Neuronal intranuclear hyaline inclusion disease

Last revised by Dr Daniel J Bell on 03 Dec 2021

Neuronal intranuclear hyaline inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs.

Originally considered as primarily a pediatric disease, neuronal intranuclear hyaline inclusion disease has been increasingly recognized to be a heterogeneous disease with highly variable clinical manifestations, and ante-mortem diagnosis has been difficult. Nevertheless, since the usefulness of skin biopsy and brain MRI for the diagnosis of NIID has been described, the number of NIID diagnoses has increased, in particular adult-onset NIID 4

The clinical presentation of patients with NIHID can be varied and includes 1-3:

  • pyramidal tract signs
  • extrapyramidal signs including parkinsonism
  • abnormal ocular movements and oculogyric crises
  • generalized cognitive degeneration and behavioral changes
  • peripheral neuropathy
    • severe muscle atrophy and weakness
    • sensory impairment in the distal limbs
    • dysphagia
  • autonomic neuropathy
    • episodic intestinal pseudo-obstruction
    • urinary and fecal incontinence
  • cardiomyopathy: reported but uncommon
  • epilepsy: reported but uncommon

The diagnosis can be made using peripheral nerve biopsy (e.g. sural nerve) 1 or myenteric plexus biopsy (e.g. rectal biopsy) 2,3

Neuronal intranuclear hyaline inclusion disease is characterized by accumulation of eosinophilic intranuclear inclusions which can be found widely within both the central and peripheral nervous system including sympathetic and myenteric ganglion neurons, dorsal root ganglion neurons, and spinal motor neurons 1-3

It is believed to be due to abnormal proteolysis, although the exact mechanism has as yet not been established 2,3.

The intranuclear inclusions fluoresce under ultraviolet light and are composed of uniform, fine straight filaments haphazardly arranged 3

Conventional brain MRI findings of patients with neuronal intranuclear hyaline inclusion disease strongly resemble those seen in fragile X-associated tremor/ataxia syndrome (FXTAS), including symmetric white matter involvement in combination with hyperintense changes of the middle cerebellar peduncles 4. Although not invariably present, only NIID typically presents on DWI with highly characteristic band-like and symmetric hyperintense changes of the corticomedullary junctions on DWI 4-6. This imaging feature is considered a strong indicator of NIID, while symmetric high signal changes on T2/FLAIR in the cerebellar hemispheres and along the cerebellar vermis are occasional ancillary findings 7.

Cortical contrast enhancement with corresponding edema and high signal on DWI has been found in a subset of patients with a younger age of onset, shorter duration of disease, and a higher incidence of a headache than those without enhancement. The enhanced lesions were selectively spread along the surface of posterior cortex and were clinically associated with encephalopathy-like episodes 6,8.

NIID is slowly progressive and has no proven therapy. 

Clinically the differential diagnosis includes 3:

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