Keywords Dentate nucleus hyperintensity - drug-induced cerebellitis - isoniazid neurotoxicity
Introduction
The dentate nucleus is the largest deep cerebellar nuclei and is affected by many
benign and potentially treatable conditions with favorable prognosis.[[1 ]] Metronidazole is the most common cause for drug-induced cerebellitis, affecting
the bilateral dentate nuclei.[[1 ]] In developing countries where tuberculosis (TB) is prevalent, isoniazid (INH) an
antituberculosis drug, induced cerebellitis, though rare,[[2 ]] is a possible condition to be aware of. Though INH toxicity is more common in children,
patients with chronic kidney disease (CKD) are more prone toits toxicity due to reduced
renal clearance.[[3 ]] The classical history of initiation of four-drug regimen (that includes INH) for
tuberculosis and onset of cerebellar symptoms in a CKD patient, should promptly raise
the suspicion of INH-induced cerebellitis.[[3 ], [4 ], [5 ]] The findings in magnetic resonance imaging (MRI) include bilateral and symmetrical
T2 and fluid-attenuated inversion recovery (FLAIR) hyperintensity of dentate nuclei
and classically being an isolated finding.[[2 ], [3 ], [4 ], [5 ]] There are only a few cases documented in literature.[[2 ], [3 ], [4 ]] Often a diagnosis of exclusion, withdrawal of INH, and pyridoxine supplementation
can potentially reverse the clinical and imaging findings, thus confirming thediagnosis.[[5 ]]
Case History and Imaging Findings
Case History and Imaging Findings
A case of 55-year-old male patient was diagnosed with pulmonary tuberculosis and was
initiated with four-drug antituberculosis regimen that includes, INH, rifampin (R),
pyrazinamide (Z), and ethambutol (E). After two weeks, the patient presented with
acute onset of dysarthria and gait disturbance. He was not a known alcoholic or hypertensive
and the blood pressure recorded was normal at the time of presentation. Clinical investigations
showed elevated serum creatinine (2.0 mg/dl) and there was no electrolyte imbalance.
His liver function tests were normal. Ultrasound (USG) was advised to assess the renal
status andit showed features of bilateral medical renal disease in the form of increased
renal cortical echoes with small-sized kidneys.
Computed tomography (CT) of brain was suggested to rule out intracranial pathology.
CT brain, however, showed no evidence of hemorrhage or infarcts [[Figure 1 ]]. Hence, MRI was further planned and it showed areas of bilateral and symmetrical
T2 and FLAIR hyperintensities in dentate nuclei of the cerebellum [[Figures 2 ] and [3 ]]. The corresponding areas also showed hyperintensity in diffusion weighted imaging
(DWI), without any signal changes in apparent diffusion coefficient (ADC) [[Figures 4 ] and [5 ]]. Metronidazole toxicity was suspected but there was no drug history of that kind,
on retrospective clinical history. Cerebrospinal fluid (CSF) analysis did not show
any signs of infection. Through the process of diagnosis of exclusion, we have made
a possible diagnosis of INH-induced cerebellitis, which is also described in literature
and case reports, in the background of renal function impairment.
Figure 1: Axial sections of CT show no infarct or haemorrhage in cerebellar hemispheres
Figure 2: Axial T2 W image shows bilateral symmetrical hyperintense signal in dentate nuclei
of cerebellum
Figure 3: Axial FLAIR image shows bilateral symmetrical hyperintense signal in dentate nuclei
of cerebellum
Figure 4: Axial DWI shows the bilateral symmetrical hyperintense signal in dentate nuclei of
cerebellum
Figure 5: Axial ADC image shows no abnormal signals in the dentate nuclei of cerebellum
Accordingly, the INH was withdrawn from the regimen and pyridoxine supplementation
was started. The patient started to show dramatic improvement clinically within a
week and with complete resolution of cerebellar symptoms after two weeks. Follow-up
MRI was done after 2 weeks, which showed complete resolution of signal changes in
cerebellar dentate nuclei, at T2/FLAIR images [[Figures 6 ] and [7 ]]. No abnormal signals wereseen in DWI/ADC [[Figures 8 ] and [9 ]], thus confirming the diagnosis of INH-induced cerebellitis.
Figure 6: Axial T2 W image shows resolved hyperintense signal in both dentate nuclei of cerebellum
Figure 7: Axial FLAIR image shows resolved hyperintense signal in both dentate nuclei of cerebellum
Figure 8: Axial DWI shows no restriction in both dentate nuclei of cerebellum
Figure 9: Axial ADC image shows no abnormal signals in the dentate nuclei of cerebellum
Discussion
The four paired deep nuclei of the cerebellum are very important in the formation
of cerebro-cerebellar circuit that relay information from the cerebellum to supratentorial
cortical and subcortical targets.[[1 ]] The dentate nuclei are the most lateral and largest among them and they are located
adjacent to vermis and roof of the fourth ventricle, on either side.[[1 ]] They are involved in the planning and execution of voluntary movements, higher-level
cognition, and sensory processing.[[1 ]]
Drug-induced cerebellitis involving dentate nuclei is classically seen with metronidazole
toxicity.[[1 ], [2 ]] Rare association with INH, an antituberculous drug, has been documented in patients
with renal function impairment.[[3 ], [4 ], [5 ]] INH is both hepatotoxic and neurotoxic.[[4 ]] The later often manifest in the form of peripheral neuropathy,[[2 ], [4 ]] due to its interference with pyridoxine metabolism resulting in vitamin deficiency.[[3 ]] Central nervous system (CNS) involvement by its metabolite, known as isonicotinylhydrazide,
can result in encephalopathy.[[3 ]] Cerebellum involvement is rare, but do occur, involving the bilateral dentate nuclei
with resultant edema due to reduced gamma-aminobutyric acid (GABA) levels and down
regulation of N-methyl-D-aspartate (NMDA) receptors.[[2 ]] INH is primarily excreted through kidneys and hence reduced clearance in CKD patients
is responsible for neurotoxicity.[[5 ]] Hence, patients with CKD are prone to INH-induced cerebellitis.[[2 ], [3 ], [4 ], [5 ]]
The clinical presentations of cerebellitis include unsteady gait, dysarthria, impaired
finger-nose test, and past pointing.[[4 ]] Association of drug initiation and the origin of such symptoms in a patient with
CKD should raise the suspicion of INH-induced cerebellitis.[[3 ], [5 ]]
MRI findings include classical bilateral and symmetrical T2/FLAIR hyperintensity involving
the dentate nuclei, suggestive of edema.[[2 ], [3 ], [4 ], [5 ]] Differential diagnosis includes methyl bromide toxicity, enteroviral infections,
maple syrup urine disease, and metronidazole toxicity.[[2 ], [5 ]] Atypical Wernicke’s encephalopathy can be considered in the differential diagnosis
if the involvement of the dentate nuclei is not an isolated finding.[[5 ]] In our case, meticulous medical history and clinical investigations excluded all
other possible differential diagnoses.
Conclusions
INH-induced cerebellitis should be considered in the differential diagnosis of bilateral
dentate nuclei hyperintensity especially in patients with renal function impairment.
Early diagnosis and treatment in the form of INH withdrawal and pyridoxine supplementation
can potentially reverse the edema and cause dramatic improvement in the patient’s
symptoms.
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