American Association of Neuropathologists:

2011 Diagnostic Slide Session

2011-8

Jeremy Deisch, M.D.Dennis Burns, M.D.Charles White III, M.D.

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

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

1150 grams

Substantia nigra

Substantia nigra

Frontal lobe

Diagnostic immunostains were performed…

Subthalamic nucleus

Dentate nucleus

Cerebellar cortex

Spinal cord, anterior horn

Ubiquitin; frontal lobe

Ubiquitin; frontal lobe

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

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

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

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

1C2 (polyglutamine); frontal lobe

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.

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

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

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

Questions?