Long-term efficacy and safety of fluphenazine in patients with Tourette syndrome.

Haloperidol and pimozide are the only drugs currently approved by the U.S. Food and Drug Administration for treatment of Tourette syndrome (TS), but their potential side effects, which include tardive dyskinesia (TD), limit their use.

Hemiparkinsonism-hemiatrophy syndrome

Objective: To characterize the clinical and radiologic features of hemiparkinsonism-hemiatrophy syndrome (HPHA). Methods: Medical records of patients with evidence of unilateral parkinsonism and ipsilateral body atrophy, evaluated at the Baylor College of Medicine Movement Disorders Clinic, were reviewed. Results: The mean age at onset of the 30 patients who satisfied the criteria was 44.2 (15 to 63) years with a mean duration of symptoms for 9.7 (2 to 20) years. Half of all patients had dystonia at onset and dystonia was present in 21 (70%) patients during the course of the syndrome. Eleven (37%) also had scoliosis. Brain asymmetry on imaging studies was noted in 9 (30%) patients. Response to levodopa was rated as good in 18, moderate in 6, and poor in 6. Nine of 19 (47%) patients in whom birth history was available had difficult birth or had severe febrile illness in the first few months of life. Overall 10 (33%) patients had difficulty in walking during early childhood. Conclusion: Although the clinical features of hemiparkinsonism-hemiatrophy syndrome are variable, suggesting a heterogeneous pathogenesis, perinatal and early childhood cerebral injury appears to play an important role in about half of the cases.

Hemidystonia-hemiatrophy syndrome.

To define the clinical and radiological features of patients with the combination of hemidystonia (HD) and hemiatrophy (HA), the HD‐HA syndrome. HD is a very disabling neurological condition that is rarely associated with HA of the affected body part, similar to the hemiparkinsonism‐hemiatrophy syndrome. Method: We reviewed the medical records of 26 patients with the HD‐HA syndrome and the data was entered into a database and analyzed. Video recordings as well as imaging studies were also reviewed. Twenty six patients (14 female) with a mean age at onset of HD at 14.9 years (1–46 years) were followed for a mean of 3.4 years. Fourteen (53%) had HD and HA on the left side and 23 (88%) had hemiparesis preceding the onset of HD. The mean latency from the onset of hemiparesis to the onset of HD was 14.7 years (2 weeks–46 years). All patients with hemiparesis had marked improvement in their weakness prior to the onset of HD. Common causes leading to hemiparesis and subsequent HD were birth or perinatal complications (N = 13) and stroke (N = 10). Seven patients (26%) had associated seizures. Twenty two patients (85%) had abnormal brain MRI: eight had lesions directly involving the basal ganglia and nine had cerebral hemiatrophy or non specific diffuse atrophy. Sixteen patients received botulinum toxin injections and responded well to treatment. HD‐HA is usually associated with static encephalopathy originating at very young age, but the syndrome may also represent delayed sequelae of a stroke or brain injury.

Movement Disorders From the Use of Metoclopramide and Other Antiemetics in the Treatment of Migraine

Nausea and vomiting are a frequent accompaniment of migraine and anti‐nausea medications are frequently used in its management. The majority of anti‐nausea medications that are used in migraine are dopamine receptor blocking agents and therefore have the potential to cause drug‐induced movement disorders. This article explores the risk of such drug‐induced movement disorders in migraineurs who were treated with these medications.

Treatment of blepharospasm with apraclonidine.

OBJECTIVE To describe improvement in blepharospasm with apraclonidine. BACKGROUND Blepharospasm is a focal dystonia involving chiefly the orbicularis oculi and periocular muscles resulting in involuntary sustained eyelid closure. Botulinum toxin injection is the mainstay of treatment with meaningful improvement in over 85% of patients, but the effects often wear off within 3-4months. Apraclonidine is an alpha-2 adrenergic receptor agonist, which causes contraction of superior tarsal (Müller) muscle which may improve blepharospasm-related eyelid closure. We propose that apraclonidine may be a useful short-term treatment in patients with blepharospasm, particularly during wearing off from botulinum toxin injection. METHODS Patients who had pre-mature wearing off of botulinum injection effect were evaluated before and after the administration of 2 drops of apraclonidine 0.5%-1% solution to each eye. Subjective patient impressions and examiners impression of symptoms pre and post-apraclonidine administration were recorded. A blinded rater evaluated the videos and provided an independent assessment of the severity of symptoms pre- and post-administration, using a 0-4 scale. RESULTS Our study included 7 patients (4 male) with a mean age of 61years and mean duration of blepharospasm of 3.6years. There was a subjective, albeit transient (about 2-4h) improvement in blepharospasm reported by all patients and by the examiner. The mean severity scores, based on blinded video ratings, showed a reduction from of 3.4 pre-administration to 2.3 post-administration of apraclonidine (p<0.025). No adverse effects were noted. CONCLUSIONS Apraclonidine is a potentially useful medication for short term management of blepharospasm symptoms while awaiting botulinum toxin injection.

SPG11 Mutations Associated With a Complex Phenotype Resembling Dopa-Responsive Dystonia

Background: The aim of this study was to describe a case of hereditary spastic paraplegia (HSP) resulting from SPG11 mutations, presenting with a complex phenotype of dopa‐responsive dystonia (DRD), diagnosed using whole exome sequencing (WES). HSP resulting from SPG11 typically presents with spasticity, cognitive impairment, and radiological evidence of thin corpus callosum. Initial presentation with DRD has not been previously reported on. Methods: This 11‐year‐old boy with delay in fine motor skills, presented at 8 years of age with progressive, generalized dystonia with diurnal variation, bradykinesia, and stiff gait. There was marked improvement in dystonia with levodopa, but he soon developed wearing‐off phenomenon and l‐dopa‐induced dyskinesia. Family history was unremarkable. Results: Brain MRI showed thinning of the anterior corpus callosum with periventricular white matter changes. 123I‐ioflupane single‐photon emission coupled tomography showed bilateral severe presynaptic dopamine deficiency. WES identified transheterozygous allelic variants in the SPG11 on chromosome 15, including a truncating STOP mutation (p.E1630X) and a second heterozygous coding variant (p.L2300R). Dystonia improved with globus pallidus internus (GPi) DBS surgery. Conclusions: HSP resulting from SPG11 should be considered in the differential diagnosis of a patient presenting with DRD, parkinsonism, and spasticity. This case expands the HSP genotype and phenotype. GPi DBS may be a therapeutic option in selected patients.

Apraclonidine in the treatment of ptosis

Transient ptosis is a known complication of botulinum toxin (BoNT) injection due to inadvertent migration of toxin into the levator palpebrae superioris muscle. Currently there is no treatment available for BoNT induced ptosis. Apraclonidine hydrochloride is a topical ophthalmic solution with selective alpha-2 and weak alpha-1 receptor agonist activity that has the ability to elevate the eye lid. Apraclonidine has been used as a diagnostic test in Horners syndrome. We evaluated the effects apraclonidine in a cohort of BoNT induced ptosis and a patient with Horner syndrome. Each patient was administered 2 drops of apraclonidine 0.5% solution to the eye with the ptosis and was re-examined 20-30min later. All 6 patients showed improvement in ptosis. There was also improvement in ptosis in a patient with Horners syndrome. Apraclonidine is not only useful as a diagnostic test in Horners syndrome, but may be an effective and safe treatment for BoNT-induced ptosis.