Neurol Sci DOI 10.1007/s10072-015-2105-5

LETTER TO THE EDITOR

An unusual case of isoniazid toxicity Odysseas Kargiotis • Markos Marangos Panagiotis Polychronopoulos



Received: 6 December 2014 / Accepted: 2 February 2015 Ó Springer-Verlag Italia 2015

Dear Editor, We present herein an unusual case of isoniazid (INH)-induced encephalopathy in a 75-year-old male patient who was diagnosed with pulmonary tuberculosis. The patient had a history of arterial hypertension and psoriasis, treated with adalimumab. He was completely independent for activities of daily living, with no evidence of significant cognitive impairment other than mild forgetfulness. Following the diagnosis, the patient was treated with rifampicin 600 mg/day, INH 300 mg/day, pyrazinamide 1,500 mg/day and ethambutol 1,200 mg/day with concurrent cessation of adalimumab. Initially, the patient responded well to treatment with amelioration of his respiratory function and attenuation of fatigue and fever. However, 3 weeks after treatment initiation, he presented with symptoms of mild cognitive dysfunction, such as disorientation in time, difficulties in sustained attention and retrieval of recently acquired information. A brain CT scan revealed multiple lacunar type ischemic lesions at the basal ganglia and the deep white matter, as well as prominent frontal and temporal cortical atrophy with no evidence of central nervous system tuberculosis. Seven days later, his cognitive status deteriorated further with no evidence of hepatic toxicity and while on pyridoxine prophylactic treatment (50 mg). The neurological examination

O. Kargiotis (&)  P. Polychronopoulos Department of Neurology, University Hospital of Patras, 26504 Rion, Greece e-mail: [email protected] M. Marangos Division of Infectious Diseases, University Hospital of Patras, 26504 Rion, Greece

revealed disorientation in time and in space, coding and retrieval deficits of newly acquired information, executive dysfunction with motor perseveration and reduced mental flexibility, as well as visuospatial deficits. There were also mild bradykinesia and upper limb rigidity. There was no nuchal rigidity, pyramidal signs, sensory deficits or cranial nerve palsies. Two weeks later, the patient complained of well formed visual hallucinations, mainly in forms of animals (bugs and cats). Interestingly, the patient’s cognitive and motor status was characterized by significant and unpredictable fluctuations during the course of the day. An electroencephalogram revealed signs of moderate encephalopathy, with an unstable, non-reactive, slow wave rhythm of 5–7 Hz and frontal intermittent delta waves (Fig. 1a). A brain MRI showed no signs of meningeal inflammation or tuberculomas (Fig. 2). The attempt to perform a lumbar puncture was unsuccessful due to advanced spine degeneration secondary to psoriatic arthritis. One week later, the patient exhibited an abrupt and severe deterioration with speech impairment (both of comprehension and fluency), severe total body bradykinesia and confusion. An urgent cerebral MRI showed no acute lesion. The patient was afebrile and routine laboratory tests were unremarkable. Because of severe visual hallucinations, we suspected drug toxicity and we decided to withdraw INH that according to the literature was the most suspicious agent. After INH withdrawal, the patient started to experience immediate and continuous improvement, starting from cessation of hallucinations. Four weeks later, the neurological assessment verified a significant amelioration of the cognitive status with improvement in visuospatial orientation and executive functioning. The patient exhibited a marked improvement in activities of daily living, self-

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Fig. 1 Initial electroencephalogram showing generalized slowing with a non-reactive 5–7 Hz rhythm as well as bilateral frontal intermittent delta waves (a). Electroencephalogram 4 weeks after

withdrawal of INH showing a stable 7 Hz posterior rhythm which is adequately suppressed on eye opening and re-emerges on eye closure (b)

hygiene as well as gait and motivation. The electroencephalogram showed a more stable, organized and reactive 7 Hz rhythm (Fig. 1b). However, the patient did not fully recover to his previous cognitive status. Given the clinical course characterized by an immediate clinical amelioration after INH cessation, we conclude that the patient most probably suffered from INH-induced encephalopathy. However, our diagnosis is limited by the absence of cerebrospinal fluid analysis and serum INH levels. INH is acetylated in the liver and secreted in both free and acetylated forms in the urine. The rate of acetylation depends on the genetic trait, autosomal dominant or recessive [1]. Patients with renal insufficiency are more susceptible to INH’s toxicity and there are reports of

toxic encephalopathy with confusion and disturbances of consciousness in this group of patients [2, 3]. In nondialyzed patients, the most frequent encephalopathic feature of INH’s toxicity consists of psychosis [4]. Neurotoxocity of INH is related to pyridoxine’s phosphorylation inhibition with a subsequent decrease in pyridoxal-5-phosphate, resulting in reduced levels of several neurotransmitters including gamma-aminobutyric acid [4]. In conclusion, our patient developed a progressive and fluctuating encephalopathy, characterized by a predominant subcortical/frontal dysexecutive syndrome and bradykinesia, despite adequate pyridoxine supplementation and normal renal function. A possible predisposing factor

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Fig. 2 Axial T2 Brain Magnetic Resonance Imaging (MRI) sequence showing multiple periventricular and deep white matter chronic ischemic lesions and absence of hydrocephalus (a, b). Axial, contrast

enhanced T1 brain MRI sequence with no evidence of basal cistern leptomeningitis or pachymeningitis (c, d)

could be the pre-existing, increased chronic vascular ischemic burden revealed by brain imaging. Unfortunately, the patient did not fully recover, despite significant improvement. Thus, it is important to be aware of the possible central nervous system neurotoxicity of INH in potentially vulnerable individuals—older age, renal insufficiency, cardiovascular disease—to early recognize the initial symptoms and withdraw the offending agent.

References

Conflict of interest of interest.

The authors declare that they have no conflict

1. Goldman AL, Braman SS (1972) Isoniazid: a review with emphasis on adverse effects. Chest 62:71–77 2. Abbas MT, Khan FY, Sulimon S, Baidaa A (2013) Encephalopathy secondary to isoniazid in patients on hemodialysis. Indian J Nephrol 23:54–56 3. Cheung WC, Lo CY, Lo WK, Ip M, Cheng IK (1993) Isoniazid induced encephalopathy in dialysis patients. Tuber Lung Dis 74:136–139 4. Prasad R, Garg R, Verma SK (2008) Isoniazid- and ethambutolinduced psychosis. Ann Thorac Med 3:149–151

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An unusual case of isoniazid toxicity.

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