American Association of Neuropathologists: 2011 Diagnostic Slide Session

1. American Association of Neuropathologists:2011 Diagnostic Slide Session 2011-8 Jeremy Deisch, M.D. Dennis Burns, M.D. Charles White III, M.D.

2. History • 21-year-old female; developmental history normal until… • Age 10 years: tremors and headaches • Age 12 years: dysarthric speech • Age 15 years: muscle biopsy demonstrated chronic neurogenic atrophy; temporal instability, tongue fasiculations, progressive dysarthria, tremors, and cognitive decline were noted • Age 18 years: Bilateral deep brain stimulator placement with temporary alleviation of tremors • Clinical condition progressed to disabling dyskinesia, severe dysphagia, and inability to walk or stand

3. History • Family History: • Maternal great grandmother with tremors, onset in the 7th decade • Maternal grandfather with tremors, onset in the 6th decade • Maternal aunt with mental retardation • Both parents report seizures in past • Because of repeated complications and in agreement between the patient and her family, the gastric feeding tube was removed; death followed shortly thereafter

4. 1150 grams

7. Substantia nigra

8. Substantia nigra

9. Frontal lobe

10. Diagnostic immunostains were performed…

11. Subthalamic nucleus

12. Dentate nucleus

13. Cerebellar cortex

14. Spinal cord, anterior horn

15. Ubiquitin; frontal lobe

16. Ubiquitin; frontal lobe

17. Summary… • Ubiquitin-immunoreactive neuronal intranuclear hyaline inclusions noted in all levels of the neuroaxis • Neocortex • Basal ganglia • Diencephalon • Brainstem • Cerebellum • Spinal cord (anterior horn) • Rare glial, endothelial inclusions noted

18. Diagnosis • Neuronal Intranuclear Hyaline Inclusion Disease (NIHID) • First described in 1980 by Joo Ho Sung et al, University of Minnesota • 21-year-old female patient with neuronal intranuclear inclusions in nearly all neuroanatomic locales (central, peripheral, and autonomic nervous system) • Electron microscopy: inclusions comprised haphazardly-arranged fine filaments measuring 8 to 9 nm

19. NIHID • Approximately 30 cases described in the literature • Slowly-progressive, multiple-system neurodegenerative condition defined pathologically by the finding of eosinophilic, hyaline intranuclear inclusions in neurons in diverse neuroanatomic locations • Heterogenous clinical and pathologic characteristics • Age of onset ranges from 2 to 72 years (mean 22.8 years) • M:F ratio = 1.08 • Variable presence of glial intranuclear inclusions • Variable presentation with personality disturbances, cognitive decline, pyramidal and extrapyramidal motor symptoms, autonomic disturbances

20. NIHID- Categorization • J. Takahashi-Fujigasaki, 2003; Proposed dividing cases into three categories • Infantile form- onset prior to age 5 years, clinical course < 10 years; ataxia, dysarthria, and tremor predominate • Juvenile form- characterized by personality change, pyramidal and extrapyramidal motor disturbances, and cerebellar disturbances; clinical course > 10 years • Adult form- cognitive disturbances predominate; clinical course highly variable (1-14 years). Glial inclusions predominate • Familial cases reported, including examples in identical twins

21. 1C2 (polyglutamine); frontal lobe

22. Polyglutamine and NIHID • Similar to NIHID, CAG repeat expansion disorders (Huntington, DRPLA, SCA1-7) show pathologic neuronal intranuclear inclusions. • Rare neurons in NIHID show 1C2 (polyglutamine) immunoreactive inclusions described by multiple authors • No CAG repeat expansion documented in any known susceptible genes • Some have hypothesized that polyglutamine expansion is occurring in a yet undiscovered gene. • Wild-type ataxin 1, ataxin 2, ataxin 3, and TBP have been demonstrated in NIIs. • Vast minority of nuclear inclusions are 1C2 immunoreactive.

23. Differential Diagnosis • Neuronal intranuclear inclusions • Poliomyelitis – rare, minute • Marinesco bodies – Small ( < nucleolus), SN, LC • Ferritinopathy – Mutation in ferritin light-chain gene gene, similar presentation, granular intranuclear, iron-reactive inclusions primarily in the basal ganglia • Polyglutamine repeat expansion disorders– intranuclear inclusions are typically sparse, tend not to be visible on routine sections. Fe

24. Differential Diagnosis • Fragile-X Dementia-Parkinson Syndrome (FXDPS); Yachnis et al, 2010 • 58-year-old female with rapidly-progressive nonfluent dementia and Parkinsonism • Fragile-X carrier; two sons with fragile-X, one normal daughter • Diffuse, symmetric white-matter attenuation • Astrocytes/glia with prominent ubiquitin-immunoreactive intranuclear inclusions in neocortex, hippocampi, deep gray, cerebellum, and brainstem

25. NIHID- Antemortem Diagnosis • Sone et al, 2011 • 7 patients with NIHID • 27 patients with other neurologic d/o • 8 normal volunteers • 7/7 patients showed ubiquitin-immunoreactive inclusions in adipocytes, sweat glands, and fibroblasts • No samples from patients with other neurologic disorders or normal control patients showed intranuclear inclusions

26. Questions?