Madam Tang was a 61 years old lady who suffered from schizophrenia and was on trifluoperazine 3mg nocte. She was admitted to the Psychiatric Unit, Kowloon Hospital because of relapse of psychosis and affective symptoms. Medications were changed to risperidone escalating from 1mg daily to 5mg daily in eight days time together with fluoxetine 10mg daily during admission.
She also had history of diabetes mellitus on diet control and cholecystectomy for cholecystitis in 1997. She lived with her husband and had independent daily activities and did not smoke or drink.
Eight days after psychiatric admission, she was transferred to the Medical Unit, Queen Elizabeth Hospital because of desaturation and coffee ground aspirated from nasogastric tube.
On physical examination, she was confused with Glasgow Coma Scale (GCS) 14/15 (E4V4M6) and clinically dehydrated with no pyrexia. Blood pressure was 125/63 mmHg with tachycardia (pulse rate 125/min) and peripheral oxygen saturation was 96% on 3 liters oxygen. Chest, cardiovascular and neurological examinations were unremarkable. Abdomen was soft, non-tender with no peritoneal sign. Per rectal examination showed no melena.
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She then developed large amount of fresh rectal bleeding with hemoglobin level dropped from 12.4g/dL to 8.9g/dL and normal platelet count and clotting profile. Urgent blood transfusion was given. Bleeding rectal ulcer was identified with bedside plication of bleeder done by the Surgical Team. She was also put on proton pump inhibitor and esophagogastroduodenoscopy showed antral gastritis and duodenitis. Biopsy later revealed chronic gastritis with no helicobacter pylori.
She remained confused and developed pyrexia (up to 39.5oC) one day later and noted muscle rigidity two days later. Examination revealed GCS 10/15 (E2V3M5) with diaphoresis and tachycardia. Generalized muscle rigidity was noted with tremulous extremities, hyporeflexia and no clonus.
Laboratory investigations showed leucocytosis (18.9x109/L) with predominant neutrophilia (15.8x109/L). Renal function test showed azotemia (urea 16.8mmol/L) with normal creatinine, sodium and potassium levels. Troponin level was normal while creatine kinase (CK) (322IU/L), lactate dehydrogenase (331IU/L) and alaine transaminase (42IU/L) were raised. Arterial blood gas showed no acidosis. Erythrocyte sedimentation rate was 43mm/hr and C-reactive protein was 38.7mg/L. Spot glucose was 10.8mmol/L and thyroid function test was normal. Chest X-ray showed no definite consolidation. Electrocardiogram showed sinus tachycardia without ischemic changes. Septic workup (including sputum, urine and blood cultures) was all negative. Computed tomography of brain showed no structural abnormality. Electroencephalogram showed body movement artifacts with no epileptiform activity. Cerebrospinal fluid analysis showed no evidence of infection of the central nervous system.
Her fever persisted with confusion and rigidity despite broad spectrum antibiotics. CK was peaked at 1066IU/L, fell and rebounded to 1020IU/L and urine myoglobin was negative. Risperidone and fluoxetine were already stopped on the day of medical admission. She was treated supportively with intravenous fluid for rehydration, nasogastric tube feeding for nutrition, anti-pyretic for fever, active chest and limb physiotherapy and splintage by occupational therapy to prevent contracture together with intensive medical and nursing care and monitoring.
Psychiatrist advised that the reading of elevated CK was not in the range of typical neuroleptic malignant syndrome (NMS) and CK increased despite anti-psychotic discontinuation though NMS could not be ruled out. It was suggested to consider other causes, start lorazepam and not to restart anti-psychotic. She was also assessed by the Infectious Disease Team and no focus of infection was found. Blood for procalcitonin was less than 0.05ng/mL.
Dantrolene was commenced for clinically suspected NMS. She remained confused with persistent fever and rigidity. She was assessed by the Neurology Team and NMS was clinically compatible. Dantrolene was stepped up and bromocriptine was added. Fever subsided and consciousness regained with improved rigidity and normalized CK. She was then transferred back to Kowloon Hospital for rehabilitation and further management of her psychiatric problem.
In Kowloon Hospital, quetiapine (50mg nocte) was reinstituted 10 days after transferral and titrated up gradually to 600mg nocte upon discharge.
During follow-up in Psychiatric Out-Patient Clinic, she achieved complete recovery and psychotic symptoms were safely controlled by quetiapine with addition of ziprasidone later. She enjoyed playing badminton with her husband and friends and planned to have a trip to Shanghai for two weeks.
Discussion: ** (total words for case history and discussion must be 1000-2000)
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In summary, Madam Tang was a 61 years old lady suffering from schizophrenia who presented with hyperthermia, confusion, muscle rigidity and autonomic instability after anti-psychotic treatment compatible with neuroleptic malignant syndrome (NMS).
Madam Tang illustrates a common presentation of risperidone-induced NMS.
NMS is a rare but potentially life-threatening adverse drug reaction with conventional or atypical anti-psychotics. Dopamine antagonists (e.g. metoclopromide, promethazine) and sudden withdrawal of dopaminergic agents (e.g. levodopa, amantadine) can precipitate NMS-like syndrome. NMS warrants special attention because of its unpredictable occurrence, potential severity, considerable morbidity and mortality (1), (2).
The prevalence of NMS is estimated to be 0.02%-2.5%. Atypical anti-psychotics are associated with less risk of NMS than conventional anti-psychotics. Mortality rate of NMS is 10-30% in earlier studies but the figure has decreased progressively with increased use of atypical anti-psychotics as first line treatment and early detection and management of NMS. The pathophysiology of NMS is proposed to be due to central dopaminergic antagonism (3), (4).
The four cardinal features of NMS include hyperthermia, mental status changes, muscle rigidity and autonomic instability. Hyperthermia may be low-grade to higher than 42oC. Mental status changes include confusion, agitation, catatonia, mutism, stupor and coma. Muscle rigidity may be described as lead pipe and movement disorders include bradykinesia, tremor and dystonia. Autonomic dysfunction includes diaphoresis, labile blood pressure, tachycardia, tachypnea, arrhythmia and urinary incontinence (1), (3), (5).
Several diagnostic criteria for NMS are in use with agreement regarding general symptoms and signs but disagreement over which of these should be primary features. DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) Criteria for the diagnosis of NMS include: (A) Development of severe muscle rigidity and elevated temperature associated with the use of anti-psychotic medication; (B) Two or more of the following: diaphoresis, elevated or labile blood pressure, tachycardia, incontinence, dysphagia, mutism, tremor, changes in the level of consciousness ranging from confusion to coma, leucocytosis and laboratory evidence of muscle injury (e.g. elevated CK); (C) The symptoms in criteria (A) and (B) are not due to another substance, neurological or other medical conditions; (D) The symptoms in criteria (A) and (B) are not better accounted for by a mental disorder (6), (7).
In response to psychiatric advice in our patient, elevated CK is not required for DSM-IV diagnosis of NMS. CK has been typically reported at levels between 1,000IU/L and 10,000IU/L in cases of NMS. Her clinical picture of hyperthermia, confusion, rigidity and dysautonomia after anti-psychotic treatment with exclusion of other causes is still compatible with NMS irrespective of CK level (5).
Laboratory findings of NMS are non-specific and non-pathognomonic but supportive for the diagnosis. Common findings are leucocytosis and elevated CK. Less common findings include elevated liver enzymes, hypoferremia, metabolic acidosis, renal impairment and myoglobinuria (1), (8).
Laboratory investigations are essential to exclude other disorders and complications of NMS.
Differential diagnoses are of utmost importance because the diagnosis of NMS is clinical and NMS is a diagnosis of exclusion. In our patient, she experienced hyperthermia, confusion, rigidity and dysautonomia. Possible differential diagnoses of NMS include infections (meningitis, encephalitis, brain abscess, sepsis), psychiatric or neurological (idiopathic malignant catatonia, benign extra-pyramidal side effects, non-convulsive status epilepticus, structural brain lesions), toxic (serotonin syndrome, malignant hyperthermia, anti-cholinergic delirium, benzodiazepine withdrawal), endocrine (thyrotoxicosis, phaeochromocytoma), environmental (heatstroke) (3).
In our patient, infectious cause is unlikely because of negative septic workup and no clinical improvement after broad spectrum antibiotics. Structural brain lesions and status epilepticus are less likely in view of normal neuroimaging and electroencephalogram. Metabolic screen is also negative for endocrine or electrolyte disturbance. There is also no history of exertion or exposure to high ambient temperature suggestive of heatstroke.
For toxic causes, drug history is important to identify the etiology. In our patient, she is not on anesthetics, anti-cholinergics and benzodiazepine suggestive of malignant hyperthermia, anti-cholinergic delirium and benzodiazepine withdrawal respectively. NMS and serotonin syndrome are the two most likely diagnoses in our patient as she is newly introduced with anti-psychotic (risperidone) and serotonin-selective reuptake inhibitor (SSRI) (fluoxetine). It can be difficult to differentiate between these two syndromes in our patient on concomitant medications (4).
Serotonin syndrome is potentially life-threatening adverse drug reaction caused by excessive serotonergic activity in central nervous system. The classical triad of serotonin syndrome includes mental status changes, neuromuscular derangements and autonomic hyperactivity (1).
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Distinguishing features between these two syndromes include speed of onset of symptoms and presence of hyperreflexia and clonus. Patients with serotonin syndrome typically present acutely within 24 hours of starting medication whereas patients with NMS can present at any time in their drug course with peak symptoms not occurring for days. Moreover, hyperreflexia, clonus and myoclonus are commonly reported in serotonin syndrome while these signs are rarely seen in NMS (4).
In our patient, she experienced hyperthermia, confusion, rigidity together with the absence of hyperreflexia and clonus more than one week after newly introduced anti-psychotic and anti-depressant. So, the clinical picture is more compatible with NMS than serotonin syndrome.
It is also important to distinguish between NMS and serotonin syndrome in our patient. It is because bromocriptine for the treatment of NMS can potentially worsen serotonin syndrome whereas chlorpromazine for the treatment of serotonin syndrome can worsen NMS. In patients in whom NMS and serotonin syndrome cannot be differentiated, benzodiazepine may be the safest therapeutic option (4).
Risperidone is the most likely offending agent of NMS in our patient. More than 25 case reports strongly implicating risperidone as a cause of NMS have been published (2).
Risk factors of NMS include patient factors (agitation, dehydration, underlying medical and neurological disorders, extra-pyramidal syndrome, mental retardation, restrain and iron deficiency), medication factors (depot administration, rapid escalation of anti-psychotic dose, concomitant lithium) and environmental factors (high ambient temperature) (1), (3), (9).
Our patient suffered from NMS after rapid titration of newly introduced risperidone and precipitated by dehydration or hypovolemia due to bleeding rectal ulcer.
Most NMS episodes are self-limited. The mean recovery time after drug discontinuation is 7-10 days with 63% of patients recovering within 1 week and nearly all within 30 days (8).
Treatment of NMS should be individualized and based on character, duration, and severity of symptoms and signs. In mild cases, drug discontinuation and supportive treatment are the mainstays of treatment. In severe cases, specific treatment may be warranted (4), (8).
In clinically suspected NMS, the most important intervention is immediate cessation of the suspected agent (3).
Supportive treatment include anti-pyretic and cooling measures for high fever; rehydration and standard treatments for metabolic abnormalities and autonomic instability, provision of intensive medical and nursing care, prevention and treatment of complications (5).
Complications include respiratory (pneumonia, pulmonary embolism), cardiovascular (arrhythmia, cardiac arrest), renal (myoglobinuria, renal failure), neurological (movement disorder and cognitive failure) sequelae (6).
Specific treatment has limited evidence in the treatment of NMS and it has not been consistently shown to be superior to supportive measures. Pharmacotherapy includes dantrolene (muscle relaxant) for muscle rigidity and dopamine agonists (bromocriptine and amantadine) to reinforce the dopamine system. Treatment should be continued for 10 days beyond symptom resolution to prevent recrudescence of NMS. Electroconvulsive therapy (ECT) may be effective if symptoms are refractory to supportive care and pharmacotherapy (3).
In our patient, her NMS fails to respond after drug discontinuation and supportive treatment. So, combined treatment of dantrolene and bromocriptine is given resulting in resolution of NMS. If she is still refractory, ECT may be considered.
Reinstitution of anti-psychotic after resolution of NMS has been associated with a 30% estimated risk of recurrence of NMS. It is generally recommended to withhold anti-psychotic for at least two weeks after resolution of NMS. With reduction of risk factors, low doses of low-potency anti-psychotics should be reintroduced and titrated gradually after a test dose with careful assessment of recurrent NMS (4), (8).
Tables and Figures: (not more than 2)
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