Case study

The patient, a man aged 27 years, was first admitted to our hospital with psychotic symptoms in June 1995. He presented with paranoid delusions and delusions of reference, acoustic hallucinations (commenting voices), formal thought disorder, and behaviour disorganisation, as well as negative symptoms such as blunted affect, poor rapport, and lack of spontaneity. At this time, he was diagnosed as having paranoid schizophrenia (ICD-10: F20.0) and showed a PANSS (positive and negative symptom scale) total score of 137 (fig 1).

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Figure 1

Positive and negative syndrome scale scores, treatment with antipsychotic agents, and the frequency of episodes of ataxia.

The patient was initially treated with risperidone (6 mg/d) which led to a slight improvement in his psychotic symptoms. After discharge from our hospital in September 1995 he regularly attended our outpatient clinic. Despite treatment with risperidone and later with haloperidol decanoate (20 mg/2 weeks), he continued to have chronic psychotic symptoms, which persisted until readmission in April 2001. At this admission he was suffering from severe psychosis (paranoid delusions, acoustic hallucinations, formal thought disorder, and behaviour disorganisation) and negative symptoms (fig 1). Antipsychotic treatment with quetiapine (800 mg/d; 4 weeks) and subsequently with amisulpride (600 mg/d; 4 weeks) did not lead to any improvement in the psychosis. At this time, a neurological investigation showed gaze evoked nystagmus and upward gaze palsy, though attacks of ataxia had neither been reported by the patient nor noticed by the nurses.

Because of persistence of the psychotic symptoms, we began treatment with clozapine (400 mg/d) and observed a gradual deterioration in psychosis over the next four weeks despite sufficient serum levels of clozapine. At that time the first severe ataxia attacks appeared. They were manifested by gait ataxia, dysarthria, and slight intention tremor of the upper extremities and persisted for at least several hours. After other causes of cerebellar dysfunction—such as inflammatory, toxic, and vascular disorders—had been excluded, the patient was diagnosed as having episodic ataxia type 2 because he met the following clinical diagnostic criteria: duration of episodes (hours to days), gait and stance ataxia, interictal absence of most symptoms (except oculomotor deficits). Consequently, we began treatment with acetazolamide (200 mg twice daily) and switched the antipsychotic medication from clozapine to zotepine (400 mg/d). This led to both a complete elimination of ataxia episodes and a gradual amelioration of the psychotic symptoms. At the time of discharge six weeks later, the patient’s total PANSS score was 90. At all subsequent follow up investigations undertaken monthly until December 2002 the psychiatric symptoms remained unchanged (fig 1) and there was no recurrence of the ataxia attacks.

Episodic ataxia in this patient obviously follows an autosomal dominant trait. The patient’s mother suffers from cerebellar atrophy with severe gait and limb ataxia, dysarthria, and oculomotor deficits. Her father is reported to have had oculomotor deficits as well.

At the age of 12 months, a neurological examination of our patient showed saccadic pursuit and vertical spontaneous nystagmus. Since the age of 18 months, spells of gait and stance ataxia have been described (15 to 20 minutes long, one to four times in four to six weeks). At the age of three years and nine months, a neurological investigation showed gaze evoked nystagmus, saccadic pursuit, and absence of optokinetic nystagmus (both horizontal and vertical). At that age a suspicion of migraine was raised but not confirmed. At the same time abnormal EEG patterns with sharp waves over the left temporal lobe were reported.

Recent EEGs done before, during, and after treatment with clozapine showed abnormal bilateral theta-delta activity (4–7 cps and 2–3 cps) in the temporal and parietal regions. Magnetic resonance (MR) imaging done in 1995, 1997, and 2001 showed no signs of atrophy or cerebral signal alteration. Proton MR spectroscopy done in July 2001 revealed decreased N-acetylaspartate to creatine ratios in the cerebellar vermis region and left cerebellar hemisphere. On ¹²³I-iomazenil SPECT in July 2002, there was a reduced density of the GABA(A)-benzodiazepine receptor complex in the cerebellum as well as in the frontal dorsolateral and occipital regions.

Comment

This case shows an association between clinically diagnosed episodic ataxia type 2 and schizophrenia. Cessation of ataxia episodes as a response to treatment with acetazolamide supports the clinical diagnosis of EA2 and rules out alternative pathologies such as SCA6 and EA1, which are known to have only a partial response to acetazolamide, if any.

Recent association studies have shown that neurodegenerative disorders may predispose to major psychosis.³ SCA6, a disorder of chromosome 19, is not associated with schizophrenia, but patients with SCA8 have shown an increased rate of association with major psychosis.³ Until now there have been no reports of an association between episodic ataxia and schizophrenia.

Autosomal dominant episodic ataxia type 2 is assumed to be caused by mutations in the gene CACNA1A (chromosome 19p13.1), which encodes the Ca_v2.1 subunit of the voltage gated P/Q calcium channels. As calcium channels are involved in the modulation of neurotransmitter release, it has been hypothesised that they play a role in the pathophysiology of schizophrenia.⁵

Cerebellar atrophy as well as mild cerebellar dysfunction are already known to be associated with schizophrenia. This is the first case of a patient suffering from episodic cerebellar ataxia and schizophrenia, and it points to a possible role of ion channel polymorphism in the pathophysiological mechanisms of schizophrenia.