Valproate-induced disabling tremor in a case of Rasmussen’s encephalitis

Sir, Rasmussen’s encephalitis (RE) is a chronic central neuroimmunological disorder characterized by inflammation of the unilateral cerebral cortex leading to intractable epilepsy, progressive cognitive decline, and neurological deficits.[1] Refractory epilepsy requires immunotherapy or cranial surgery along with standard anti-seizure medication (ASM) polytherapy at high dosages. Valproate is a broad-spectrum ASM. Valproate-induced tremors are a dose-related adverse effect due to gamma-aminobutyric acid-ergic (GABAergic) pathogenesis.[2] Here, we report a young woman suffering from prominent tremors and describe the clinical features, electroencephalogram, and outcome. This 27-year-old female presented with abnormal movements in her head, neck, and left upper limb (UL) for 3 months. It started insidiously in her head which progressed to the neck over a week. Ten days later, noticed a similar movement in her left UL. The movements were involuntary, nonsuppressible, rapid, to-and-fro, and rhythmic which disappeared during sleep. There was no aggravating factor, sensory trick, or specific timing of the appearance of movement, but it affected her daily activities. She has been suffering from epilepsy since 2 years of age when she had a fever, altered consciousness, and generalized tonic-clonic seizures (GTCS). She was diagnosed with encephalitis but she was partially treated. Since then, she witnessed frequent episodes of GTCS lasting for 2–3 min. The frequency increased from one in 2–3 months initially to two attacks monthly for the last 4 months. She has been on regular ASM for the last 3 years (valproate 750 mg twice daily, oxcarbazepine 450 mg twice daily, and levetiracetam 500 mg twice daily). Recently, over 3 months, she has become more agitated, with episodes of abnormal laughter and irrelevant talking. There is no history of weakness, paresthesia, headache, difficulty in micturition, abnormal birth history, developmental delay, or head injury. Her general examination was unremarkable. A nervous system examination showed a Glasgow Coma Scale of E4V4M6 and normal cranial nerves. Motor examination showed normal bulk, cogwheel rigidity (left UL > right UL), generalized hyperreflexia, and extensor plantar response. There was evidence of high-frequency resting tremors in both thumbs (left > right) at the flexion-extension plane, postural fine tremors of the left > right hand and fingers at the metacarpophalangeal and wrist joints with flexed posture of left UL, and yes-yes type head tremor without intentional component [Video 1]. The rest of the examination, including other systems, was normal. Her neuropsychiatric assessment showed severe deficits in attention and concentration, memory, executive functioning, and visio-motor and visio-spatial integration, along with mild–moderate deficits in phonemic fluency, working memory, verbal intelligence, and comprehension. Her blood investigations showed normal hemogram, renal, liver, and thyroid functions, and electrolytes with elevated ammonia levels (120 ug/dL). Her serum valproate level (75 μg/mL) was elevated. Her brain magnetic resonance imaging showed focal right-sided temporoparietal atrophy with nonenhancing T2/FLAIR white matter asymmetric hyperintensities [Figure 1]. The electroencephalogram showed focal areas of slowing. She was diagnosed with RE and intravenous immunoglobulin (IVIg) was started. Valproate was stopped, and she was put on additional lacosamide (100 mg) and propranolol (20 mg) twice daily. Her tremors improved over 1 month and she was able to do her daily activities. At 3-month follow-up, after three cycles of IVIg, she had a significant decrease in seizure frequency and a better quality of daily life index.Figure 1: Magnetic resonance imaging of the brain showing (a) right temporoparietal atrophy (yellow arrow) in the axial T1 section, (b) right temporoparietal T2 axial white matter hyperintensities (yellow arrow), (c) right temporoparietal white matter hyperintensities (yellow arrow) in axial FLAIR sequence of the brain with atrophic changesRE is a chronic inflammatory neurodegenerative disease of the cerebral hemisphere mainly affecting children. It leads to refractory epilepsy and progressive neurocognitive deficits. The index case of RE was presented by renowned neurosurgeon Dr. Theodore Rasmussen et al.[1] in 1858 at the Montreal Neurological Institute. The exact etiology of RE is unknown, but cytotoxic T-cell reaction against cerebral neurons has been proposed. Imaging studies help toward monitoring the disease progression and excluding important differentials, including Dyke–Davidoff–Masson syndrome, Sturge–Weber syndrome, uni-hemispheric cerebral vasculitis, hemi-megalencephaly, intracranial space-occupying lesions, and head injury. The early initiation of immunotherapy in RE has been shown to alter the natural course and improve the outcome. Immunotherapy with IVIg, tacrolimus, rituximab, high-dose steroids, natalizumab, azathioprine, and surgical excision form the therapeutic armamentarium. Intractable epilepsy is an important component of RE, and polytherapy of ASM is being widely used. However, it leads to a multitude of adverse drug effects, of which tremors are an important neurological phenomenon. Valproate-induced tremor is a dose-related phenomenon appearing as a high-frequency, low-amplitude tremor resembling adrenergic and essential tremor. The incidence of tremors in valproate therapy approximates 5%–57% with mean blood levels ranging 71–123 μg/mL.[3] Approximately 25% of patients on valproate therapy can develop tremors within 3 months to 1 year on initiation.[4] Central GABAergic dysfunction is involved in its genesis, and drugs such as propranolol, amantadine, diphenhydramine, benztropine, and cyproheptadine which are capable of enhancing the GABAergic neurotransmission are effective in the treatment. In a study by Alonso-Juarez et al., a significantly high rate of valproate-induced tremor is observed in females, ULs, postural type, and higher dose.[5] Valproate-induced tremor is partially reversible with discontinuation of valproate acid. However, the use of valproate in young females of reproductive age group should be judiciously advocated. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published, and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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