Title: Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease (nifid)

Neurology/2004/048785 

 

Title: Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease (NIFID)  

 

Correspondence to:  

Nigel J. Cairns PhD MRCPath 

Center for Neurodegenerative Disease Research 

Department of Pathology and Laboratory Medicine 

University of Pennsylvania School of Medicine 

Maloney 3, HUP, 3600 Spruce Street 

Philadelphia 

PA 19104-4283 

USA 

E-mail:  

[e-mail]

 

 

 

 

Supplementary data 

 

Results 

 

Vignettes 

 

Vignette (E)V-1.  

  

Patient 1  

This 28-year-old woman presented at the age of 23 with lack of awareness and increasing disinterest. One year later there was 

increasing anxiety, psychotic symptoms, dysphasia and six months later aphasia. Structural neuroimaging (CT and MRI) at age 24 

revealed no abnormalities. At age 26 she was non-communicative and required constant nursing care. Deep tendon reflexes were 

symmetrically exaggerated; the plantar responses were normal. Ophthalmologic examination did not reveal any pathology. MRI 

revealed cortical and central atrophy, and EEG was normal. A muscle biopsy showed type II atrophy, no ragged red fibres, and normal 

enzyme activity. Electromyography was normal. Bedridden and mute, the patient died of bronchopneumonia aged 28 years. This 

woman was given the clinical diagnosis of atypical dementia. 

Vignette (E)V-2. 

Patient 2  

This 29-year-old woman developed speech difficulties at age 25 with impairments in both verbal comprehension and fluency. 

She demonstrated inappropriate behaviour, impaired judgement and poor short-term memory. She became apathetic and abulic and 

was unable to care for her family.  Prior neurological history was notable for complex partial seizures at the age of 4 years which had 

been well controlled with phenytoin and phenobarbital, and she had been seizure-free since the age 10 years. By age 26, the patient 

had developed proximal weakness and difficulty with balance. At age 27 years, she was unable to communicate due to spastic 

dysarthria. There was impaired comprehension of spoken language and perseveration. There were prominent snout, suck, 

palmomental and grasp reflexes, and gaze apraxia. Gag reflex was intact. Motor examination disclosed spasticity and mild weakness 

of the extremities. There was no muscle atrophy, fasciculations, or other movement abnormalities. Deep tendon reflexes were brisk. 

Gait was broad-based, but coordination was normal. Swallowing was abnormal and there was a weight loss of 10 kg.  MRI at 

presentation, EEG, and CSF were normal. The clinical impression was FTD with MND affecting upper motor neurons.  

Vignette (E)V-5. 

Patient 5 

A 39 year-old right-handed male mechanic in previously good health became indifferent and isolated. Depression was 

diagnosed and treated, but without success. Dysarthria developed as well as some swallowing difficulties. Tendon reflexes were brisk 

and a pyramidal syndrome of the four limbs was recorded. There was a pseudobulbar palsy with uncontrollable crying or laughing, 

and a supranuclear palsy (both for horizontal and vertical eye movements). An extrapyramidal syndrome was observed with 

generalised akinesia, amimia, a defect in the initiation of voluntary movements, bradykinesia, rigidity of the gegenhalten type, and 

postural instability. Reflexes of the facial muscles were brisk and a palmomental reflex was elicited. There was no evidence of motor 

neuron disease.  Neuropsychological testing at age 42 years revealed a Mini-Mental State Examination (MMSE) score of 13/30, 

executive dysfunction, dyscalculia, loss of oral language, and defects in several cognitive domains (Mattis scale: attention: 13/37, 

initiation: 6/37, construction: 0/6, concepts: 12/39, and memory: 16/25). A PET scan revealed hypometabolism in the frontal cortex. A 

brain biopsy was performed and no prion protein deposits were seen but novel variably ubiquitin-positive, tau-negative inclusions 

were identified. He died three and a half years after the onset of disease at age 43 years.  The symptoms were consistent with a 

diagnosis of FTD.  

Vignette (E)V-6. 

Patient 6  

This man presented at age 47 with behavioral changes consisting of impulsivity, aggressiveness, and a failure of to perform his 

usual household chores. He subsequently developed short term memory loss, anxiety and psychosis. Examination at age 49 revealed 

parkinsonism, rigidity, primitive reflexes and normal deep tendon reflexes and plantar responses.  Initial MRI examination was normal 

but at age 49, MRI showed moderate atrophy of the frontal and temporal lobes. He died at age 50 of respiratory complications and was 

thought to have had FTD.  

Vignette (E)V-7. 

 

Patient 7  

This 52-year-old man developed gradual loss of function in his left arm at age 48 years. In addition to bradykinesia, he had loss of fine 

motor dexterity in the digits and eventually the hand.  He later developed left hemidystonia. Within two years, the syndrome had 

become bilateral with loss of fine and gross motor dexterity, as well as severe truncal and appendicular paratonic rigidity with 

hyperactive reflexes and flexor plantar responses. By the third year, he developed progressive pseudobulbar palsy with hypophonia 

and dysphagia which eventually led to aspiration pneumonia. Cognitively he remained intact until the last six months of life when he 

began to develop mild frontal cognitive dysfunction without dementia; specifically, neuropsychological testing at that time revealed 

that his attention, mental control and memory, particularly acquisition of new information in memory, were below expectation.  

Peripheral nerves, sensation, and autonomic function remained intact. There was no clinical or EMG evidence of lower motor neuron 

disease.  Neuroimaging (MRI) was normal. A clinical diagnosis of primary lateral sclerosis was made.

  

Vignette (E)V-8. 

 

Patient 8  

This man presented with short-term memory deficits, fine motor deficits and urinary frequency at age 48 years. He became 

sensitive to small sounds which made him cry easily. Voluntary speech and verbal fluency were impaired. He was aware of his 

decline. Neurological examination revealed “slight dementia”, loss of postural stability, pseudobulbar paralysis and bilateral 

pyramidal and extrapyramidal signs. Neurological status declined rapidly during the first 2 years and ultimately he was rendered non-

ambulatory, mute and indifferent to visitors He received artificial alimentation and respiratory support until death at age 61.  He had 

been diagnosed with Pick’s disease.  

 

 

Vignette (E)V-9. 

Patient 9  

This woman presented with apathy, memory loss, agnosia, and functional decline at age 52 years. There was progressive 

deterioration with inattentiveness, disorientation, dyspraxia, dysphasia, impaired insight, perseveration, mutism and increased sleep. 

At age 53 years, neuropsychological testing documented agitation, apathy, concrete thinking, neologisms, perseveration and 

impairments on tests of attention, verbal and visual memory, digit span, spelling and arithmetic with normal psychomotor speed.  

MMSE score was 14/30. Neurological examination revealed extrapyramidal signs including bradykinesia, facial hypomimea, rigidity, 

and reduced arm swing, primitive reflexes and increased tendon reflexes later in the disease. There was no evidence of anterior horn 

cell disease. MRI revealed bilateral symmetrical cerebral atrophy, and marked atrophy of the caudate nucleus and putamen. Functional 

imaging with SPECT showed hypoperfusion of the left frontal lobe and both parietal lobes. The clinical diagnosis was FTD.  

Vignette (E)V-10. 

 

Patient 10 

 

This 60-year-old man presented with progressive impairments in thinking and memory since age 56 years. He subsequently 

became depressed, hyperphagic, hypersomnolent, obsessive-compulsive, apathetic, sluggish and confused and exhibited mutism with 

occasional, inaudible mumbling speech. He required assistance in basic activities of daily living. He was treated with various 

antidepressant and antipsychotic medications as well as electroconvulsive therapy. Neurological examination revealed parkinsonian 

bradykinesia with statue-like posture, mask-like facies, and hypophonia. MRI showed cerebral and hippocampal atrophy and 

ventricular enlargement. Functional imaging with SPECT showed bilateral reduction in frontal lobe blood flow, greater on the left, 

compatible with Pick’s disease. Six months before death, the patient was able to walk but wandered with fixed stare and was mute. 

The diagnostic impression was severe FTD with mild parkinsonism.  

 

Table (E)T-1. Clinical features 

Variable Patient 

1 

 

Patient 2  

Patient 3 

 

Patient 4 

 

Patient 5 

 

Patient 6 

 

Patient 7 

Patient 8  

 

Patient 9 

Patient 10 

Demographic features 

Gender F F  M  F  M  M M  M F 

M 

Age at onset 

(years) 

23 25 

32  38  39  47  48  48 52 56 

Duration 

(years) 

5 4 

3  3  3.5  3  4  13 

2.7 

4 

Age at death 

(years) 

28 29 

35  41  43  50  52  61 54 60 

Family 

history 

N N

1

 N 

N 

N N 

N N 

N 

N 

Presentation 

Presenting 

symptom (s) 

 

Apathy, 

dysphasia 

Disinhibition, 

dysphasia, 

dysarthria 

Left arm 

weakness 

Memory, 

behavior 

Apathy 

Disinhibition 

Loss of fine 

motor 

dexterity, 

rigidity of left 

hand 

Disinhibition, 

motor 

weakness 

Memory, 

apathy 

Memory 

Cognitive 

Cognitive 

impairment 

Y Y 

Y  Y  Y  Y  N  Y Y Y 

Memory loss  

Y 

Y 

N 

Y 

Y 

Y 

Y 

Y 

Y 

Y 

Language 

deficit 

Y Y 

N  Y  Y 

-  N  Y Y Y 

Executive 

dysfunction 

- Y 

-  Y  Y  Y  -  - Y Y 

Attention 

deficits 

- Y 

Y  Y  Y  -  Y  Y Y - 

Disorientation - 

- 

N 

Y 

Y 

Y 

N 

- 

Y 

- 

Dyspraxia -  Y 

Y 

Y 

Y 

Y 

N 

Y  Y  - 

Dementia 

Y 

Y 

29/30 at age 33 

Y 

13/30 at 41 years 

Y 

Mild 

Y 

8/30 at 

53 years 

Y 

Mutism Y Y 

Y  Y  Y  Y  N  Y Y Y 

Psychiatry 

Frontal lobe 

signs 

Y Y 

Y  Y  Y  Y  N  Y Y Y 

Psychotic Y  - 

N 

N 

N 

Y  N 

N  N  N 

signs 

Depression N 

- 

Y 

Y 

Y 

N 

Y 

Y  N  Y 

Anxiety Y  - 

-  -  - 

Y  N  N - - 

Loss of 

insight 

Y - 

Y  Y  Y  Y  N  Y Y - 

Behavioural 

change 

Y Y 

N  Y  Y  Y  N  N Y Y 

Hyperorality N 

N 

N 

N 

Y 

- 

N 

N 

N 

Y 

Altered eating 

N 

Weight loss 

N 

N 

Y 

- 

N 

N 

N 

Y 

Neurology 

Pyramidal 

signs 

Y Y 

Y  Y  Y  Y  -  Y Y - 

Plantar 

reflexes 

Flexor Extensor  Extensor  Flexor Flexor  Flexor Asymmetric, 

flexor 

- Extensor - 

Deep tendon 

reflexes 

↑ 

↑ 

↑ 

↑ 

↑ 

↑ 

↑ 

↑ 

↑ - 

Primitive 

reflexes 

N Y 

Y  Y  Y 

-  Y  - Y - 

Glabella  

- 

Y 

- 

Y 

Y 

- 

N 

Y 

Y 

- 

Palmomental - 

Y 

Y 

Y 

Y 

- 

N 

Y 

Y 

- 

Pout - 

Y Y 

Y 

Y - 

N 

- 

Y 

- 

Gag - 

Y - 

Brisk 

Y - 

Hyperactive 

- 

- 

- 

Dysphagia N  Y 

Y 

Y 

Y 

- 

Y 

Y  Y  Y 

Dysarthria -  Y 

Y 

- 

Y 

- 

Y, 

progressed 

to aphonia 

Y -   

Extra-

pyramidal 

signs 

N N 

Y  Y  Y  Y  Y  Y Y Y 

Akinetic-rigid 

disorder 

N - 

Y  Y  Y  Y  Y  Y Y Y 

Cogwheeling N 

- 

N 

N 

N 

- 

Y 

N 

N 

- 

Tremor N - 

N  N  N  -  N  N N - 

Bradykinesia N 

- 

Y 

Y 

Y 

Y 

Y 

Y 

Y 

Y 

Myoclonus Y 

- 

N 

N 

N 

N 

N 

N  N  - 

Dystonia -  - 

- 

- 

- 

- Left 

arm 

dystonia 

- - - 

Orofacial  

N 

Y 

Amimia 

Amimia 

Amimia 

Amimia 

Hypomimia 

Amimia 

Amimia 

Y 

Sialorrhoea N 

- 

Y 

Y 

Y 

- 

Y 

- 

Y 

- 

Gait - 

Broad-based 

Reduced 

arm 

swing 

Stooped, 

reduced 

Stooped - 

Reduced 

arm 

swing 

Stooped, 

elbow flexion 

Reduced 

arm 

- 

arm swing 

swing 

Other neurologic signs 

Lower motor 

neuron signs 

N N 

N  N  N  N  N  - N N 

Co-ordination - 

N 

- 

N 

- 

- 

- 

N 

N 

- 

Pupils N 

N  N N N  N N N 

N 

- 

Oculomotor 

abnormalities 

N Gaze 

apraxia 

Supranuclear 

ophthalmoplegia 

Gaze 

apraxia 

Supranuclear 

ophthalmoplegia 

N N 

Convergence 

palsy, 

saccadic, slow 

pursuit 

N - 

Incontinence Y 

- 

- 

- 

- 

- 

Late 

Y 

- 

- 

Neurodiagnostics 

CT/MRI 

Atrophy  

F,T Atrophy 

F 

F,T 

F 

F,T 

N 

F,T,S F,T, 

S F,T 

PET/SPECT - 

- 

- 

- 

F 

↓  

- 

S ↓ - 

Left 

F, 

bi-P ↓ 

- 

EEG N 

N N 

N 

N N 

N 

N 

N 

- 

EMG N 

Mild 

myopathy 

N N N  - N  - 

N 

- 

Other investigations 

CSF N 

N N 

N 

N 

Protein 

↑ N 

N  N  N 

HIV N 

N N 

N 

N N 

N 

N 

N 

N 

Huntington 

gene  

N - 

-  N  -  N  N  N N N 

Hypertension N 

N 

N 

N 

N 

N 

N 

N 

N 

N 

Blood 

investigations 

N N 

N  N  N  N  N Hepatic 

transaminase 

↑ 

N N 

Recreational 

substances 

N N 

N 

Cigarettes 

5/day, 

alcohol 2 

units/day 

N - 

N N 

N 

N 

Other features 

- 

Epilepsy at 4 

years, rare 

atrophic 

muscle fibres 

- - -  - 

Rare 

atrophic 

muscle fibres 

Pollakisuria -  Hypo-

thyroidism 

Clinical 

diagnoses 

Atypical 

dementia 

FTD, MND 

CBD, PLS 

Pick’s 

disease 

FTD 

FTD 

PLS 

Pick’s disease 

FTD 

FTD + 

parkinsonism 

1

A weak family history of late-onset dementia was recorded, the patient’s grandmother had depression and a third cousin had childhood onset neuronal ceroid lipofuscinosis. Y = 

present; N = absent;  - = not available; ↑ = increase; ↓ = decrease; F = frontal lobe; T = temporal lobe;  S = striatum;  FTD = frontotemporal dementia; MND = motor neuron 

disease; CBD = corticobasal degeneration; PLS = primary lateral sclerosis. 

 

Figures 

  

Figure (E)F-1.  Inclusions in subcortical, brainstem and cerebellar nuclei in NIFID. Neuronal IF inclusions in the medial dorsal 

nucleus of the thalamus (a), inferior olivary nucleus of the medulla oblongata (b), and a  spherical inclusion in a neuron of the dentate 

nucleus in the cerebellum. 

α-Internexin immunohistochemistry. Scale bar = 10µm. 

 

Figure (E)F-2.  Axonal degeneration and neuronal inclusions in the spinal cord in NIFID. (a) There is myelin pallor of the lateral 

columns (arrows) in comparison to the dorsal columns (arrowhead) in the cervical spinal cord of a case of NIFID. (periodic acid-

Schiff and luxol fast blue). (b) Normal motor neurons, a pyknotic neuron (arrow), and axonal spheroids (arrowheads) are present in 

the anterior horn of the spinal cord. Neurofilament (RMO 24) immunohistochemistry. (c) Inclusions containing epitopes of 

α-

internexin are present within neurons of the central grey matter of the spinal cord. 

α-Internexin immunohistochemistry.  (d) A Bunina 

body in a motor neuron of the spinal cord. Cystatin C immunohistochemistry.  (a) Scale bar = 1mm; (b-d) scale bar = 10

µm. 

 

Correspondence to:  

Nigel J. Cairns PhD MRCPath 

Center for Neurodegenerative Disease Research 

Department of Pathology and Laboratory Medicine 

University of Pennsylvania School of Medicine 

Maloney 3, HUP, 3600 Spruce Street 

Philadelphia 

PA 19104-4283 

USA 

E-mail:  

[e-mail]