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: cairns@mail.med.upenn.edu 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 nonambulatory, 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 23 25 32 38 39 47 48 48 52 56 (years) Duration 5 4 3 3 3.5 3 4 13 2.7 4 (years) Age at death 28 29 35 41 43 50 52 61 54 60 (years) Family N N 1 N N N N N N N N history Presentation Presenting symptom (s) Apathy, dysphasia Left arm weakness Memory, behavior Memory, apathy Memory Cognitive Cognitive impairment Disinhibition, dysphasia, dysarthria Apathy Disinhibition Loss of fine motor dexterity, rigidity of left hand Disinhibition, motor weakness Y Y Y Y Y Y N Y Y Y Memory loss Y Y N Y Y Y Y Y Y Y Language Y Y N Y Y - N Y Y Y deficit Executive - Y - Y Y Y - - Y Y dysfunction Attention - Y Y Y Y - Y Y Y - deficits 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 Y 53 years 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 Y - Y Y Y Y N Y Y - insight Behavioural Y Y N Y Y Y N N Y Y change 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 Flexor Extensor Extensor Flexor Flexor Flexor Asymmetric, - Extensor - reflexes flexor Deep tendon - reflexes Primitive N Y Y Y Y - Y - Y - reflexes 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 Y - to aphonia Extrapyramidal signs N N Y Y Y Y Y Y Y Y Akinetic-rigid N - Y Y Y Y Y Y Y Y disorder 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 N N N N N N N - N N neuron signs Co-ordination - N - N - - - N N - Pupils N N N N N N N N N - Oculomotor N Gaze apraxia Supranuclear Gaze Supranuclear N N Convergence N - abnormalities ophthalmoplegia apraxia ophthalmoplegia palsy, saccadic, slow pursuit Incontinence Y - - - - - Late Y - - Neurodiagnostics CT/MRI F,T Atrophy F F,T F F,T N F,T,S F,T, S F,T Atrophy 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 N - - N - N N N N N gene 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 Other features - Epilepsy at 4 years, rare atrophic muscle fibres Clinical diagnoses Atypical dementia FTD, MND CBD, PLS Pick s disease N - N N N N - - - - Rare atrophic muscle fibres Pollakisuria - Hypothyroidism 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 = 10µm.
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: cairns@mail.med.upenn.edu