Primary Psychiatry. 2003;10(8):74-76
Dr. Malhotra is clinical assistant professor of psychiatry at the University of Medicine and Dentistry of New Jersey (UMDNJ) in Newark, NJ, and an attending in the Department of Psychiatry at Overlook Hospital in Summit, New Jersey. Dr. Isenberg is a specialist in behavioral neurology and neuropsychiatry in the New Jersey Neuroscience Institute at JFK Medical Center in Edison. Dr. Barash is co-principal investigator in the Department of Microbiology and Microbial Genetics at UMDNJ.
Disclosure: Dr. Malhotra is on the speaker’s bureau of AstraZeneca, Eli Lilly, and Bristol-Myers Squibb; Dr. Isenberg is on the speaker’s bureau of Janssen, Novartis, and Pfizer.
Please direct all correspondence to: Harish K. Malhotra, MD, Department of Psychiatry, Overlook Hospital, 33 Overlook Rd, Suite 212, Summit, NJ 07901; Tel: 908-273-6164; Fax: 908-277-1439; E-mail: email@example.com
• It is recommended that whenever there are associated soft neurological symptoms and signs in a case of psychosis, medical causes should be considered in the etiology of the presenting psychosis.
• Longitudinal progression of a psychosis can uncover previously hidden aspects of the disease.
• Neurodegenerative disorders may become evident as psychiatric syndromes at different stages of life.
Niemann-Pick disease is a neurometabolic genetic disorder. Types A and B reflect a primary and severe acid sphingomyelinase (ASM) deficiency. The ASM enzyme is ordinarily found in lysosomes and is required to metabolize the lipid, sphingomyelin. If ASM is absent or not functioning properly, sphingomyelin cannot be metabolized properly and is accumulated within the cell, eventually causing cell death and the malfunction of major organ systems. Niemann-Pick type A (neurovisceral) is a severe neurological disease in infants, which generally leads to death by 2–3 years of age. Infants with Niemann-Pick disease type A have extremely low levels of ASM (generally <5% of normal). Niemann-Pick disease type B (visceral) generally has little or no neurological involvement and patients may survive into adulthood. Type B has higher levels of ASM (perhaps 10% to 60% of normal). Type A and B are both diagnosed by measuring the ASM activity in white blood cells.
Niemann-Pick disease type C (NPC) is a lipid storage disease that can present in infants, children, or adults. The classic presentation occurs in middle to late childhood with the insidious onset of ataxia, vertical supranuclear gaze palsy (VSGP), dementia, and liver and lung failure. Dystonia and seizures are common. Dysarthria and dysphagia become disabling, making oral feeding impossible. Types C and D are characterized by secondary and variable sphingomyelinase alterations.1-8 The diagnosis of NPC is assay for the deficiency, which shows impaired ability of cultured fibroblasts to esterify exogenously supplied cholesterol, and positive filipin staining. Types C1 and D are indistinguishable except for the occurrence of type D in patients of Nova Scotian Acadian ancestry.
Symptoms mimicking schizophrenia can present in many conditions.4 We describe a patient who carried a diagnosis of schizophrenia for 14 years requiring psychiatric hospitalizations. He was subsequently diagnosed with NPC. The characteristic features of adult-onset NPC and the obstacles to early diagnosis are presented here.
J.S., a single caucasian male, was 32 years of age in 1999 when his case was reviewed. His psychiatric history dated back to 18 years of age. J.S. had been diagnosed as learning disabled and perceptually impaired, and had completed high school through special classes. At the onset of his illness, J.S. believed that people were changing into bears, dancing around him, and trying to scare him. From July 1996 through August 1997, he was hospitalized for psychiatric treatment three times. During those hospitalizations J.S. presented with bruises on his face, mumbling, and an inability to explain what happened to him. J.S. was casually attired, disheveled, nonspontaneous, incoherent, loud, and threatening. His speech was described as irrelevant. His mood was anxious and his affect was constricted. His behavior was destructive and required seclusion. J.S. showed grossly impaired judgment, loose association, tangential thinking, and no insight. He was unable to give goal-oriented answers. J.S. admitted to “buzzing noises” in his ears. His sensorium was clear, but he was unable to name recent or past dates. He showed no signs of suicidal or homicidal ideas.
During another hospital admission J.S. was described as having auditory hallucinations, paranoid delusions, low frustration toleration, intrusiveness, poor speech communication, and difficulty following directions. J.S. was evaluated by a speech therapist and was found to have dysarthric speech. During that hospitalization, J.S. was diagnosed as having schizophrenia chronic undifferentiated type, polysubstance dependence, borderline intellectual functioning, phonological disorder, and mixed expressive language disorder.
Personal and Family History
Family history revealed that J.S.’s father was a 64-year-old electrician and his mother was a 58-year-old secretary who had been adopted. His mother suffered from a history of alcoholism, and the paternal side of family had a history of mental illness.
Personal history revealed that J.S. was a full-term baby, delivered by induction of labor. He had a poor APGAR score (measure of respiration, heart action, muscle tone, skin color, and reflexe adequacy in a newborn) and spoke and walked late. J.S. had suffered some traumatic experiences: he had been raped in 1995 (the rapist was apprehended and convicted). In addition, he had been a victim of a bus accident from which he sustained a head injury, but details were not available. He had a history of arrest for drug possession. He worked in Union County Vocational Rehabilitation as a cook and was on supplemental social security income. He lived in a group home.
The first author (H.K.M.) had been treating J.S. for the last 2 years in a day program for the chronically mentally ill. In January 1999, H.K.M. noted that the patient complained of repeated falls, difficulty with balance, and difficulty controlling eye movements. Hence a referral was made to the second author (N.B.I.), a neurologist.
The patient was examined by N.B.I. on February 10, 1999, who noted the patient had a history of poor balance and was prone to falling, especially when attempting to climb stairs. Moreover, his balance had worsened over the last 2 years. J.S. had falling incidents almost daily and had difficulty rising from a chair and climbing or descending stairs. J.S. denied light-headedness, vertigo, akathisia, stiffness, dystonia, motor weakness, or auditory/visual hallucinations in the interval prior to the examinations. He also denied having any recent change in his speech, but said that he had problems with slurring of his speech for as long as he could remember.
N.B.I. noted that J.S. was taking divalproex 250 mg PO QID, thiothixene 5 mg QAM and 10 mg QHS, and benztropine 4 mg/day in divided doses.
Neurological examinations revealed that J.S. was sitting comfortably in the chair without adventitious movements. His blood pressure was 100/70 mm Hg (mercury) when seated, with a pulse of 70, which was regular. He was alert. J.S.’s attention and concentration were easily distracted, but he was able to repeat six digits forward and four digits backward. When asked to say the months backward, he repeated them forward. J.S. was unable to spell “world” backward. On memory functions, J.S. was oriented to self, time, and place. He was able to immediately encode three words on the first try, and to recall three words at 5–10 minutes without any cues. His fund of knowledge was poor and he was unable to name the current president. His recollection of the king’s story (a one-paragraph story used to assess comprehension of narrative) was with poor details and lack of assimilation of the gestalt. His visual spatial memory showed that he was able to encode three objects on the first try and recall all three at 5 and 10 minutes as well. He had very good recall of lurid details of a movie he had seen the previous evening.
Language functioning showed that spontaneous speech was fluent without paraphasic errors, but with prominent lingual dysarthria. J.S. was able to follow simple commands (left/right, multi-step, and cross mid-line). Repetition was intact, as was naming both high- and low-frequency words. Reading was intact. When asked to write any sentence, he wrote, “I am smart.” Calculations were impaired with mistakes on simple subtractions, as well as making changes.
J.S. had no evidence of dyspraxia or apraxia. Visuospatial construction showed that pentagons were well constructed, while a cube gave some difficulty. Frontal executive function examination showed that his clock drawing demonstrated very poor organization, and writing of consecutive numbers up to fifteen. J.S. was able to make the clock hands say 10 minutes after two o’clock without difficulty.
Ramparts demonstrated stimulus-bound behavior and J.S.’s multiple loops demonstrated closing in, as well as perseverance. He was unable to learn the Luria hand sequence (frontal lobe evaluation where examiner asks patient to repeat the hand sequence fist, chop, flat) in less than five repetitions, and was unable to perform go/no/go (frontal lobe evaluation where examiner asks patient “When I tap my hand once, you tap twice; when I tap twice, do not tap at all”). Fluency was impaired for both semantic, as well as phonemic cues. Similarities were concrete. J.S. also had slowness noted on execution of movements and perseverance.
On examination of his cranial nerves, J.S.’s pupils were equally round and reactive to light and accommodation. His discs were bilaterally sharp. Visual fields were full. J.S. had a vertical supranuclear gaze palsy, which was most pronounced on downward gaze. He had absent optokinetic nystagmus in the vertical direction with a symmetrical intact vestibulo-ocular response. There was slight hypomimia with a symmetrical slow smile. The remainder of his cranial nerves, including hearing, was intact. No orobuccal or lingual dyskinesia were noted. Motor examination showed normal bulk, mildly increased tone with slight rigidity, and cog-wheeling bilaterally. Rapid alternating movements were clumsy and slowed, more on the right than on the left.
Sensory examination showed that J.S. was intact to all four modalities, including joint position sense, vibration, pinprick, and light touch. No axial rigidity was noted. Finger-to-nose and heel-to-shin was intact and without evidence of dysmetria. His reflexes were three plus throughout, with toes upgoing bilaterally. Glabellar and snout reflexes were present. J.S. had a wide-based gait. He was able to arise from a chair only with prominent retropulsion. He was able to walk on his toes and heels, exhibiting mildly reduced arm swing. The Romberg test was negative although he had a very prominent retropulsion. (Romberg test: patient stands with eyes open and then closed with feet approximated; sign is positive if closing eyes increases unsteadiness, indicating loss of proprioceptive control).
Magnetic resonance imaging was reviewed with a neuroradiologist and was thought to be most consistent with perinatal insult with mildly increased signal in T-2 in the periventricular region. Laboratory values were notable for normal ceruloplasmin, copper, complete blood count, SMAC (basic chemistry profile), vitamin B12 level, hexoscamidase-A levels and serum acanthocytes. Laboratory data was noted for a cholesterol count of 144, which was low. Vitamin E (α-tocopherol portion) was slightly low as well. In addition, fibroblast culture was notable for an abnormal cholesterol esterification, which was depressed by over 20%, confirming the diagnosis of NPC (Figures 1, 2, and 3).
J.S. had a constellation of signs and symptoms of ataxia and VSGP, which may be suggestive of NPC. Other possible causes of VSGP and dysarthria supranuclear gaze palsy include spinocerebellar degeneration, progressive supranuclear gaze palsy, ataxia, Huntington’s disease, and Parkinson’s disease, all of which were unlikely to be present in J.S. given his absence of the other commonly associated signs. A β-lipoproteinemia or vitamin E deficiency is also unlikely to be responsible for the symptoms, due to the absence of peripheral neuropathy. Although vitamin B12 deficiency could also present with psychosis, the absence of weakness, anterior and posterior columnar dysfunction, or peripheral neuropathy, further made this diagnosis unlikely as well. A blood smear for acanthocytes for β-lipoproteinemia was negative.
Cholesterol esterification and fibroblast assays may be abnormal and low in familial hypercholesterolemia, hyperlipidemia type 2, Wolman’s disease, and mucolipidosis type 2 and 3. The patient’s low peripheral cholesterol, however, was inconsistent with the initial two diagnoses, namely, hyperlipidemia type 2 and 3, and Wolman’s disease. Also, J.S. did not have any of the phenotypic features of mucolipidosis, which were disorders present in early childhood.
His life-long diagnoses of schizophrenia chronic undifferentiated type, borderline intellectual functioning, phonological disorder, and mixed expressive language disorder all could be explained by the slowly developing neurological disorder NPC which took 14 years to become severe enough to be correctly diagnosed. The new diagnosis of psychiatric disorder due to medical condition of NPC would not change the pharmacologic management but would help guide the future planning.
The final impression was that this 32-year-old gentleman, with a prior diagnosis of schizophrenia, showed disinhibition, frontal executive dysfunction, dementia, supranuclear vertical gaze palsy, dysarthria, and ataxia. All of them were slowly progressive with fibroblast culture abnormal for cholesterol esterification. The clinical picture was consistent with the diagnosis of NPC. It is recommended that whenever there are associated soft neurological symptoms and signs in a case of psychosis, medical causes should be considered in the etiology of the presenting psychosis. PP
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