Akathisia with Low-Dose Quetiapine in Cases of Autoimmune Encephalitis and Possible Central Nervous System (CNS) Vasculitis

Quetiapine is generally well tolerated and preferred for behavioral disturbances in neurological conditions, ¹ as it is proposed to have a lesser tendency to cause extrapyramidal symptoms (EPS), including akathisia. This is attributed to higher 5-HT2a/D2 receptor antagonism and fast dissociation from D2 receptors. ² The incidence of akathisia in first-episode psychosis with quetiapine was found to be 3.5% in a pooled analysis of three randomized open-label trials, lesser than that with olanzapine (3.6%), aripiprazole (18.2%), risperidone (20%), and haloperidol (57%). ³ Akathisia associated with antipsychotic use was shown to improve after switching over to quetiapine. ⁴ Hence, switching to quetiapine from other first and second-generation antipsychotics has been indicated as a first-line measure in the treatment of akathisia. ⁵ However, akathisia has been reported with quetiapine. Most of the case reports are with doses of quetiapine above 100 mg per day,^6–10 barring two reports of akathisia with low-dose quetiapine in patients with psychiatric diagnoses. ¹¹ We report two patients with neurological conditions, leucine-rich glioma inactivated-1 (LGI-1) autoimmune encephalitis and possible central nervous system (CNS) vasculitis, respectively, who developed akathisia with low-dose quetiapine.

Case 1

A 39-year-old man presented with a six-month-history of elated mood, increased energy, sleep disturbances, aggressive behavior, delusions of persecution and grandiosity, episodes of sudden impaired awareness, posturing of left upper limb and face with perioral automatisms lasting for two to four minutes followed by confusion, and nearly one-month-history of forgetfulness and decreased self-care. Considering no previous history of similar presentation, haloperidol starting from 5 mg and hiked up to 12.5 mg/day over multiple consultations, trihexyphenidyl 2 mg/day and diazepam starting from 10 mg up to 20 mg/day was started by a psychiatrist from another hospital. Following this, he developed stiffness in both upper and lower limbs and was brought to our hospital for further evaluation.

On examination, he was not oriented to time and place, had mild spastic speech, saccadic intrusion along with opsoclonus, and rigidity in all four limbs with brisk deep tendon reflexes. Hemograms, liver function tests, renal function tests, thyroid function tests, lipid profiles, serum calcium, ammonia, lactate, and random blood glucose were within normal limits. His serum sodium levels were 124 mEq/L (normal range: 136–146mEq/L) at presentation. Magnetic resonance imaging (MRI) of the brain showed T2/fluid attenuated inversion recovery hyperintense signal changes in bilateral hippocampus (right more than left) and right amygdala, subtle signal changes in bilateral insula and anterior cingulate, sulcal effacement with leptomeningeal enhancement in bilateral frontal, and temporo-occipital sulcal spaces. The clinical presentation of new-onset behavioral disturbances, seizures, and cognitive decline, along with MRI brain findings, was suggestive of a possibility of autoimmune encephalitis as one of the differential diagnoses. Hence, a serum and cerebrospinal fluid (CSF) autoimmune encephalitis panel was done, and the LGI-1 antibody test was strongly positive.

CSF analysis showed three cells (lymphocytes) with normal sugar and proteins. A high titer of serum antithyroid peroxidase antibody was also detected. The remaining autoimmune profile and paraneoplastic panel were negative. Haloperidol was tapered and stopped because of the EPS. Trihexyphenidyl was stopped, given the delirium. Diazepam was decreased to 5 mg, along with gradual correction of hyponatremia. Two days after stopping haloperidol, because of sensitivity to antipsychotics for EPS, quetiapine 25 mg was chosen for behavioral symptoms.

The patient gradually became oriented with a decrease in rigidity of the limbs. On day three of quetiapine initiation, the patient reported a sense of restlessness, an urge to move around, and difficulty sitting in one place. The patient scored eight on the Barnes akathisia rating scale, suggesting marked akathisia. ¹² Quetiapine was then stopped, and diazepam was increased to 10 mg. The patient reported a 60% decrease in restlessness by day nine of stopping quetiapine. He was diagnosed with LGI-1 autoimmune encephalitis in liaison with neurologists. He was advised to take brivaracetam up to 150 mg/day for seizures along with Intravenous methylprednisolone (IVMP) pulse therapy and five cycles of large-volume plasmapheresis. Long-term immunomodulation was planned, and one gram of rituximab was given, with a second dose planned two weeks after discharge. ¹³ The patient was contacted over the telephone and was reported to have a resolution of symptoms of akathisia within 20 days after stopping quetiapine. He improved in terms of cognitive functions and decreased the frequency of his seizure episodes. Behavioral symptoms persisted, for which he was started on olanzapine 10 mg by another psychiatrist. During the follow-up, it was reduced to 5 mg, on which he showed 90% improvement in behavioral symptoms with significantly improved occupational functioning.

Case 2

A 65-year-old male presented with delusions of persecution and infidelity, physical aggression, and sleep disturbances for two months, along with four episodes of tonic–clonic movements of the right upper and lower limbs with up rolling of eyes and frothing on the day of presentation. He had a history of alcohol consumption in a dependence pattern for the last three years, with the last intake one day before presentation. The patient was drowsy and not oriented to time, place, and person on examination. The hemogram, coagulation profile, liver function test, renal function test, serum electrolytes, vitamin B12 and folate, serum homocysteine, lipid profile, and thyroid function test were within normal limits. Intravenous injection of levetiracetam 1 gram was given along with thiamine replacement and diazepam 10 mg twice daily. He was diagnosed initially with delirium tremens with a differential diagnosis of postictal confusion. Hepatitis B surface antigen, hepatitis C core antibody, and human immunodeficiency virus were negative. MRI brain revealed hyperintensities in bilateral deep periventricular white matter involving the external capsule, microbleeds in the bilateral cerebral and cerebellar hemispheres, and mild diffuse neuroparenchyma atrophy. Vessel wall imaging revealed enhancement of the bilateral middle cerebral artery suggestive of CNS vasculitis. Electrocardiogram, chest X-ray, abdomen ultrasound, and CSF biochemical and microbiological analysis were normal. The serum autoimmune encephalitis panel and paraneoplastic panel were done to rule out other secondary causes of vasculitis, which were negative. He was discharged with a referral to a general hospital, given the need for multidisciplinary care with a plan to review for long-term treatment of vasculitis after stabilization with the advice of oral diazepam 20 mg/day in tapering doses, levetiracetam 1 gram/day, risperidone 4 mg/day, folate 10 mg/day, and thiamine 100 mg/day. The patient had partial improvement in behavioral symptoms over the next two weeks but also reported EPS in the form of stiffness and slowness of movements. He stopped the medication by himself for a week, with which EPS improved, but there was an increase in irritability and aggression. Risperidone was restarted by the family members, resulting in decreased irritability and aggressive behavior. The EPS increased over the next one and a half months, and he was brought to our hospital. On examination, he had mask-like facies, hypophonic, dysarthric speech with mild up gaze restriction, slow, hypometric saccades, drooling of saliva with generalized bradykinesia, diminished deep tendon reflexes, axial and appendicular rigidity. Digital subtraction angiography done under vasculitis protocol was normal. Considering the possibility of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a skin biopsy was done, which did not show any significant changes. A diagnosis of possible CNS vasculitis was kept, and five days of IVMP pulse followed by injection of cyclophosphamide 500 mg infusion for three days was given.

Risperidone was tapered and stopped, quetiapine was started from 12.5 mg/day and titrated up to 37.5 mg/day, along with trihexyphenidyl up to 4 mg/day. The patient reported restlessness and an urge to move around on day five of quetiapine initiation. He was constantly pacing around in the hospital ward and was unable to sit in one place, with disturbed sleep and distress due to his inner restlessness. The patient scored five on the Barnes Akathisia Rating scale, suggesting moderate akathisia. ¹² Quetiapine was then stopped, and clonazepam up to 0.75 mg/day and propranolol up to 40 mg/day were started. The patient reported decreased restlessness and improved sleep and was discharged with a plan to continue cyclophosphamide and IVMP for three days for two cycles. The patient had resolution of symptoms of akathisia within 15 days of stopping quetiapine.

Discussion

We have presented two cases in which quetiapine was started to manage behavioral symptoms. Both patients developed akathisia after initiation of quetiapine at low doses of 25 mg/day and 37.5 mg/day, respectively. There was an improvement in symptoms of akathisia after stopping quetiapine. On evaluation with Naranjo adverse drug reaction probability scale, ¹⁴ the scores of both the patients were +5, indicating a possible adverse drug reaction to quetiapine. Our cases show that the development of EPS with other antipsychotics can be one pointer toward vulnerability to develop akathisia with quetiapine, as reported in two past cases as well.^6,7The organicity in the form of encephalitis and CNS vasculitis might have increased the likelihood of these patients developing akathisia even with quetiapine, which is supposed to have lesser rates of extrapyramidal side effects.

Another possibility that could explain the akathisia is antipsychotic-withdrawal akathisia, which emerges within two weeks of antipsychotic discontinuation or dose reduction. ¹⁵ There have been case reports of withdrawal with risperidone and amisulpride where patients developed akathisia on discontinuation or reduction in dosage.^16,17 In our first patient, the symptoms of akathisia started a week after discontinuation of haloperidol with the addition of quetiapine in between. In the second patient, there was no report of akathisia when the patient stopped risperidone after the first discharge. In both patients, the first antipsychotic medication was gradually tapered and stopped. Temporal correlation points toward akathisia being more likely to be caused by quetiapine than antipsychotic withdrawal.

The etiology of akathisia caused by quetiapine needs to be clarified. Inhibition of dopaminergic neurons located in the ventral tegmental area directly or via noradrenergic and serotonergic fibers with significant input on the dopaminergic neurons may contribute to akathisia caused by quetiapine. ¹¹ Propranolol, mirtazapine/mianserin, antimuscarinic agents, cyproheptadine, benzodiazepines, and clonidine are advocated for managing akathisia associated with antipsychotic use. Olanzapine and clozapine are other antipsychotics that are reported to be less likely to cause akathisia.^5,18

It is important to consider the possibility of akathisia with quetiapine, even at low doses, especially in those with a neurological illness and who have had a history of sensitivity to other antipsychotics. Slow up-titration and careful monitoring for akathisia need to be ensured in the vulnerable population to mitigate this risk. Olanzapine can be an alternative in managing behavioral symptoms, as it has low incidence rates for akathisia. ³ Benzodiazepines can also be an option if there are no clear psychotic symptoms.