Approach Considerations
Historically, the treatment of patients with pantothenate kinase-associated neurodegeneration (PKAN) was mostly symptomatic. However, novel therapies have been studied as potential disease-modifying agents. These include iron chelators as well as fosmetpantotenate.
In terms of symptomatic therapy, tremor responds best to dopaminergic agents. The anticholinergic agent benztropine may be used to help rigidity and tremor. Benzodiazepines have been tried for choreoathetotic movements.
Hypertonia is usually a combination of rigidity and spasticity and may be difficult to treat. Dopamine agonists and anticholinergics may help to reduce rigidity. Baclofen in moderate doses relieves the stiffness and spasms and can reduce dystonia. Intramuscular botulinum toxin has also been used, in adults as well as children. [22, 38]
Deep brain stimulation, in particular targeting the bilateral subthalamic nuclei, has been tried for patients with prominent appendicular symptoms. [39] Symptoms such as drooling and dysarthria can be troublesome. Medications such as methscopolamine bromide can be tried for excessive drooling. Dysarthria may respond to medications used for rigidity and spasticity. Speech therapy also may be useful, and computer-assisted devices may be used in advanced cases. A gastrostomy feeding may be necessary as the dysphagia progresses.
A multidisciplinary team approach involving physical, occupational, and speech therapists may be needed in selected patients with a protracted course to improve functional skills and communication.
Systemic chelating agents, such as desferrioxamine, have been used in an attempt to remove excess iron from the brain, but these have not proved beneficial. Dementia is progressive, and no treatment has proved clearly effective.
In vitro, pluripotent stem cells derived from PKAN patients responded to the administration of coenzyme A by preventing neuronal death and reactive oxygen species formation. [40]
Inpatient care
Admission for supportive care is occasionally necessary.
Referrals
Referral to a neurologist, particularly a movement disorders specialist, is helpful. Rehabilitation physicians often are consulted to coordinate the different therapy regimens.
Treatment of Dystonia
Dystonia is the most prominent and disabling symptom of PKAN and may respond modestly to dopaminergic agents such as levodopa and bromocriptine (a dopamine agonist). Other dopamine agonists, such as ropinirole or pramipexole, can also be considered, although no formal studies have been conducted on their efficacy in PKAN.
Anticholinergics, such as trihexyphenidyl, may be used when dopaminergic agents are not helpful. However, these medications bring only transient relief for dystonia, and physical therapy is often of limited benefit as well. Botulinum toxin can be injected into severely affected muscles to relieve dystonia.
Medical Care
Deferiprone, an iron chelator used to treat patients with thalassemia, has emerged as a potential therapy for PKAN. It crosses the blood-brain barrier and is thought to reverse brain iron deposition. A pilot study examined the effects of deferiprone 15 mg/kg on five patients with PKAN. The patients experienced clinical improvement, and MRI studies showed decreased iron accumulation in the globus pallidus. [41]
Another promising treatment in the form of fosmetpantotenate has been suggested. Fosmetpantotenate bypasses the enzymatic defect induced by the PANK2 mutation. An open-label, uncontrolled 12-month trial of fosmetpantotenate in one patient with late-onset PKAN induced symptomatic improvement. It was noted to be well tolerated with only transient liver enzyme elevation that normalized after dose reduction. [42]
Surgical Care
Because dystonia is a prominent feature of PKAN, the globus pallidus has been a target for surgical treatment. Stereotactic pallidotomy and bilateral thalamotomy have occasionally been tried in patients with severe dystonia, resulting in partial relief of symptoms. [43] Deep brain stimulation of the globus pallidus as well as the subthalamic nucleus has been used in these patients with promising results. [39, 44, 45]
In 2005, six individuals with PKAN underwent DBS. At follow-up, 6 to 48 months later, they all showed improvements in writing, speech, walking, and global measures of motor skills. In addition, a multicenter retrospective study of 23 patients from 16 centers, the majority of whom had PKAN, were tracked for 15 months post DBS. Overall, patients reported improvement in dystonia and quality of life. Patients with the most severe dystonia seemed to be the ones who benefited most from DBS. [22]
Continuous intrathecal baclofen infusion has been tried for refractory, generalized dystonia without much success. An alternative is intraventricular baclofen, of interest because this site may deliver benefit in patients who have primarily upper-body and facial dystonia, such as blepharospasm. [46]
Diet
Diet may play a role in the treatment of PKAN. A case study performed on a set of brothers with PKAN indicated a positive response to a hypercaloric diet. The brothers were placed on a diet of 50 kcal/kg for 2 weeks, and both were noted to have improvement particularly with regards to dystonia of the neck and trunk, as well as with gait and strength of hand grip. [47]
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Magnetic resonance imaging (MRI) has increased the likelihood of antemortem diagnosis of Pantothenate kinase-associated neurodegeneration (PKAN). The typical MRI findings include bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypointensity in the globus pallidus, on T2-weighted images. These imaging features, which are fairly diagnostic of PKAN, have been termed the "eye-of-the-tiger sign." The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling. The surrounding hypointensity is due to loss of signal secondary to iron deposition.
