Schizophrenia in a Patient With Spinocerebellar Ataxia 2: Coincidence of Two Disorders or a Neurodegenerative Disease Presenting With Psychosis?
An Afro-Caribbean man was diagnosed with schizophrenia and subsequently developed cognitive and cerebellar dysfunction. Ten years later, he was genetically diagnosed with spinocerebellar ataxia type 2 (SCA2). Patients with a number of neurodegenerative disorders may develop psychotic symptoms at some point in their disease course; however, no cases have been reported in which psychosis was the presenting feature of SCA2. In SCA2, both cerebellar and basal ganglia pathologies may contribute to psychiatric disease. It remains unknown in our patient whether the psychosis should be attributed to schizophrenia or SCA2, but this case highlights the need for awareness of neurodegenerative disorders in patients with psychiatric symptoms, in particular in patients who are treated with neuroleptics and exhibit neurological abnormalities such as movement disorders.
While psychiatric and neurological illness may co-occur in one subject, a number of neurodegenerative disorders can present with a combination of psychiatric, cognitive, and neurological symptoms. Disorders affecting primarily the basal ganglia, such as Huntington’s disease, are well recognized as presenting with psychiatric symptoms, including depression and psychosis. Additionally, a variety of neuropsychiatric deficits have been reported with the spinocerebellar ataxias. We report the case of a subject with clinically diagnosed schizophrenia who subsequently developed a cerebellar syndrome that was genetically confirmed to be SCA2. While the co-occurrence of both psychiatric and neurodegenerative conditions in this subject may be coincidental, this case illustrates that the development of neurological findings in patients with psychiatric illness may indicate an underlying neurodegenerative process. If psychiatric symptoms manifest themselves before neurological symptoms, they may be attributed to an axis I diagnosis. Motor symptoms in the context of psychiatric illness may be attributed erroneously to neuroleptic side effects, which would delay neurological workup. These considerations have important implications for management and genetic counseling.
Case Presentation
Mr. A, an Afro-Caribbean man, came to our facility at the age of 22 after carrying the diagnosis of schizophrenia, paranoid type, for 6 months. He had no significant past medical history, apart from the diagnosis of essential hypertension, treated with metoprolol, no history of intellectual deficits or need for educational remediation, and no history of alcohol or drug abuse. There was no known family history of neurological or psychiatric disease, although little history was available from the paternal side.
Mr. A’s symptoms dated from age 21, when he was on active military duty. At that time, he began to complain that the left side of his brain was “swollen” and “had a sore on it” and that the material of his brain moved, preventing thoughts from traveling from one side of the brain to the other and causing his face to twist and his left eye to roll back into his head. These complaints were interpreted as somatic delusions. He developed paranoid ideation concerning his shipmates and ideas of reference regarding the television. Auditory hallucinations were present throughout most of the course of his illness but were never prominent, and details were not documented. Nine months after initial presentation at age 21, he required hospitalization and was diagnosed with schizophrenia, for which he was given risperidone with limited response. After discharge, he was switched to olanzapine. When interviewed at age 27, he was working and enrolled in a technical school but reported that his personality had changed from being “outgoing and full of energy” to “introverted and spending all my time alone.”
Over the next 6 years, Mr. A’s psychotic symptoms were treated sequentially with risperidone, olanzapine, and ziprasidone, titrated to effectiveness but with significant dose variation due to side effects. Even with the best clinical response, the putative somatic delusions remained, as did residual paranoid ideation, ideas of reference, and auditory hallucinations. He complained of “tightness” around the eyes and stiffness in the head, neck, and knees. Usually these complaints were interpreted as a psychotic elaboration of neuroleptic side effects and treated with benztropine but with minimal response.
Mr. A complained of anxiety, particularly in social situations, which exacerbated both his paranoia and somatic delusions. To address anxiety, he was treated with selective serotonin reuptake inhibitors and intermittently with benzodiazepines, which were variably effective.
At age 27, while receiving a trial of ziprasidone, Mr. A started to stutter (most prominently when he was anxious) and developed lip and mouth “twitching”; however, he received a total score of 1 on the Abnormal Involuntary Movement Scale (1) , below the threshold for the diagnosis of tardive dyskinesia. He also complained of weakness and depressed mood. He was unable to concentrate and was failing all of his examinations at technical school. Ziprasidone was switched to olanzapine, but he continued to complain of problems with memory (despite scoring 30 of 30 on the Mini-Mental State Examination) and of feeling “clumsy,” “off balance” at times, and “cloudy.” This last symptom caused him to have difficulties at work. Upon subsequent examination, oral dyskinesias were noted, and his speech was described as “slurred.”
At age 29, his anxiety worsened, and he developed panic attacks. His somatic complaints and speech difficulty progressed. An otolaryngological evaluation revealed a hyperfunctioning larynx, with scissoring of the left arytenoid cartilage. The anxiety, stuttering, and comprehensibility improved both subjectively and objectively with paroxetine titrated to 40 mg/day.
Psychotic symptoms, anxiety, and medication side effects intermittently interfered with his ability to study and work; however, he was able to complete his degree from technical school and intermittently work in various technical jobs, at times holding two jobs simultaneously, until the age of 31.
At this time, Mr. A started to complain of dysphagia with solids, “dizziness” with positional change, cramping of his hands, occasional spasms when holding objects, dry mouth, and blurred vision. Upon neurological examination, deep tendon reflexes were diminished throughout, and there was mild distal vibration loss and mild gait ataxia. His eye movements were normal.
At age 32, Mr. A experienced a marked decline in cognitive function. Neuropsychological testing revealed significant impairments in some—but not all—domains. Working memory appeared intact, but there was impairment in consolidation and recall. Timed aspects of executive function testing, verbal fluency, and naming ability were all impaired, but alternation and accuracy in these tasks were good, suggesting psychomotor slowing with less evidence of typical frontal dysfunction. These results indicated subcortical rather than cortical dementia.
Based on clinical assessment and a neurological examination, medication adjustments resulted in some improvement in cognitive function, truncal and gait ataxia, and alertness.
Upon repeat neurological evaluation (5 months after the first), there was moderate, generalized chorea, mild scanning dysarthria, staccato speech, moderate dysmetria, and dysdiadochokinesia, more pronounced on the left. His gait was slightly wide-based, with mild bilateral foot drop. He was unable to perform tandem gait. There was diminished joint position and vibration sense in his toes and fingers bilaterally. Deep tendon reflexes were absent throughout, and plantar responses were bilaterally flexor. His eye movements remained normal.
Laboratory and Radiological Findings
At the time of the second neurological evaluation, Mr. A underwent extensive laboratory testing. With the exception of an elevated prolactin level of 28.5 ng/ml (reference range=0–15 ng/ml), all laboratory tests were within normal limits, including CBC; peripheral smear; erythrocyte sedimentation rate; serum chemistries; liver enzyme tests; vitamin B 12 ; folate; rapid plasma reagin; HIV; antinuclear antibody; thyroid stimulating hormone; ceruloplasmin; ferritin; 24-hour urine copper excretion; apolipoprotein B, anti-Ri, anti-Hu, and antineuronal nuclear antibodies; Lyme titer; CSF glucose; protein; cell count; and 14-3-3 protein. Genetic testing for Friedreich’s ataxia, Huntington’s disease, SCA1, SCA3, SCA6 was negative.
Magnetic resonance imaging showed minimal bilateral periventricular and subcortical high signal white matter changes consistent with chronic microvascular ischemic changes due to hypertension, as well as moderate bilateral cerebellar atrophy; the pons appeared slightly symmetrically reduced in size.
Electroencephalography was normal during the awake state but showed a large amount of biphasic delta waves during drowsiness, which could be either normal or consistent with mild diffuse cerebral dysfunction. At the time, Mr. A was receiving risperidone, 6 mg/day; paroxetine, 40 mg/day; and benztropine, 1.5 mg/day. Electromyography was normal except for absent H reflexes. A modified barium swallow showed mild spasm of the distal esophagus, and laryngoscopy showed cricopharyngeal spasm and dystonia (spasmodic dysphonia). SCA2 testing showed 22 CAG repeats on one allele and 39 on the other (upper limit of normal=31).
Discussion
SCA2 is an autosomal dominant neurodegenerative disease caused by a pathological expansion of a CAG repeat sequence on chromosome 12q24 (MIM 183090). It is believed that the resultant mutated ataxin2 protein gains a toxic function leading to neuronal cell death and neurodegeneration (2) , primarily in the cerebellum, brainstem, and spinal cord but also affecting the basal ganglia and cerebral cortex (3) . Typically, SCA2 develops in adulthood with slowed saccadic eye movements, peripheral neuropathy, decreased tendon reflexes, parkinsonism, myoclonus, and dementia. While most of the 28 types of autosomal dominant SCA reported to date involve some degree of neuropsychological deficit (4 – 6) , including depression and personality change (7) , psychosis appears to be less common. There is some evidence that SCA17 may appear with psychosis with or without chorea (8) ; however, to our knowledge, there are no cases of SCA2 in which psychosis was either the presenting symptom or a development during the course of the disease. A possible association exists between trinucleotide repeat expansions of the gene believed to cause SCA8 and susceptibility to major psychosis (9 , 10) ; however, no such association has been reported for the repeat expansion that causes SCA2. In this case, we must ask whether SCA2 can account for the full spectrum of psychiatric, cognitive, and neurological symptoms or whether the concomitant diagnosis of schizophrenia is warranted.
Neurodegenerative disorders primarily affecting the striatum, such as Huntington’s disease and chorea-acanthocytosis, may present initially as movement disorders and/or psychiatric disturbances (11 , 12) . When psychiatric symptoms develop in cerebellar disorders, they are often associated with neurological symptoms suggestive of striatal involvement (13) . This association suggests the possibility that psychosis in cerebellar disorders may be due to striatal involvement rather than to cerebellar pathology.
Alternatively, cerebellar dysfunction may account for psychiatric disease. In addition to the disorders of motor coordination and eye movements classically associated with cerebellar dysfunction, cerebellar abnormalities have been implicated in psychiatric disorders, including psychosis (14 , 15) . It may be hypothesized that the co-occurrence of motor and psychiatric impairment in this case reflects the relative involvement of motor and cognitive domains that are known to be mediated by the frontal lobes and subserved by parallel circuits synaptically linking the frontal cortex, striatum, and thalamus (16) . Each of these frontostriatal circuits receives modulatory input from the cerebellum (17) . Within the cerebellum, the various functional domains, e.g., motor, vestibular, limbic, and cognitive, are topographically segregated (15) and form parallel interfaces with the frontostriatal circuits (17) . The diffuse atrophy of the cerebellum that our patient exhibited could conceivably contribute to dysfunction across multiple domains.
The etiology of our patient’s dementia is unclear because his neuropsychological deficits are consistent both with the type of subcortical dementia seen in a subset of schizophrenic patients (18) and with that seen in SCA2 (19 , 20) . Although the precise chronology of the patient’s cerebellar disease is difficult to determine, the apparent temporal co-occurrence of the marked cognitive decline with the appearance of the first cerebellar motor impairments suggests that SCA2 accounts for the dementia.
Arguing against the hypothesis that SCA2 is responsible for our patient’s psychiatric disease is the fact that his age at presentation was typical for schizophrenia. In contrast, in SCA2, a repeat size in the range of that of our patient is typically associated with a slightly older age of onset, i.e., mid-20s to mid-50s (21) . Moreover, the development of somatic delusions, paranoia, and auditory hallucinations that resulted in the diagnosis of schizophrenia in our patient predated the appearance of chorea and other neurological symptoms by 6 years. In retrospect, however, one must question whether the physical complaints present from age 21 and interpreted as somatic delusions were in fact psychotic elaboration of sensations due to the emergence of a neurodegenerative disorder.
It is not possible to determine the etiology of our patient’s psychiatric disease or its relationship, if any, to his molecular diagnosis of SCA2. However, this case illustrates the importance of considering the possibility of neurodegenerative disease in patients who present with psychiatric symptoms. In particular, clinicians should be quick to evaluate unexpected cognitive or neurological symptoms that may be interpreted mistakenly as psychiatric in origin or as side effects of neuroleptics and anticholinergic medications. Correct and prompt diagnosis is essential for appropriate management, assessment of prognosis, and genetic counseling.
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