Asymmetrical Holmes’ Tremor Heralding HIV-Associated Neurocognitive Disorder

Sir,

HIV-associated neurocognitive disorder (HAND) describes the spectrum of cognitive dysfunction associated with HIV infection. Prior to the introduction of antiretroviral therapy (ART), HAND was frequent and often progressed to severe cognitive impairment, called HIV-associated dementia (HAD). With the advent of ART, HAD has become rare, although HAND continues to prevail. Although movement disorders have been reported to occur in nearly 50% of persons with HIV, these usually coexist with other features such as neuropathy, myelopathy, seizures, and cognitive impairment.[1] We present a rare case of a patient presenting chiefly with prominent asymmetrical Holmes’ tremor with mild cognitive decline, as a heralding feature of HAND.

A 17 years-old female presented with right upper limb tremors for 10 months, left upper limb tremors for three months, and gait ataxia for three months. She was born at term by home delivery and had a delayed cry. Subsequent developmental milestones showed global delay. She had moderate mental retardation (intelligence quotient score 50-55). She was able to conduct basic activities of daily living. However, parents had noted some decline in executive function and processing speed for the past three months, leading to impairment in usual activities. She had a history of recurrent chest infections with repeated hospitalizations since the age of 6-7 years. She had also developed bilateral chronic suppurative otitis media (CSOM). She had developed disseminated tuberculosis (involving lungs and abdomen) four years back for which she had been managed with anti-tuberculous therapy, with complete recovery. She had undergone cholecystectomy for symptomatic cholelithiasis one year previously. Records for these procedures and hospital admissions were unavailable to the patient at the time of presentation to our center.

On examination, the detailed cognitive evaluation showed impaired attention, executive dysfunction, and recent memory impairment. She was observed to have an asymmetrical tremors of both upper limbs (right more than left) at rest, in posture, and with intentional component [Supplemental Video]. She had spastic-cerebellar dysarthria. She had spasticity of limbs (right > left). Features of incoordination were observed (impaired finger-nose test, rapid alternating movements, and heel-knee-shin test). The gait was ataxic. Deep tendon reflexes were brisk (right > left). Systemic examination showed bilateral CSOM but was otherwise unremarkable. The evaluation showed normal hemogram, and renal, hepatic, and thyroid function tests. The Erythrocyte sedimentation rate was elevated (86 mm/hr). MRI brain, which had initially been done three months into the illness, showed bilateral T2-weighted periventricular subcortical white matter signal change, and cerebral and midbrain atrophy [Figure 1a]. MRI brain, repeated at admission seven months later, showed extensive diffuse bilateral periventricular white matter T2/FLAIR hyperintensity without contrast enhancement, and diffuse cerebral atrophy [Figure 1b-d]. Cerebrospinal fluid analysis showed no cells, protein 50 mg/dL, and glucose 66 mg/dL (concomitant blood glucose 101 mg/dL). Cytology for atypical cells, Gram stain, bacterial culture, India Ink stain, cryptococcal antigen, acid fast bacilli smear, GeneXpert for tuberculosis, VDRL, and PCR for JC virus was negative. Anti-NMO/MOG, Hepatitis B and anti-HCV serology and serum VDRL were negative. HIV-1 serology was positive. CD4 cell count was 101 cells/mm3. Nerve conduction studies and electroencephalography (EEG) was normal. The leukodystrophy genetic panel was negative. A diagnosis of HAND was established, and she was initiated on ART with TLD (tenofovir, lamivudine, dolutegravir), and trimethoprim-sulfamethoxazole prophylaxis. For tremors, she was initiated on levetiracetam, clonazepam, and propranolol, with mild symptomatic relief.

Figure 1.

(a) T2/FLAIR axial section of the brain at presentation showing bilateral asymmetrical (left > right) subcortical confluent white matter hyperintensities (b) T2-weighted axial section showing increase in subcortical white matter hyperintensities (c) T2-weighted axial section showing global and brainstem (midbrain) atrophy (d) T2/FLAIR axial sections showing extensive periventricular confluent white matter hyperintensities

HAND encompasses a spectrum of disorders[2]: asymptomatic neurocognitive impairment, characterized by impairment in at least two cognitive domains (≥1 standard deviation [SD]) without interference in daily function; mild neurocognitive disorder (MND) characterized by impairment (≥ 1SD) in at least two cognitive domains which leads to mild-moderate interference in daily functioning; and HAD, characterized by severe impairment (≥2 SD) leading to marked impairment in daily functioning. Nearly 15-55% of persons with HIV reportedly develop HAND. With ART, the milder variants of HAND have become more frequent compared to the severe forms, in contrast to the pre-ART era.[3] Moreover, motor impairment, predominantly bradykinesia and ataxia, were more commonly associated with HAND in the pre-ART era compared to the ART era.[4]

Movement disorders associated with HIV eventually develop in nearly 50% of patients,[1] and include hyperkinetic movement disorders, including tremors, chorea, ballism, myoclonus, tics, and hypokinetic disorders including parkinsonism, as well as opsoclonus-myoclonus-ataxia syndrome[5] and isolated ataxia as well.[6] These may be associated with opportunistic infections like toxoplasmosis, neoplasms like lymphoma, progressive multifocal leukoencephalopathy,[7] or HIV itself. One patient with Holmes’ tremor had tuberculosis and toxoplasmosis co-infection involving the midbrain and the cerebellum.[8] In terms of treatment, the tremor is often resistant to pharmacological measures. VIM thalamotomy[9] and deep brain stimulation have been tried successfully in Holmes’ tremors in association with immune reactivation inflammatory syndrome (IRIS).[10]

Our patient demonstrated certain unusual features. Firstly, she developed a hyperkinetic movement disorder as a major feature of HAND, with less prominent cognitive deterioration. A clue to the diagnosis was achieved by the past medical history of recurrent infections, and the involvement of other axes in the neurological system, such as spasticity, avoiding an unnecessary diagnostic odyssey, The second unusual feature was de novo presentation with Holmes’ tremor as a heralding manifestation of HAND, which has rarely been reported.[8] Although Holmes’ tremor has been described commonly with thalamic, brainstem, or cerebellar lesions, our patient had nonthalamic supratentorial lesions not involving the aforementioned structures, which may be seen in a small portion of patients with Holmes’ tremor.[11] Moreover, as our patient had a history of perinatal insult, the initial MRI may have been misinterpreted as suggestive of perinatal hypoxia. A repeat imaging, showing progression consistent with clinical worsening, provided vital clues towards a progressive illness rather than static perinatal insult.

Our case highlights a rare presentation of HAND, in the form of asymmetrical Holmes’ tremor, in combination with ataxia, spasticity, and subtle cognitive decline. HAND represents a possibly treatable albeit uncommon cause of de novo movement disorder.

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