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
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–
–
–
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
Fe
the basal ganglia
– Polyglutamine repeat expansion disorders –
intranuclear inclusions are typically sparse, tend not
to be visible on routine sections.
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 ubiquitinimmunoreactive 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 ubiquitinimmunoreactive inclusions in
adipocytes, sweat glands, and
fibroblasts
• No samples from patients with
other neurologic disorders or
normal control patients showed
intranuclear inclusions
Questions?