Neuronal Intranuclear Inclusion Disease: Longitudinal case report of motor and non-motor symptoms

Abstract

Neuronal Intranuclear Inclusion Disease (NIID) is a rare, neurodegenerative disorder with onset in childhood. We report a single case natural history over 10 years and present a review of juvenile parkinsonism and NIID. Our patient was initially seen at the University of Rochester at age 12 years after four years of progressive dysarthria, dysphagia, and clumsiness. His neurologic examination was notable for parkinsonism. He had excellent initial response to levodopa, but subsequently developed dopa-induced motor fluctuations, dyskinesias, psychosis, and dystonia. Later in the course, he developed multiple non-motor symptoms and ultimately died from respiratory failure. Neuropathology demonstrated large eosinophilic nuclear inclusions and small ubiquitin-related modifier 1 (SUMO-1) immunoreactivity, confirming the diagnosis of NIID. This diagnosis should be considered in a patient presenting with juvenile parkinsonism. Clues to the diagnosis include early-onset dopa-induced dyskinesias, gastrointestinal dysfunction, and oculogyric crises.

Introduction:

Neuronal Intranuclear Inclusion Disease (NIID), also known as Neuronal Intranuclear Hyaline Inclusion Disease, is a rare, neurodegenerative disorder. Although it typically affects children in the first two decades of life, adult-onset disease has also been reported^1–5. Most reported cases of NIID are sporadic but familial cases have occurred^6–9. The disease affects the central, peripheral and autonomic nervous systems; thus, the clinical presentation may vary^2,10–14. Common early symptoms include bulbar dysfunction, cognitive or behavioral changes, and dopa-responsive parkinsonism. The initial motor benefit from levodopa is often followed by increasing motor fluctuations and severe dyskinesias^10–12.

The diagnosis of NIID is made by demonstrating intranuclear inclusions with immunoreactivity to ubiquitin and small ubiquitin-related modifier 1 (SUMO-1)^12,15. Either antemortem diagnosis (via full thickness rectal biopsy)^16,17 or postmortem diagnosis (brain tissue at autopsy) may be done. Limitations to rectal biopsy include pain with the procedure and risk of perforation. Skin biopsy may also be an effective means of antemortem diagnosis⁹.

Although motor symptoms have been described in case reports, non-motor symptoms may also occur and can cause significant impairment. We describe a patient that we followed for over 10 years for juvenile parkinsonism who was ultimately diagnosed with NIID via postmortem analysis. This report provides a longitudinal study of one patient with both significant motor and non-motor symptoms (Figure 1). Written consent for publication of this case and accompanying videos was obtained from the patient’s parents.

Figure 1:

The symptoms and treatments over the patient’s disease course, including symptom onset and initial response to medications (A), progressive decline in motor and non-motor symptoms (B), and eventual symptom stabilization prior to death (C).

Case:

An 11-year-old boy with a history of congenital nystagmus presented to a neurologist with new onset imbalance, limb stiffness, and mood changes (depression and anxiety) in the setting of 3 years of impaired speech articulation (progressing to anarthria) and difficulty chewing food. All initial testing was negative or normal including creatine kinase level, thyroid, Fragile X, and chromosome microarray. Electromyography (EMG) at that time was inconclusive due to poor patient tolerance of the test. By age 12 years old, his symptoms had progressed such that he could not ambulate independently and had increased drooling. A magnetic resonance imaging scan (MRI) of his brain was normal. Further testing was also normal, including alpha fetal protein, pyruvate, lactate, vitamin E, and immunoglobulins. Outside records reported negative testing for Myasthenia Gravis, Wilson’s Disease, and Huntington’s Disease. A brief but insufficient carbidopa/levodopa trial was considered ineffective.

He was referred to the University of Rochester Pediatric Movement Disorders Clinic and his initial neurologic examination was notable for marked parkinsonism with hand tremor, bradykinesia, rigidity, and postural instability. Nystagmus was noted at the time of our first evaluation, but it was reported by parents to be unchanged from birth. Genetic testing for mutations in PARKIN and PINK-1 genes was negative. He was rechallenged with appropriate carbidopa/levodopa doses and had an excellent response initially. Within 3 months, the patient developed dopa-induced dyskinesias (Video 1) that progressively worsened despite addition of amantadine and pramipexole to try to reduce fluctuations. Over time, he achieved improved motor control such that he was able to participate in multiple sports and attend school. At age 13 years, he underwent psychoeducational testing that revealed a full scale IQ of 95 on the WISC-IV. At age 15 years, he started the rotigotine dermal patch and had excellent motor control; however, it was recalled by the FDA later that year and his motor fluctuations worsened off of the patch. In addition to progressive motor symptoms, he developed chronic constipation. He had increasing school absences due to poor motor control; ropinirole treatment was initiated. He had a clear deterioration around age 16 years. Motor symptoms included worse motor fluctuations with prolonged off periods in the morning (Video 2), severe left foot dystonia (Figure 2), impaired mobility with frequent falls, and development of REM sleep disorder.

Figure 2:

Picture of patient’s foot dystonia. Motor fluctuations were also characterized by periods of painful foot dystonia secondary to off-periods.

Non-motor symptoms included orthostatic hypotension (contributing to falls), impaired impulse control, poor mood (social isolation and ongoing depression), obsessiveness, significant fatigue, heat and cold intolerance, swallowing difficulties, and hallucinations. He also had new-onset seizures with an electroencephalogram (EEG) revealing generalized spike-wave discharges. He did have a period of excessive energy and visual hallucinations, but these improved with reduction of pramipexole. By 17 years old, there was a steady cognitive and behavioral decline. A Montreal Cognitive Assessment completed in the office revealed a score of 15/30 (Figure 3). Increasing impulsivity and significant hallucinations resulted in a hospital admission. Both symptoms improved with discontinuation of pramipexole and amantadine and introduction of quetiapine. His swallowing function declined and a G-tube was placed. Motor symptom control improved with reintroduction of the rotigotine dermal patch although he suffered from increased dyskinesias on higher doses. At age 18 years, carbidopa/levodopa was discontinued and he was maintained on rotigotine as his only dopamimetic. This resulted in stabilization of the motor symptoms. By age 21 years, he began to have recurrent episodes of aspiration pneumonia, and he ultimately died at age 22 years from respiratory failure.

Figure 3:

Drawing samples from the patient’s Montreal Cognitive Assessment (MoCA) done when he was 16 years old. (A) Cube drawing. (B) Clock drawing. He was asked to draw the clock at ”10 past 11 o’clock.”

While the patient was alive, the option of pursuing a full thickness rectal biopsy to evaluate for NIID was proposed. Since there are no known treatments for the condition, the family opted to not pursue this testing due to risks inherent to the procedure. The family agreed to an autopsy.

At autopsy, the whole brain was removed and the fixed brain weighed 1050 grams. Grossly, there was no notable atrophy in the hemispheres, cerebellum or brainstem. There were no focal lesions. There was moderate depigmentation of the substantia nigra and the locus ceruleus. Microscopically, numerous large eosinophilic intranuclear inclusions were found in the mesencephalon, pons (specifically, the locus ceruleus), and the inferior olivary complex (Figure 4). Fewer inclusions were seen in the frontal cortex, caudate, putamen, hippocampus, subthalamic nuclei and cerebellum. The inclusions demonstrated ubiquitin immunoreactivity. No Lewy bodies or alpha synuclein immunoreactive inclusions were seen. Subsequently, SUMO-1 staining also showed immunoreactivity, further supporting the diagnosis of NIID.

Figure 4:

Neuropathology confirms diagnosis of NIID A-C: Hematoxylin and eosin stained sections of inferior olivary complex (A), tectum (B) and putamen (C) in postmortem analysis of the patient. Slides show eosinophilic inclusion bodies characteristic of NIID (indicated by yellow arrows). D: SUMO-1 staining (magnified to 1000x, hematoxylin counter stain) shows immunoreactivity (indicated by arrow) in mesencephalon Abcam 1:1000 dilution).

Discussion:

NIID is a rare disorder and fewer than 40 cases have been reported to date. Motor symptoms that have been reported include parkinsonism, cerebellar ataxia, chorea, dystonia, nystagmus, and pyramidal signs. Our patient had parkinsonism with significant motor fluctuations and dopa-induced dyskinesias and dystonia. Oculogyric crises have been reported in several cases of NIID^10,12 and may be a hallmark of the disease. Interestingly, our patient did not have this symptom but did have congenital nystagmus, which we thought was unrelated to his underlying disease.

Parkinsonism was the predominant motor symptom in our patient and has been commonly reported in other children with juvenile-onset disease^11,18,19. The differential diagnosis for juvenile parkinsonism is quite broad and includes PARK gene disorders (ie PARK2, PARK6 or PINK1 early-onset), dopa-responsive dystonia, Wilson’s Disease, Juvenile Huntington’s Disease, Neurodegeneration with Brain Iron Accumulation, the Neuronal Ceroid Lipofuscinoses, metabolic disorders, space occupying lesions, and autoimmune disease (Figure 5). Like dopa-responsive dystonia, NIID tends to have an asymmetrical onset and shows initial levodopa responsiveness, as was seen in our patient. However, the NIID course also involves oromotor symptoms, autonomic disturbances, and cognitive regression with a relentlessly downhill course.

Figure 5:

Algorithm for the diagnosis of Juvenile Parkinsonism.

Non-motor symptoms that have been reported in NIID include cognitive stagnation or decline, seizures, peripheral neuropathy, autonomic instability and labile mood¹⁰. Our patient had a number of non-motor symptoms: autonomic dysfunction (chronic constipation and orthostatic hypotension), cognitive decline, depression, obsessiveness, REM sleep disorder, and seizures. His hallucinations and impulse control disorder were likely related to his dopamine therapy, and these symptoms limited our ability to treat his significant motor impairment.

A diagnosis of NIID should be considered in a patient presenting with juvenile parkinsonism, particularly if the symptoms are asymmetric in onset with initial response to levodopa therapy. Clues to the diagnosis include early-onset dopa-induced dyskinesias, slowed gut motility, and oculogyric crises. Although motor symptoms are commonly reported, this case highlights the importance of assessing for non-motor symptoms as well. These symptoms can complicate the disease course and cause significant morbidity and dysfunction.

Supplementary Material

Supp 1

Video 1: The patient experienced dopa-induced dyskinesias that were difficult to control.

Supp 2

Video 2: Over time, the patient had worsened motor fluctuations. He was particularly bothered by prolonged early morning off periods characterized by significant bradykinesia and rigidity.