Pantothenate kinase‐associated neurodegeneration (PKAN) is a rare autosomal recessive disorder causing progressive generalized dystonia characterized by neurodegeneration and brain iron accumulation (NBIA) due to pantothenate kinase 2 (PANK2) gene mutations.1 The radiological hallmark of PKAN, the “eye‐of‐the‐tiger” sign, characterized by bilateral hypointensity with central hyperintensity in the globus pallidus on T2‐weighted brain Magnetic Resonance Imaging (MRI) may be absent in some cases.2 Hence, clinicians may rely on phenotypic clues to aid diagnosis. Despite genetic advances, treatment for NBIA remains symptomatic. Bilateral globus pallidus internus deep brain stimulation (GPi‐DBS) has been successful in PKAN patients refractory generalized dystonia.3 Herein we report a case of an atypical PKAN patient with severe dystonic opisthotonus and absent eye‐of‐the‐tiger sign who obtained significant improvement following bilateral GPi‐DBS.
A 25‐year‐old Malay male was referred for progressive generalized dystonia that started at age 14. It began in the upper limbs with writing difficulties, and over the next five years, progressed to involve his face, neck, trunk, and lower limbs. By age 16, he had severe axial and craniocervical dystonia. He was treated with baclofen, clonazepam, diazepam, and trihexyphenidyl with minimal response. On examination, there was marked back arching (dystonic opisthotonus) with retrocollis that affected his posture and balance when standing and walking. There were prominent mouth‐opening oromandibular dystonia and frequent action‐induced painful facial and jaw dystonic spasms with speech difficulty. Both upper limbs were dystonic, with superimposed distal myoclonus (Video 1). Brain MRI showed absent eye‐of‐the‐tiger sign (Fig. 1); however, the severe opisthotonic posturing raised a clinical suspicion of PKAN. Molecular analysis of the PANK2 gene 7 coding exons showed homozygous missense mutation NM_153638.2:c.332 T > A(rs71647828) in exon 1 with Leucine111Glutamine (L111Q) mutation,4 confirming the diagnosis of atypical PKAN.
Figure 1.
Brain MRI performed at age 20 in (A) axial T2WI, at age 25 in (B) axial T1WI, (C) axial T2WI, (D) coronal FLAIR, (E) axial FLAIR thin (1 mm), and (F) axial T2 thin (1 mm) show normal signal intensity of globus pallidus.
Failing oral therapies, he underwent bilateral GPi‐DBS surgery. Day one, post‐operatively, with the neurostimulator ON (amplitude 3.5 V; pulse‐width 60 usec; frequency 130 Hz), there was a dramatic improvement in the dystonic opisthotonus, retrocollis, oromandibular, and upper limbs dystonia, and the patient was able to vocalize. The distal myoclonus had disappeared (Video 2, Segment 1). Dystonia severity assessment using Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS) at one month demonstrated a 31.3% improvement on the motor scale score (preoperatively 80/120; postoperatively 55/120; Table 1). The disability scale score improved by only one point in walking (preoperatively 13/30; postoperatively 12/30), although the patient reported significant improvement in painful spasms, gait, and postural stability. After the surgery, the patient developed mild parkinsonism bilaterally, which improved with subsequent stimulation adjustments. The correction of axial dystonia and hand myoclonus remained sustained two years after the surgery (Video 2, Segment 2–4), with further improvement of the motor scale score (postoperatively 46/120) following multiple adjustments (Table 1).
Table 1.
Serial changes in the severity of dystonia and disability rated using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS) at baseline and 1 month, 1 year, and 2 years after bilateral globus pallidus internus deep brain stimulation (GPi‐DBS).
| Time after bilateral GPi‐DBS | ||||
|---|---|---|---|---|
| Section/region | Baseline | 1‐month | 1‐year | 2‐year |
| BFMDRS‐Motor | ||||
| Eyes | 2 | 2 | 4.5 | 4.5 |
| Mouth | 8 | 3 | 4.5 | 4.5 |
| Speech/swallowing | 12 | 6 | 9 | 9 |
| Neck | 8 | 4 | 4 | 4 |
| Right arm | 16 | 12 | 6 | 6 |
| Left arm | 16 | 12 | 12 | 12 |
| Trunk | 12 | 4 | 2 | 2 |
| Right leg | 3 | 6 | 1 | 1 |
| Left leg | 3 | 6 | 3 | 3 |
| Total score (% improvement) | 80 | 55 (31.3) | 46 (42.5) | 46 (42.5) |
| BFMDRS‐Disability | ||||
| Speech | 4 | 4 | 4 | 4 |
| Handwriting | 1 | 1 | 1 | 1 |
| Feeding | 2 | 2 | 2 | 2 |
| Eating/swallowing | 1 | 1 | 1 | 1 |
| Hygiene | 1 | 1 | 1 | 1 |
| Dressing | 1 | 1 | 1 | 1 |
| Walking | 3 | 2 | 2 | 2 |
| Total score (% improvement) | 13 | 12 (7.7) | 12 (7.7) | 12 (7.7) |
The maximal motor score is 120 points (normal being 0), and the maximal disability score is 30 points (normal being 0). The total motor and disability improvements are expressed in percentage and are calculated as follows: (preoperative score‐postoperative score)/preoperative score.
Action‐induced dystonic opisthotonus has been described as a “red‐flag” sign of NBIA related to PANK2 and PLA2G6 mutations.5 Our case strengthens this clinical association and highlights the importance of recognizing dystonic opisthotonus as a useful phenotypic clue of PKAN syndrome, particularly in patients with absent eye‐of‐the‐tiger sign. However, this feature can also occur in other conditions.5 Suspicion for genetic testing should, therefore, be guided by careful history in conjunction with other NBIA signs (such as oromandibular dystonia).
Our experience also corroborated previous findings of bilateral GPi‐DBS efficacy in ameliorating refractory generalized dystonia in PKAN.3 In our case, the dystonic opisthotonus improved significantly, with the least improvement in oromandibular dystonia. To our knowledge, this is the first reported case of successful bilateral GPi‐DBS in PKAN patient with absent eye‐of‐the‐tiger sign. Nevertheless, it is unclear whether the absence of this hallmark sign on MRI is a predictor of good response to GPi‐DBS. It was argued that the central T2 hyperintensity might have “faded” with time due to a “secondary obscuration” process from iron accumulation as the surrounding T2 hypointensity became more evident in late‐onset PKAN.2 Interestingly, our patient developed parkinsonism post‐surgery. We postulate that this could be due to stimulation effects of the contralateral GPi electrode, or direct lesioning effects of the GPi electrodes, or even the sequelae of the disease progression. Hypokinesia following bilateral pallidal DBS has been reported to more likely occur with high‐frequency stimulation and more ventral active contact.6 Stimulating another target, such as subthalamus, could be considered a possible alternative in this condition.7
Finally, the subjective improvement in our patient's overall function was not reflected by the BFMDRS disability scale scores, possibly because the improvement in postural stability and pain were not adequately captured. Moreover, the motor scale lacked assessment of other non‐dystonia features such as myoclonus and parkinsonism, which were present in our patient. Perhaps, this calls for a more specific rating scale for NBIA patients.
Author Roles
1. Research Project: A. Conception, B. Organization, C. Execution; 2. Statistical Analysis: A. Design, B. Execution, C. Review and Critique; 3. Manuscript: A. Writing of the first draft, B. Review and Critique.
N.A.M.F.: 1A, 1B, 1C, 3A, 3B
N.M.I.: 1A, 1C, 3B
S.A.M.M.: 3B
T.J.: 3B
Z.A.A.: 3B
Disclosures
Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed consent has been obtained from the patient. The authors also confirm that the approval of an institutional review board was not required for this work.
Funding Sources and Conflict of Interest: No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work.
Financial Disclosures for the previous 12 months: The authors declare that there are no additional disclosures to report.
Supporting information
Video 1. Segment 1 (age 16): The video shows the patient prior to bilateral GPi DBS. He had severe action‐induced dystonic opisthotonus with retrocollis, left torticollis and upper limbs dystonia affecting his posture and balance requiring constant supervision. There were prominent mouth‐opening oromandibular dystonia and painful facial and jaw dystonic spasms worsened by voluntary actions. He had marked speech difficulty but able to vocalize some words. Segment 2 (age 20): The patient had persistent oromandibular and upper limbs dystonia. The action‐induced axial dystonia and retrocollis had improved slightly with medications. There was superimposed distal hand myoclonus on finger‐nose testing.
Video 2. Segment 1 (day 1, post‐GPi DBS): The video shows dramatic improvement of the dystonic opisthotonus, retrocollis, oromandibular dystonia and dystonic spasms. He was able to open and close his mouth, smile, and count. The distal hand myoclonus had also disappeared. Segment 2 (month 1, post‐GPi DBS): The improvement in dystonic opisthotonus and retrocollis was sustained with improved posture and balance. The oromandibular dystonia had improved with reduced facial and jaw dystonic spasms. There was mild parkinsonism bilaterally with difficulty turning and short‐stepped gait. Lower limbs dystonia had worsened slightly. Segment 3 and 4 (year 1 and year 2, post‐GPi DBS): The improvement of axial dystonia remained sustained, with residual oromandibular and facial dystonia, mild left torticollis, and left hemidystonia. Patient had received three monthly botulinum toxin injections for his oromandibular dystonia during the last 6 months of year 2 post‐surgery.
Acknowledgments
We would like to thank the patient, his family, and all clinicians, especially Dr. Hasnur Zaman Hashim from Department of Medicine, Hospital Sultanah Nur Zahirah, Kuala Terengganu, Malaysia and Dr. Azlina Ahmad Anuar from Department of Biomedical Science, University of Malaya who provided the clinical information.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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Associated Data
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Supplementary Materials
Video 1. Segment 1 (age 16): The video shows the patient prior to bilateral GPi DBS. He had severe action‐induced dystonic opisthotonus with retrocollis, left torticollis and upper limbs dystonia affecting his posture and balance requiring constant supervision. There were prominent mouth‐opening oromandibular dystonia and painful facial and jaw dystonic spasms worsened by voluntary actions. He had marked speech difficulty but able to vocalize some words. Segment 2 (age 20): The patient had persistent oromandibular and upper limbs dystonia. The action‐induced axial dystonia and retrocollis had improved slightly with medications. There was superimposed distal hand myoclonus on finger‐nose testing.
Video 2. Segment 1 (day 1, post‐GPi DBS): The video shows dramatic improvement of the dystonic opisthotonus, retrocollis, oromandibular dystonia and dystonic spasms. He was able to open and close his mouth, smile, and count. The distal hand myoclonus had also disappeared. Segment 2 (month 1, post‐GPi DBS): The improvement in dystonic opisthotonus and retrocollis was sustained with improved posture and balance. The oromandibular dystonia had improved with reduced facial and jaw dystonic spasms. There was mild parkinsonism bilaterally with difficulty turning and short‐stepped gait. Lower limbs dystonia had worsened slightly. Segment 3 and 4 (year 1 and year 2, post‐GPi DBS): The improvement of axial dystonia remained sustained, with residual oromandibular and facial dystonia, mild left torticollis, and left hemidystonia. Patient had received three monthly botulinum toxin injections for his oromandibular dystonia during the last 6 months of year 2 post‐surgery.