An Autopsy Case of Progressive Supranuclear Palsy with Incidental

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Discussion | This pilot study successfully explored the effect size 3. Korte J-M, Kaila T, Saari KM. Systemic bioavailability and cardiopulmonary of timolol eyedrops on migraine headaches. Several partici- effects of 0.5% timolol eyedrops. Graefes Arch Clin Exp Ophthalmol. 2002;240 (6):430-435. pants responded extremely well to the timolol. Further re- 4. Migliazzo CV, Hagan JC III. Beta blocker eyedrops for treatment of acute search is needed to determine what patient factors might pre- migraine. Mo Med. 2014;111(4):283-288. dict responsiveness to timolol. 5. Chiam PJT. Topical beta-blocker treatment for migraine. Int Ophthalmol. 2012; 32(1):85-88. Limitations. Study limitations include a small sample size, a 6. Headache Classification Committee of the International Headache Society. lack of investigator masking, and an imperfect placebo, as The international classification of headache disorders, 3rd edition (beta artificial tears tend to cause less of a burning sensation than version). https://www.ichd-3.org/wp-content/uploads/2016/08/International -Headache-Classification-III-ICHD-III-2013-Beta-1.pdf. Accessed June 1, 2016. timolol. With a half-life of 4 hours, timolol ophthalmic is unlikely to have had an association with repeated headaches or beyond the 3-day washout period. Four 50-μL drops of timolol, 0.5%, represent 1 mg of timolol, which An Autopsy Case of Progressive Supranuclear compares with an oral prophylactic dosage of 10 to 30 mg of Palsy With Incidental ATXN2 Expansion timolol daily. Future research should aim for a target enroll- A case of multiple system atrophy with predominant parkin- ment of more than 86 participants and explore optimal dos- sonism (MSA-P) with ATXN2 (OMIM 601517) expansion was ing regimens. previously reported.1 However, the autopsy in that patient showed tauopathy without evidence of spinocerebellar ataxia Conclusions | Timolol is an effective abortive treatment for some type 2 (SCA2). Herein, we present the pathologic findings to patients with migraines. Future research should focus on iden- correct the previous misdiagnosis. This patient is case 3 in the tifying which patients will respond and at what dosage. previous report,1 which details clinical history and examination. He died when he was in his late 60s due to pneumonia, Matthew Cossack, MD 9 years after onset of the disease. A rare chance to examine Edward Nabrinsky, BA MSA-P with low-range ATXN2 expansion prompted us to per- Heath Turner, BA form an autopsy. Ashley Abraham, MD Methods | Sean Gratton, MD General autopsy was carried out with routine pro- cedure. The time from death to the postmortem examination Author Affiliations: University of Missouri–Kansas City School of Medicine, was 17 hours. The half brain was stored in a deep freezer Kansas City. (−80°C) and the remaining half brain was fixed in 10% neu- Accepted for Publication: February 23, 2018. tral formalin for 4 weeks. After fixation, formalin-fixed Corresponding Author: Sean Gratton, MD, University of Missouri–Kansas City paraffin embedded blocks were cut as 5-μm thickness. Hema- School of Medicine, 2301 Holmes St, Kansas City, MO 64108 (grattons@umkc toxylin-eosin, glial fibrillary acidic protein (1:200 dilution; .edu). Dako), phosphorylated tau (1:300 dilution AT8; Ther- Correction: This article was corrected online July 16, 2018, for errors in the moFisher), 3 repeat tau (1: 40 000 dilution; Merck), 4 repeat Table and Results section. tau (1:10 000 dilution; Millipore), α-synuclein (phospho S129, Published Online: May 14, 2018. doi:10.1001/jamaneurol.2018.0970 1: 200 dilution; Abcam), phosphorylated TDP43 (1:10 000 Author Contributions: Dr Cossack had full access to all of the data in the study dilution; Cosmo Bio), phosphorylated neurofilaments (1: and takes responsibility for the integrity of the data and the accuracy of the data analysis. 10 000 dilution; Milipore), NeuN (1:500 dilution; Milipore), and Concept and design: Cossack, Abraham, Gratton. 1C2 (1:200 dilution; Milipore) immunohistochemistry and Acquisition, analysis, or interpretation of data: All authors. Luxol fast blue staining were carried out. Permission for au- Drafting of the manuscript: All authors. Critical revision of the manuscript for important intellectual content: Cossack, topsy was granted by the family, and the study was approved Gratton. by the institutional review board of the Seoul National Statistical analysis: Cossack, Nabrinsky. University Hospital. Administrative, technical, or material support: Turner, Abraham, Gratton. Supervision: Gratton. Results | The weight of the fresh brain was 1450 g. Gross Conflict of Interest Disclosures: None reported. autopsy findings showed mild cortical atrophy with sulcus Trial Registration: ClinicalTrials.gov Identifier: NCT02630719 widening. Prominent pontine atrophy with cerebellar involve- Additional Contributions: We thank statistician An-Lin Cheng, PhD, University of Missouri–Kansas City, for her help with the statistical analysis and John ment was seen. The globus pallidus was atrophic. The puta- Hagan, MD, Discover Vision Centers, and Carl Migliazzo, MD, Shawnee Mission men, caudate nucleus, and hippocampus were preserved. De- Medical Center, for assisting with the conception of the study and patient pigmentation was observed in the substantia nigra and locus recruitment. None of these individuals were compensated for their coeruleus. Microscopic examination showed widespread neu- contributions. ronal loss with reactive gliosis in the globus pallidus, subtha- 1. Bobik A, Jennings GL, Ashley P, Korner PI. Timolol pharmacokinetics and lamic nucleus, substantia nigra, colliculi, periaqueductal gray effects on heart rate and blood pressure after acute and chronic administration. matter, and the dentate nucleus of the cerebellum. Numer- Eur J Clin Pharmacol. 1979;16(4):243-249. doi:10.1007/BF00608402 ous tau-positive, ubiquitin-negative globose tangles, and tufted 2. Urtti A, Rouhiainen H, Kaila T, Saano V. Controlled ocular timolol delivery: systemic absorption and intraocular pressure effects in humans. Pharm Res. astrocytes were seen in the brainstem, thalamus, basal gan- 1994;11(9):1278-1282. glia, hippocampus, cortex, cerebellum, and cervical spinal cord

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Figure. Immunohistochemical Staining

A Spinal cord C1 B Cerebellum

C Hippocampus D Frontal cerebral cortex

Phosphorylated Tau-positive globose tangles and tufted astrocytes in the spinal cord C1 vertebra (phospho-Tau [AT8]; original magnification ×40) (A), cerebellum (phospho-Tau [AT8]; original magnification ×50) (B), hippocampus (phospho-Tau [AT8]; original magnification ×45) (C), and frontal cerebral cortex (phospho-Tau [AT8]; original magnification ×100) (D). Inset in the upper right of each image shows the location of the image in the brain.

(Figure). There was no Lewy body, neurite, or senile plaque of 32 were found in a control population.4 Our case highlights pathology. No positive reaction, except for a few areas of weak that rigorous examination of clinical relevance is critical in the granular staining in neuronal soma, was observed in 1C2 interpretation of genetic test results, as shown in a previous (antibody specific for polyglutamine) immunostaining. report.5

1 Discussion | In the previous report, possible MSA-P was diag- Ahro Kim, MD nosed based on rapidly progressive parkinsonism, poor re- Sung-Hye Park, MD, PhD sponse to levodopa, recurrent falling, erectile dysfunction, and Beomseok Jeon, MD, PhD hyperreflexia. In retrospect, this patient showed clinical char- acteristics of progressive supranuclear palsy. Mild limitation of downward eye movement was suspected. He showed no Author Affiliations: Department of Neurology, Seoul St Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea (Kim); Department of prominent ataxia and urinary dysfunction, which was not suf- Pathology, College of Medicine, Seoul National University Hospital, Seoul, ficient for MSA criteria. There was a cognitive bias of anchor- Republic of Korea (Park); Department of Neurology, College of Medicine, Seoul ing toward parkinsonism with cerebellar ataxia that is MSA National University Hospital, Seoul, Republic of Korea (Jeon). because of ATXN2 expansion. We thought that mild cerebel- Accepted for Publication: February 6, 2018. lar atrophy was suggestive of MSA, but mild cerebellar atro- Corresponding Author: Beomseok Jeon, MD, PhD, Department of Neurology, phy may be found in progressive supranuclear palsy.2 We con- College of Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul 110-744, Korea ([email protected]). clude that our patient had progressive supranuclear palsy, and ATXN2 expansion is incidental. Pathologic changes in this case Published Online: May 7, 2018. doi:10.1001/jamaneurol.2018.0652 involved dentate nucleus, which is commonly spared in most Author Contributions: Drs Park and Jeon had full access to all of the data in the 3 study and takes responsibility for the integrity of the data and the accuracy of patients with SCA2. Moreover, the rarity of polyglutamine the data analysis. staining in this patient suggested that SCA2 did not contrib- Study concept and design: Jeon. ute to the pathologic effects. In addition, 2 of his children (even Acquisition, analysis, or interpretation of data: Kim, Park. Drafting of the manuscript: Kim, Park. though they are only in their late 30s) with same expansion Critical revision of the manuscript for important intellectual content: Jeon. 4 number of 32 are neurologically normal. Ross et al observed Administrative, technical, or material support: Park, Jeon. a significant association of expanded ATXN2 repeats with pro- Study supervision: Jeon. gressive supranuclear palsy. They also reported that repeats Conflict of Interest Disclosures: None reported.

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Additional Contributions: Prof Shigeo Murayama, Tokyo Metropolitan Institute should have been performed before gene testing for MLD to of Gerontology, reviewed the microscopic findings. avoid delays of administering the correct diagnosis and therapy. 1. Kim JM, Hong S, Kim GP, et al. Importance of low-range CAG expansion and These points should have been discussed to render the case CAA interruption in SCA2 Parkinsonism. Arch Neurol. 2007;64(10):1510-1518. more instructive for clinicians. 2. Koga S, Josephs KA, Ogaki K, et al. Cerebellar ataxia in progressive supranuclear palsy: an autopsy study of PSP-C. Mov Disord. 2016;31(5):653-662. Letterio S. Politi, MD 3. Estrada R, Galarraga J, Orozco G, Nodarse A, Auburger G. Spinocerebellar ataxia 2 (SCA2): morphometric analyses in 11 autopsies. Acta Neuropathol. 1999; Ettore Salsano, MD 97(3):306-310. Alessandra Biffi, MD 4. Ross OA, Rutherford NJ, Baker M, et al. Ataxin-2 repeat-length variation and neurodegeneration. Hum Mol Genet. 2011;20(16):3207-3212. Author Affiliations: Division of Hematology/Oncology and Department of Radiology, Boston Children’s Hospital, Boston, Massachusetts (Politi); Advanced 5. McNeill N, Nasca A, Reyes A, et al. Functionally pathogenic EARS2 variants in Magnetic Resonance Imaging Center, Department of Radiology, University of vitro may not manifest a phenotype in vivo. Neurol Genet. 2017;3(4):e162. Massachusetts Medical School, Worcester (Politi); Unit of Rare Neurodegenerative and Neurometabolic Diseases, Fondazione Instituto COMMENT & RESPONSE di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico “C. Besta,” Milan, Italy (Salsano); Gene Therapy Program, Dana Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts (Biffi); Gene Therapy Metachromatic Leukodystrophy: Program for Rare Diseases, Boston Children’s Hospital, Boston, Massachusetts Too Frequent (Mis)Diagnosis? (Biffi). To the Editor Recently, Wu et al1 reported the case of an adult pa- Corresponding Author: Letterio S. Politi, MD, Division of Hematology/ tient with late-onset cobalamin C disease who received an Oncology and Department of Radiology, Boston Children’s Hospital, 300 Longwood Ave, Fegan 703, Boston, MA 02115 ([email protected] incorrect diagnosis of adult metachromatic leukodystrophy .edu). (MLD). In this patient, the disease onset was characterized by Published Online: June 18, 2018. doi:10.1001/jamaneurol.2018.1515 acute psychiatric symptoms and spastic paraparesis. A brain mag- Conflict of Interest Disclosures: None reported. netic resonance imagining (MRI) scan performed 2 months af- 1. Wu C, Sun Q, Fan D. Serial magnetic resonance imaging changes in a patient ter the onset showed an area of hyperintensity on fluid- with late-onset cobalamin c disease with a misdiagnosis of metachromatic attenuated inversion recovery images in the right occipital leukodystrophy. JAMA Neurol. 2018;75(3):374-375. subcortical white matter. The involvement of bilateral occipi- 2. Eichler F, Grodd W, Grant E, et al. Metachromatic leukodystrophy: a scoring tal white matter and centrum semiovale was evident at a system for brain MR imaging observations. AJNR Am J Neuroradiol. 2009;30 (10):1893-1897. follow-up MRI that was performed 21 months after the onset. 3. Biffi A, Cesani M, Fumagalli F, et al. Metachromatic leukodystrophy— At this time, arylsulfatase A (ARSA) enzyme activity was mutation analysis provides further evidence of genotype-phenotype tested in peripheral blood leukocytes, and the results showed correlation. Clin Genet. 2008;74(4):349-357. that the levels were half of the normal lower limit. Metachromat- 4. Kreysing J, Bohne W, Bösenberg C, et al. High residual arylsulfatase A (ARSA) ic leukodystrophy was suspected and the patient underwent ge- activity in a patient with late-infantile metachromatic leukodystrophy. Am J netic testing. This is an interesting case, but in our opinion, it is Hum Genet. 1993;53(2):339-346. confounding to emphasize MLD in the differential diagnosis 5. Herz B, Bach G. Arylsulfatase A in pseudodeficiency. Hum Genet. 1984;66(2- 3):147-150. because it could have been ruled out much sooner. Acute psychiatric symptoms and spastic paresis of the lower limbs could be present at onset in adult MLD. However, In Reply We thank Politi et al for their interest in our article.1 in these cases, MRI demonstrates a typical initial involve- Politi and colleagues point out that it is confounding to em- ment of the frontal periventricular white matter that extends phasize metachromatic leukodystrophy (MLD) in the differ- to the corpus callosum and the more posterior white matter ential diagnosis because it could have been ruled out much structures over time.2 In the published images, the initial white sooner from the brain magnetic resonance imaging (MRI) and matter alteration is in the occipital lobe. No clear periventricu- the level of arylsulfatase A (ARSA) activity. lar white matter involvement is identified, and the tigroid First, we agree that the demyelinating process of adult MLD patter that is typical for MLD is not present. To our knowl- usually starts in the frontal white matter and extends to more edge, no case of adult MLD with initial occipital white matter posterior white matter structures over time. However, in late- alterations has ever been described. Further, in patients with infantile MLD, the lesions usually start in the occipital white MLD, the level of ARSA activity is usually less than 6% of nor- matter and are more prominent in the occipital lobes than the mal activity3 and, until recently, no case of a patient with MLD frontal lobes.2 The cause of the different demyelinating pat- with an ARSA activity higher than 10% has ever been terns between adult and late-infantile MLD is not well clari- documented4 (excluding very rare children with saposin-B de- fied. Although the tigroid pattern is a typical sign of MLD, it ficiency). Notably, the level of ARSA activity that was de- presented in about 50% of patients with MLD in a study in- scribed in this patient is typical for a carrier of a disease- cluding 28 patients with MLD.3 Meanwhile, the brain MRI scans causing mutation or a pseudodeficiency allele. The possibility of some patients with MLD are atypical or even without white of a pseudodeficit in patients that present with ARSA activity matter lesions.4 Singh et al4 described a patient with late- reduction in the heterozygote range should always be consid- infantile MLD without white matter involvement on brain MRI. ered, since a pseudodeficiency allele is present in up to 15% In our case report,1 the serial brain MRI scans show a spread- of the population.5 For all the previously mentioned reasons, ing from occipital white matter lesions to confluent white investigations for other causes of leukoencephalopathies matter lesions in the bilateral centrum semiovale and periven-

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