Dear Editor,
An 80-year-old female presented with generalised weakness, poor speech
and intermittent movements of bilateral hands and peri-oral area of 10
days duration, and fever for 2 days. She had been bedridden for the past
10 days. The patient had a background history of hypertension, type 2
diabetes mellitus, hypothyroidism, and chronic bronchitis. She was
receiving cilnidipine 10mg b.i.d, thyroxine 50µg o.d, zolpidem 5mg o.d,
glimepride 2mg o.d, metformin 1000mg o.d, metered dose inhaler(MDI) of
salmeterol- fluticasone and an over-the-counter analgesic of unclear
identity on as needed basis for osteoarthritis of the knees. She was
febrile, well oriented at the time of admission, with stable vitals.
Chest examination revealed bilateral crackles. Bilateral upper limb
tremors were present with generalised rigidity. After routine
investigations (Table 1 ), a provisional diagnosis of urinary
tract infection resulting in sepsis and acute kidney injury was made.
Meropenem was initiated at the dose of 500mg 8-hourly and linezolid at
the dose of 600mg 12-hourly. Prophylaxis for deep vein thrombosis was
initiated.
On day-3 of admission, the patient had one episode of generalized tonic
clonic seizures (GTCS) and became delirious. Injectable phenytoin 100mg
was given 8-hourly along with oral carbamazepine 200mg b.i.d and
clobazam 10mg o.d. Magnetic resonance imaging (MRI) of the brain done on
day-4 of hospital stay was normal. Electroencephalogram (EEG) done on
day-5 of hospital stay was non-specific with features of metabolic
encephalopathy. Cerebrospinal fluid examination was planned but withheld
as consent could not be obtained. The patient’s blood pressure and heart
rate were normal in the first few days of hospitalization but showed
marked fluctuations thereafter during continuous monitoring, requiring
multiple drug and dose modifications. As her general condition including
tremors failed to improve, a provisional diagnosis of neuroleptic
malignant syndrome was made, and bromocriptine was started at the dose
of 2.5mg BD on day-12. Marked improvement in tremors and general
condition was seen within 24 hours of starting
bromocriptine. Carbamazepine was tapered and stopped over the next few
days. Since the patient developed excessive sedation with bromocriptine,
it was replaced by levodopa-carbidopa 62.5 mg t.i.d. This was well
tolerated by the patient. A repeat MRI of the brain was again
non-contributory, and the patient was discharged on day-20.
To identify the cause of NMS, drug review was repeated, and the
caregivers were asked to bring the over-the-counter analgesic which the
patient had been taking. The OTC analgesic prescribed one-month back was
PANADOL (paracetamol 500mg). Instead, the patient started consuming
PANIDO-L (pantoprazole 40mg- Levosulpiride 75mg). This had been
prescribed to the patient by her family physician 5 months back,
probably for dyspepsia. The exact amount of consumption of PANIDO-L
could not be ascertained, but the caregivers gave a history of once to
twice daily dosing of the drug for the past 20 days before she got
admitted. At present with uneventful follow up of more than 1 year, the
patient is maintained on thyroxine, nifedipine, chlorthalidone and MDI
of salmeterol-fluticasone.
Neuroleptic malignant syndrome(NMS) is a lethal idiosyncratic reaction
characterized by fever, rigidity, altered sensorium and autonomic
disturbances.1NMS carries a mortality rate of 10-20%
if untreated. The aetiopathogenesis of NMS is still unclear but dopamine
blockade in hypothalamus, meso cortical system and striatum has been
linked to fever, altered sensorium and Parkinsonian features,
respectively. Increased sympathoadrenal activity and abnormal regulation
of calcium in skeletal myocytes are thought to produce autonomic
disturbances and muscle rigidity.1 In many cases, the
typical features of NMS are preceded by the development of Parkinsonian
features, as was in our case. Here, we reported a case of levosulpiride
associated NMS with normal CPK in an elderly female with moderate renal
dysfunction. CPK is raised in many cases of NMS but it is no longer
uncommon to find NMS with normal CPK.1,2Levosulpiride, S(-) enantiomer of sulpiride, belongs to the benzamide
class of antiemetics and is a blocker of dopamine (D2) receptors. The
drug is available in India, Korea, and some European countries. It is
used for gastrointestinal disorders at the dose of 25 mg thrice daily
while a higher dose of 200-400 mg is advised for the management of
psychiatric illnesses. Since the primary route of elimination of
levosulpiride is renal, toxicity can occur even when the drug is used at
therapeutic dose in patients with renal derangement. On Naranjo scale,
the reaction shared a ‘probable’ association with levosulpiride and was
rated as ‘severe’ in Hartwig’s severity assessment scale.
The common differential diagnoses of NMS include viral encephalitis,
serotonin syndrome, lethal catatonia and nonconvulsive status
epilepticus and were reasonably excluded in our patient
(Supplementary table 1 ).1 Lack of clinical
improvement with reasonable course of antibiotics and antiepileptics and
marked improvement within 24 hours of bromocriptine administration are
the major features supportive of NMS. On PubMed search, we found only
one published case of levosulpiride associated NMS. The case occurred in
a 53-year-old female of rheumatoid arthritis and type 2 diabetes
mellitus with adrenal insufficiency who developed acute renal injury
secondary to gentamycin injections and then developed nausea and
vomiting for which she received parenteral levosulpiride. NMS like
features developed soon after.3 Another drug suspected
to contribute to our patient’s condition was cilnidipine. Though we
could not find any relevant reports of possible association of NMS with
cilnidipine, a possibility of drug interaction between levosulpiride and
cilnidipine cannot be excluded. Cilnidipine belongs to the class of L
type calcium channel blockers and some members of this class have been
linked with Parkinsonian syndrome complex.4
The present case highlights two major points. First, NMS can occur with
levosulpiride at the recommended therapeutic dose, particularly in the
presence of renal dysfunction. Discontinuation of the offending drug,
prompt symptomatic therapy and institution of bromocriptine are the life
saving measures which make NMS treatable. Second, the case also
highlights how a minor difference in the brand names of two drugs can
lead to inadvertent administration of a wrong drug and produce undesired
consequences, especially in elderly patients. Such easily available over
the counter medications with confusing brand names need to be under
stricter scrutiny of regulatory bodies.
Acknowledgment: None
Conflict of interest: None
Funding: None