Learning Objectives

After completing this exercise, the reader should be able to:

1. Recognize autonomic dysfunction as a possible presenting manifestation of neuronal intranuclear inclusion disease (NIID).
2. Develop a differential diagnosis for chronic urinary retention with overflow incontinence.
3. Appreciate the diagnostic importance of characteristic MRI findings in NIID.
4. Understand the role and limitations of genetic testing.
5. Recognize the value of multidisciplinary thinking when symptoms do not fit common diagnoses.

Case Presentation

A man in his early seventies presented with an 8-year history of nocturnal urinary incontinence and a 4-year history of gradually progressive memory decline.

Initially, his symptoms consisted of:

• Frequent urination
• Urgency
• Overflow incontinence during sleep
• Sexual dysfunction

Daytime voiding remained relatively preserved.

Because of lower urinary tract symptoms and prostatic enlargement, he was diagnosed with benign prostatic hyperplasia and underwent transurethral resection of the prostate. Despite surgery, urinary symptoms persisted.

Four years later, family members noted:

• Progressive short-term memory loss
• Slowed responses
• Disorientation
• One episode of getting lost outdoors

There was no tremor, gait disturbance, dysarthria, or parkinsonism.

Teaching Pause 1

At this stage, what diagnoses should be considered?

Differential Diagnosis

Urologic disorders

• Benign prostatic hyperplasia
• Detrusor underactivity
• Neurogenic bladder

Neurodegenerative disorders

• Multiple system atrophy
• Parkinson disease
• Dementia with Lewy bodies
• Alzheimer disease
• Neuronal intranuclear inclusion disease

Structural spinal cord disorders

• Cervical myelopathy
• Cauda equina syndrome

Peripheral neuropathies

• Diabetic autonomic neuropathy
• Amyloidosis

Other causes

• Medication effects
• Normal-pressure hydrocephalus

Neurologic Examination

Examination showed:

• Intact cranial nerves
• Normal strength
• Normal sensation
• Preserved reflexes
• Mild dysmetria
• No pyramidal signs
• No parkinsonism
• No gait ataxia

Cognitive testing demonstrated:

• MMSE 24
• MoCA 16 (education-adjusted)

Orthostatic vital signs were normal.

Teaching Pause 2

The combination of:

• Autonomic dysfunction
• Cognitive impairment
• Mild cerebellar signs

suggests a neurodegenerative process rather than isolated urologic disease.

Which investigations are most likely to help?

Additional Studies

Routine laboratory testing was unrevealing.

Electrodiagnostic studies demonstrated subclinical mixed sensorimotor axonal polyneuropathy affecting all four limbs. Clinically, however, strength and sensation remained normal.

CT urography showed:

• Bladder wall thickening
• Multiple diverticula
• Bilateral hydronephrosis
• Enlarged prostate

suggesting neurogenic bladder.

Bladder ultrasound revealed a postvoid residual volume of 375 mL.

Teaching Pause 3

Severe urinary retention with hydronephrosis raises concern for significant autonomic dysfunction.

What imaging finding might point toward a specific diagnosis?

Brain MRI

Diffusion-weighted imaging demonstrated diffuse high-signal abnormalities along the corticomedullary junction involving:

• Frontal lobes
• Temporal lobes
• Parietal lobes
• Occipital lobes

with accompanying cerebral atrophy.

This characteristic appearance—the "lace sign"—is highly suggestive of adult-onset NIID.

Clinical Reasoning

At this point, the syndrome consists of:

Cognitive dysfunction

• Progressive memory impairment

Autonomic dysfunction

• Neurogenic bladder
• Overflow incontinence

Peripheral nervous system involvement

• Subclinical axonal neuropathy

Characteristic MRI abnormalities

Together, these findings strongly suggest neuronal intranuclear inclusion disease.

Teaching Pause 4

Would whole exome sequencing establish the diagnosis?

Surprisingly, no.

Whole-exome sequencing was negative.

Because NIID is caused by GGC repeat expansion in the 5′ untranslated region of NOTCH2NLC, repeat-primed PCR and amplicon-length PCR were subsequently performed.

These demonstrated:

115 GGC repeats in NOTCH2NLC

confirming NOTCH2NLC-associated NIID.

Family Screening

Further testing showed identical repeat expansions in:

• Two daughters
• One grandson

revealing previously unrecognized familial NIID.

The case initially appeared sporadic, but genetic evaluation demonstrated autosomal dominant inheritance.

Final Diagnosis

Familial neuronal intranuclear inclusion disease (NIID)

caused by a NOTCH2NLC GGC repeat expansion presenting initially as neurogenic bladder with overflow urinary incontinence.

Why Was the Diagnosis Missed?

Several factors contributed:

Anchoring bias

The enlarged prostate led clinicians to attribute symptoms solely to benign prostatic hyperplasia.

Specialty silos

Symptoms were initially viewed through a urologic rather than neurologic framework.

Delayed cognitive manifestations

Memory impairment appeared four years after urinary symptoms.

Disease rarity

NIID remains unfamiliar to many clinicians.

Negative exome sequencing

Standard sequencing methods may miss repeat expansions.

Pathophysiology

Urinary dysfunction in NIID probably results from combined involvement of:

Central pathways

• Cortex
• Basal ganglia
• Brainstem micturition centers

and

Peripheral autonomic nerves

leading to detrusor dysfunction and sphincter imbalance.

Management

No disease-modifying therapy currently exists.

The patient received:

• Donepezil
• Finasteride
• Tamsulosin
• Acupuncture

without significant improvement.

Future therapies under investigation include:

• RNA interference
• Antisense oligonucleotides
• CRISPR-based approaches

Teaching Pearls

Pearl 1

Urinary symptoms may precede neurologic manifestations of NIID by many years.

Pearl 2

Persistent urinary dysfunction despite prostate surgery should prompt reconsideration of the diagnosis.

Pearl 3

Subclinical peripheral neuropathy is common in NIID.

Pearl 4

The corticomedullary DWI "lace sign" is one of the most valuable clues to diagnosis.

Pearl 5

Negative whole-exome sequencing does not exclude repeat expansion disorders.

Pearl 6

Targeted NOTCH2NLC testing should be considered when NIID is suspected.

Clinical Pitfalls

• Assuming all urinary retention in elderly men is due to BPH.
• Missing subtle cognitive decline.
• Failing to obtain brain MRI.
• Overreliance on whole-exome sequencing.
• Not considering repeat expansion disorders.

Board-Style Questions

Question 1

An elderly patient develops years of unexplained urinary retention followed by cognitive decline. MRI demonstrates corticomedullary junction hyperintensity on diffusion-weighted imaging. Which diagnosis is most likely?

A. Multiple system atrophy
B. Alzheimer disease
C. Neuronal intranuclear inclusion disease
D. Progressive supranuclear palsy
E. Normal-pressure hydrocephalus

Answer

C. Neuronal intranuclear inclusion disease

Explanation: The "lace sign" on DWI together with autonomic dysfunction and cognitive impairment is highly characteristic of NIID.

Question 2

Which genetic abnormality causes most adult-onset NIID?

A. C9orf72 expansion
B. NOTCH2NLC GGC repeat expansion
C. HTT CAG repeat expansion
D. SNCA duplication
E. MAPT mutation

Answer

B. NOTCH2NLC GGC repeat expansion

Explanation: Expansion of GGC repeats in the 5′ untranslated region of NOTCH2NLC is the major genetic cause of NIID.

Question 3

Which MRI finding is most characteristic of NIID?

A. Dawson fingers
B. Midbrain hummingbird sign
C. Lace sign at the corticomedullary junction
D. Pulvinar sign
E. Hot-cross-bun sign

Answer

C. Lace sign at the corticomedullary junction

Explanation: Curvilinear DWI hyperintensity at the corticomedullary junction is a classic radiographic hallmark.

Question 4

Which test may fail to detect NIID?

A. Repeat-primed PCR
B. Amplicon-length PCR
C. Targeted NOTCH2NLC analysis
D. Whole-exome sequencing
E. Skin biopsy

Answer

D. Whole-exome sequencing

Explanation: Standard WES may not adequately evaluate repeat expansions within noncoding regions.

Question 5

The most important lesson from this case is:

A. Prostate enlargement always explains urinary retention.
B. NIID should only be considered after gait impairment develops.
C. Autonomic dysfunction can be the earliest manifestation of NIID.
D. Whole-exome sequencing excludes repeat expansion disorders.
E. Peripheral neuropathy is uncommon in NIID.

Answer

C. Autonomic dysfunction can be the earliest manifestation of NIID.

Explanation: This case demonstrated isolated overflow incontinence for eight years before the diagnosis of NIID, emphasizing the need to recognize autonomic symptoms as an early manifestation.

Take-Home Message

When urinary dysfunction appears disproportionate to urologic disease, especially when accompanied by cognitive decline or subtle neurologic findings, clinicians should broaden the differential beyond the genitourinary tract. In NIID, autonomic symptoms may precede overt neurologic manifestations by years, and the combination of the MRI "lace sign" with targeted NOTCH2NLC testing can establish the diagnosis long before the full syndrome becomes apparent.