Treatment-responsive Holmes tremor in a child with low-pressure hydrocephalus: video case report and systematic review of the literature

Stephano J. Chang MD, PhD1, Ruth Mitchell BA, BSc, BMBS2, Juliette Hukin MBBS3, and Ash Singhal MD, MSc2
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  • 1 Division of Neurosurgery, Department of Surgery, University of British Columbia;
  • | 2 Faculty of Medicine and the Division of Neurosurgery, University of British Columbia and British Columbia Children’s Hospital; and
  • | 3 Divisions of Neurology and Hematology/Oncology/Bone Marrow Transplant, Department of Pediatrics, University of British Columbia and British Columbia Children’s Hospital, Vancouver, British Columbia, Canada
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OBJECTIVE

Holmes tremor (HT) is a rare and debilitating movement disorder comprising both rest and action tremor, and it is known for its resistance to treatment. Its most common causes include ischemic or hemorrhagic insults and trauma. Mechanistically, the combined rest and action tremor is thought to require a double lesion of both the dopaminergic nigrostriatal system and the dentatorubrothalamic pathways, often near the midbrain where both pathways converge. The aim of this study was to characterize HT as a presenting sign in cases of hydrocephalus and to discuss potential pathomechanisms, clinical presentations, and treatment options.

METHODS

MEDLINE and Web of Science were searched for cases of HT with hydrocephalus from database inception to August 2021, and these were compiled along with the authors’ own unique case of treatment-responsive HT in a child with low-pressure obstructive hydrocephalus secondary to a tectal tumor. Patient characteristics, presenting signs/symptoms, potential precipitating factors, interventions, and patient outcomes were recorded.

RESULTS

Nine patients were identified including the authors’ video case report. All patients had a triventriculomegaly pattern with at least a component of obstructive hydrocephalus, and 4 patients were identified as having low-pressure hydrocephalus. Parinaud’s syndrome and bradykinesia were the most commonly associated signs. Levodopa and CSF diversion were the most commonly used and effective treatments for HT in this population. This review was not registered and did not receive any funding.

CONCLUSIONS

HT is a poorly understood and probably underrecognized presentation of hydrocephalus that is difficult to treat, limiting the strength of the evidence in this review. Treatment options include CSF diversion, antiparkinsonian agents, antiepileptic agents, deep brain stimulation, and MR-guided focused ultrasound, and aim toward the nigrostriatal and dentatorubrothalamic pathways hypothesized to be involved in its pathophysiology.

ABBREVIATIONS

DBS = deep brain stimulation; DRTT = dentatorubrothalamic tract; ETV = endoscopic third ventriculostomy; HT = Holmes tremor; ICP = intracranial pressure; NST = nigrostriatal tract; STN = subthalamic nucleus; Vim = ventral intermediate nucleus; VPS = ventriculoperitoneal shunt.

OBJECTIVE

Holmes tremor (HT) is a rare and debilitating movement disorder comprising both rest and action tremor, and it is known for its resistance to treatment. Its most common causes include ischemic or hemorrhagic insults and trauma. Mechanistically, the combined rest and action tremor is thought to require a double lesion of both the dopaminergic nigrostriatal system and the dentatorubrothalamic pathways, often near the midbrain where both pathways converge. The aim of this study was to characterize HT as a presenting sign in cases of hydrocephalus and to discuss potential pathomechanisms, clinical presentations, and treatment options.

METHODS

MEDLINE and Web of Science were searched for cases of HT with hydrocephalus from database inception to August 2021, and these were compiled along with the authors’ own unique case of treatment-responsive HT in a child with low-pressure obstructive hydrocephalus secondary to a tectal tumor. Patient characteristics, presenting signs/symptoms, potential precipitating factors, interventions, and patient outcomes were recorded.

RESULTS

Nine patients were identified including the authors’ video case report. All patients had a triventriculomegaly pattern with at least a component of obstructive hydrocephalus, and 4 patients were identified as having low-pressure hydrocephalus. Parinaud’s syndrome and bradykinesia were the most commonly associated signs. Levodopa and CSF diversion were the most commonly used and effective treatments for HT in this population. This review was not registered and did not receive any funding.

CONCLUSIONS

HT is a poorly understood and probably underrecognized presentation of hydrocephalus that is difficult to treat, limiting the strength of the evidence in this review. Treatment options include CSF diversion, antiparkinsonian agents, antiepileptic agents, deep brain stimulation, and MR-guided focused ultrasound, and aim toward the nigrostriatal and dentatorubrothalamic pathways hypothesized to be involved in its pathophysiology.

In Brief

Researchers performed a systematic review of cases of Holmes tremor secondary to hydrocephalus, to identify clinical associations, pathomechanisms, and treatment options. Obstructive triventriculomegaly with low pressure was a common association, as were oculomotor deficits, bradykinesia, and rigidity. CSF diversion and levodopa administration were the most common and effective treatments, providing insights into the pathophysiology of this rare and refractory condition.

Holmes tremor (HT), also known as rubral or midbrain tremor, is an uncommon and poorly understood tremor syndrome of the upper extremities characterized by its low frequency (2–5 Hz) and coarse amplitude.1,2 Named for Dr. Gordon Holmes,3 the diagnostic criteria for this eponymous tremor require a combination of rest and intention tremor, although a postural component is also often present.2 It is associated with midbrain lesions and is usually unilateral, but can be bilateral depending on the extent of the lesion.1 Stroke is the most commonly reported cause, with trauma, infection, demyelination, vascular malformations, and tumors also described as etiologies.1 When a discrete timing of onset for the lesion is known, there is usually a variable delay to tremor onset between 1 and 24 months.4 It is classically thought to be irreversible and resistant to pharmacotherapy, although some successes with antiparkinsonian agents (such as levodopa5 and trihexyphenidyl6) and antiepileptic medications (such as topiramate,1 levetiracetam,7 and zonisamide8) have been noted in the literature. Deep brain stimulation (DBS) has also been reported to be successful at treating HT, with targets including the ventral intermediate nucleus (Vim), the caudal zona incerta, and combinations of Vim and globus pallidus internus or subthalamic nucleus (STN).9–12

Several lines of evidence, including nonhuman primate lesioning data,13 pathoanatomical and functional imaging studies,4,14 and clinical observations,15 have traditionally suggested a "two-hit" pathomechanism for HT, with dysfunction of both the dopaminergic nigrostriatal tract (NST) and the dentatorubrothalamic tract (DRTT), usually by a lesion near the midbrain where both pathways coincide. However, more recent studies looking at dopamine transporter imaging and lesion network mapping have cast some doubt on the necessity of involvement of the NST.16,17 One possible interpretation is that based on the current clinical diagnostic criteria, HT represents a heterogeneous group of disorders of similar phenotypes with different underlying pathophysiological mechanisms.17 Under this view, refining these criteria to allow differentiation of etiological subgroups may be more clinically useful.

One recognized but uncommon cause of tremor is hydrocephalus. Here, we present a unique case of treatment-responsive HT in a child secondary to low-pressure hydrocephalus, and we discuss the potential pathophysiology based on a review of the literature.

Methods

A comprehensive literature review was performed by S.J.C. in PubMed and Web of Science by using the search "(Holmes OR rubral OR midbrain) AND tremor AND hydrocephalus." To ensure inclusion of HT not described as such, a second more general search using the keywords and MeSH terms "(tremor OR parkinsonism) AND hydrocephalus" was also added (Fig. 1). Duplicates were removed, as were cases in which neither the tremor was described as a Holmes/rubral/midbrain tremor nor was a clear description of HT as per the Consensus Statement of the Movement Disorder Society criteria included.2 Cases not clearly including hydrocephalus as part of the presentation or not describing the management and outcomes of hydrocephalus and tremor were also removed. Only articles written in English were included. Abstracts, conference presentations, editorials, and expert opinions were excluded. Review articles were omitted because of potential publication bias and duplication of results. Eight previously published cases of HT with concomitant hydrocephalus were found. Data extraction was performed by S.J.C., with the list of cases and a summary of relevant features compiled in Table 1.18–25 This review was not registered or a part of a protocol.

FIG. 1.
FIG. 1.

PRISMA-style flowchart of studies.

TABLE 1.

Summary of case reports of HT in patients with hydrocephalus

Authors & YearID; Age (yrs), SexDxTremorAssociated Signs & SymptomsSurgical ManagementSubsequent Course/OutcomeLevodopa Response
Benton et al., 1966181; 6.5, F3VCBilat hands R/IHB (2–3 Hz), macrocephaly, optic atrophy, hyperreflexia, cognitive impairmentFenestration of cyst wallResolution of hand tremors w/ improved but persistent HB; no recurrence of cyst 2 yrs laterNA
Sypert et al., 1973192; 28, MaSAH; basal cistern arachnoiditis, aqueduct ependymitisGeneralized R/I, including tongueHA, bradykinesia, rigidity, postural instability, hypomimia, sialorrhea, dysphagia, hypophonia, dysmetria, dysdiadochokinesia, incontinence, irrational behavior, catatoniaVentriculo-mastoidostomy (IVP <40 mm H2O)Complete resolution of motor abnormalities, incontinence, & cognitive deficits 1 mo postop, w/ reduction in ventricle sizeNA
Jankovic et al., 1986203; 14, FASBilat arm & lt leg R/I (4–5 Hz)HA, papilledema, Parinaud’s syndrome, bradykinesia, rigidity, postural instability, hyperreflexia, hypomimia, sialorrhea & dysphagia, hypophonia, micrographiaLow-pressure VPS markedly improving parkinsonismRequired 3 revisions, each time improving parkinsonism & resolving completely w/ addition of levodopa/carbidopaResolution w/ levodopa
Mascalchi et al., 1999214; 58, FMesencephalothalamic lacunaeRt arm rubral tremor (5–6 Hz)Parinaud’s syndrome, gait ataxia, bradykinesia, rigidity, urinary urgency, cognitive impairmentVPS (medium-pressure Holter valve)Prompt improvement of gait ataxia, urinary urgency, bradykinesia, & cognition; resolution of ventriculomegaly w/ increase in no. & size of lacunae w/o improvement in rubral tremor or Parinaud’s syndromeNA
Racette et al., 2004225; 44, MAS; VPS malfunctionBilat arm R/I (3 Hz)HA, Parinaud’s syndrome, bradykinesia, personality change, lethargy, confusion, bradyphrenia, reduced speechVPS revision (shunt opening pressure = 0)Radionuclide study confirmed functioning shunt despite lack of improvement; levodopa improved verbal response time, bradykinesia, & rigidityResolution w/ levodopa
Hertel et al., 2006236; 58, MIschemic midbrain lesionRt arm R/P/I (5–6 Hz)Ataxia in rt armVPS w/ 6 mos of immediate tremor resolutionRecurrence of tremor w/o shunt dysfunction (no DatSCAN abnormality, no perfusion abnormality); treated w/ Vim DBS successfullyNA
Prashantha et al., 2008247; 38, M4th ventricle NCC; previous rt VPS (failed)Bilat upper & lower limb R/I, worse on rt (5–5.5 Hz)Bradykinesia, hypomimia, dysarthriaLt VPSLt VPS improved sensorium, but 3 days later pt had onset of his tremors; 5 wks after onset, was started on levodopa & trihexyphenidyl, w/ good response at 3 wks & minimal hypomimia & lt arm tremor off all meds at 3 mosGood temporizing response to levodopa
Boelmans et al., 2012258; 39, FRt midbrain neuroglial cystLt arm coarse R/P/I (4 Hz)Lt skew deviation, incomplete upgaze palsy, downgaze torsional nystagmus, lt dysdiadochokinesia & dysmetria, mild pyramidal weakness on lt sideVPS VPS improved HAs, but not tremorImproved rest tremor w/ partial improvement in postural & intention tremor
Present study9; 6, MTectal pilocytic astrocytomaBilat coarse R/P/I (4–6 Hz)HA, Parinaud’s syndrome, dysphagia, truncal rigidity, hypomimia, palatal tremorETV, VPS, revisions & externalization, low-pressure valveTremors improved w/ VPS & further improved w/ levodopaGood temporizing response to levodopa

AS = aqueductal stenosis; aSAH = aneurysmal subarachnoid hemorrhage; Dx = diagnosis; HA = headache; HB = head bob; IVP = intraventricular pressure; NA = not applicable; NCC = neurocysticercosis; pt = patient; R/P/I = resting/postural/intention (tremor); 3VC = third ventricular cyst.

Report of the Present Case

This 6-year-old boy initially presented to our neurosurgical service at 28 months old with symptomatic triventriculomegaly secondary to a tectal lesion. The presumed tectal glioma was originally managed conservatively, with the patient undergoing an endoscopic third ventriculostomy (ETV) for his hydrocephalus. This improved his symptoms, although he was noted to remain mildly ataxic in gait and tremulous and dysmetric in his hands, with mild bilateral ptosis. An endoscopic biopsy was performed due to interval growth of the tumor on serial imaging, with a diagnosis of juvenile pilocytic astrocytoma with tandem BRAF gene fusion duplication. Despite this, continued growth of the tumor and dissemination of the disease both intracranially and to the spinal cord prompted the initiation of several chemotherapy regimens, with a transient response to vinblastine/bevacizumab combination therapy, disease progression on vinblastine monotherapy, tumor shrinkage on a vincristine/carboplatin regimen (unfortunately stopped due to development of anaphylaxis to carboplatin), and progression on trametinib as part of a study.

Approximately 3 years after the ETV, the patient was started on levetiracetam for seizures that were likely to have been secondary to a disseminated lesion to the left parahippocampal gyrus. At approximately the same time, a metastatic deposit in the infundibulum occluded the patient’s ETV site, reestablishing his ventriculomegaly, initially without clear symptoms of raised intracranial pressure (ICP). Each of these deposits had similar MRI characteristics to the tectal lesion (T2 hyperintense, T1 hypointense, mild heterogeneous enhancement with high diffusivity). Eventually, the patient developed a transient left third cranial nerve palsy, and the decision was made to implant a left-sided Medtronic PS Medical medium-pressure ventriculoperitoneal shunt (VPS) prior to starting further chemotherapy. Of note at this time was the fact that disseminated disease included primary disease in the midbrain, and in the red nucleus with dissemination to hypothalamus, cerebellum, and left temporal lobe. The patient was noted to have normal gait, be without dysmetria in his limbs, and was on a chemotherapy holiday at this time.

Three weeks later, the patient presented to the emergency department with headaches, emesis, and lethargy. A CT scan showed progressive hydrocephalus with periventricular edema, and an intraoperative exploration of the VPS revealed obstruction of the ventricular catheter with debris. Revision of the ventricular catheter restored flow, although it was not under high pressure. Ten days later the patient returned with headache and lethargy that improved with manual pumping of the VPS, which was suggestive of a low-pressure hydrocephalus. The parents were instructed to continue to pump the VPS for 10 days with a gradual tapering of the frequency of pumping. Two weeks after stopping manual pumping of the VPS, the patient presented with a severe and coarse (4–6 Hz) resting, postural, and intention tremor of the upper extremities more than lower extremities, along with palatal tremor, dysphagia, hypomimia, Parinaud’s syndrome, severe irritability, and persistent ventriculomegaly (Fig. 2A–C; Video 1).

VIDEO 1. Demonstration of coarse resting, intention, and postural tremor before and at several points after definitive management of low-pressure hydrocephalus. Copyright Stephano J. Chang. Published with permission. Click here to view.

FIG. 2.
FIG. 2.

T2-weighted, FLAIR, and postcontrast T1-weighted brain imaging before (A, B, and C, respectively) and after (D, E, and F, respectively) CSF diversion reversing signs of HT. White arrows show the primary tectal lesion (C, F). White arrowheads indicate disseminated deposits, including a left hippocampal deposit (A, D) and a third ventricle deposit obstructing the ETV site (C).

There was no bradykinesia. Standing and stepping were limited by retrocollis, truncal rigidity, and severe tremor. Sleep was severely disrupted, although resting tremor disappeared during sleep.

The shunt was externalized and was found to have a negative ICP, confirming the diagnosis of low-pressure hydrocephalus. Drainage of CSF only markedly improved the patient’s tremor and other motor abnormalities (Fig. 2D–F) once it was draining at −5 cm H2O. Clonazepam did not provide much symptomatic relief; he remained on levetiracetam. The patient was concurrently started on a low-dose trial of levodopa/carbidopa for potential involvement of the nigrostriatal pathway, at the time of drainage to −5 cm H2O, and this combination led to improvement of his tremor. Over 1 month, the external ventricular drain was raised to 5 cm H2O, with trials of neck wrapping and jugular compression in an attempt to decrease brain compliance.26 A new VPS equipped with a programmable Strata valve at the lowest resistance setting was placed on the other side. The previous externalized shunt system was removed, and the patient was discharged home with minimal tremor on levodopa/carbidopa at 0.45 mg/kg/day of levodopa. At his 6-month postoperative follow-up, he had full extraocular movements, steady gait, and returned to baseline minimal postural and action tremor even with a reduction of levodopa/carbidopa and a brief levodopa/carbidopa holiday.

Results

Nine patients, including our current case, were identified (4 female patients) with a mean ± SD age of 32.4 ± 20.1 years (range 6–58 years), which is similar in demographics to the most recent review on HT.1 Underrecognition of this tremor syndrome by clinicians may contribute to underreporting in the literature. Each patient with HT had a triventriculomegaly pattern of hydrocephalus with at least a partly noncommunicating, obstructive component. Congenital aqueductal stenosis (2/9); posthemorrhagic stenosis (1/9); and ischemic, cystic, or neoplastic lesions in the region of the third ventricle (1/9), fourth ventricle (1/9), and midbrain (4/9) contributed to obstructive hydrocephalus in this series of patients. Four of the patients had a unilateral tremor, and in these patients CSF diversion was least successful in treating the tremor, potentially reflecting the fact that the intrinsic lesion and not the hydrocephalus was the primary contributing factor to the tremor.27 One patient had successful unilateral Vim DBS to treat persistent tremor. Levodopa had an acute and favorable response in all 5 patients in whom it was tried, and was often used concurrently with CSF diversion as an adjunct or temporizing measure. In 5 patients, surgical restoration of CSF flow significantly improved or resolved the tremor and other associated signs and symptoms, in some cases multiple times with each VPS revision, strongly implicating that the hydrocephalus was a contributing etiology of the tremor. Interestingly, in case 7, VPS revision improved headache and mental status, but was soon followed by onset of the HT. This tremor responded to levodopa and self-resolved within 3 months.

VPS was the most common form of CSF diversion attempted (7/9), although in case 1 fenestration of a third ventricular cyst was used to restore CSF flow and remove mass effect, and in case 2 a ventriculomastoidostomy was used. In 4 of the cases the intraventricular pressure was noted to be low (< 5 cm H2O), and in our case the pressure was found to be subatmospheric. Low-pressure or negative-pressure hydrocephalus is a poorly understood entity that can complicate management,28 and it has been suggested that ventricular enlargement at lower pressures (increased distensibility of periventricular structures) may more readily elicit parkinsonian signs.29 Other signs and symptoms commonly encountered along with HT in these patients included Parinaud’s syndrome/oculomotor deficits (5/9), bradykinesia (5/9), headache (4/9), dysphagia/dysarthria (4/9), rigidity (4/9), hypomimia (3/9), and cognitive or mental status changes (3/9). In particular, Parinaud’s syndrome appears to be more heavily represented in this series (56%) than in other series of HT from all causes (7%),1 or in general series of patients with obstructive or nonobstructive hydrocephalus (9%).30 Anatomically, these findings are in keeping with involvement of nearby midbrain and periventricular structures, such as the tectum and the nigrostriatal pathway.

Discussion

Association of Tremor and Movement Disorders With Hydrocephalus

Tremor, either alone or—more commonly—with other movement disorders, has a known but understudied association with hydrocephalus. A case series of 118 consecutive adult patients with hydrocephalus reported by Krauss et al.31 found that 35% had tremor in one or more parts of the body, with only 1% meeting criteria for HT. Other associated findings included akinesia (i.e., hypomimia, hypokinesia, bradykinesia: 62%); rigidity (13%); and dystonia (6%). Some of these movement disorders have been shown to respond to CSF diversion,31 making hydrocephalus an important potentially treatable cause of tremor and other movement disorders. In another smaller consecutive series by Grant et al.,32 4 of 11 (36%) children with tectal plate gliomas and obstructive hydrocephalus developed tremor, of which 1 resolved and 3 improved notably with CSF diversion.

FIG. 3.
FIG. 3.

A 3D schematic of DRTT pathways. Posterior (A) and posterior oblique (B) views of standardized brain atlas reconstructions of the DRTT pathways using publicly available subcortical maps in Lead-DBS.44,45 Both the decussating (cyan) and nondecussating (fuchsia) fiber tracts are shown. In panel B the red nucleus (RN), substantia nigra (SN), and STN are depicted for reference. Coronal T2-weighted MRI slices obtained before (C) and after (D) CSF diversion reversing HT, depicting the region of the red nuclei (white arrows) in our patient. Figure is available in color online only.

The pathophysiology underlying tremor and other movement disorders in hydrocephalus is not known. General mechanistic hypotheses include neuronal or axonal dysfunction secondary to mechanical compression of periventricular structures such as the midbrain and diencephalon due to raised ICP,33 mechanical distention of periventricular white matter tracts due to ventriculomegaly,34 and reduced perfusion of periventricular structures (due to either raised ICP or mechanical distortion).31,33 Specific structures that have been proposed to be involved include the substantia nigra, the STN, the caudate nucleus, the putamen, the globus pallidus, and the motor thalamic nuclei, as well as periventricular fiber tracts such as the DRTT, NST, fibers interconnecting the basal ganglia (i.e., ansa lenticularis, fasciculus lenticularis), and thalamocortical output fibers (to supplementary motor area).33 The occurrence of severe HT in the setting of low-pressure hydrocephalus in our case suggests that compression due to raised ICP was not a contributing factor and that mechanical distention of periventricular white matter tracts and vasculature were the most likely mechanisms.

Low-pressure (or negative-pressure) hydrocephalus is a rare presentation of symptomatic ventriculomegaly in the presence of very low or negative ICP, believed by some to be along the same spectrum of pathophysiology as normal pressure hydrocephalus.34,35 These cases are most often associated with chronic hydrocephalus, subarachnoid hemorrhage, or tumor, and treatment strategies most often involve negative CSF drainage, as in our case.28,35,36 The mechanisms involved in this counterintuitive condition are not fully understood, although theories usually center on alterations of brain tissue compliance or its ability to resist deformation in response to external forces; abnormal fluid shifts in the brain, including altered mechanisms of cranial venous drainage; and shifts in relative pressures of CSF compartments. These hypotheses remain controversial, with some groups suggesting that interstitial fluid in the brain tissue is reduced, allowing for expansion of the ventricles without high pressures, whereas other groups believe that increased water content in the brain tissue is what allows for increased brain compliance. Similarly, there is debate as to whether brain tissue viscoelasticity or stiffness is increased or decreased in low-pressure hydrocephalus.37

Movement disorders associated with normal or low-pressure hydrocephalus and improving with CSF diversion and decreased ventriculomegaly, such as in our case, support the significance of mechanical stretching of neural structures as an underlying cause rather than pressure per se. A more complete understanding of the changes in CSF dynamics, fluid shifts, parenchymal compliance, and tissue perfusion involved in various subtypes of hydrocephalus, such as normal pressure hydrocephalus and low-pressure hydrocephalus, is likely to enhance our understanding and treatment of associated tremors and movement disorders.

Pathophysiology of HT

Although HT is strictly a syndromic classification based on clinical features, multiple case series have identified the most common lesion topographies as involving the midbrain, thalamus, or both.1 This implicates one or more circuits passing through these structures in its pathophysiology, and these are generally thought to include the NST and the DRTT (Fig. 3).1 A recent review of the literature found that vascular lesions were the most common etiology of HT (approximately 50%), followed by trauma (approximately 20%).1 In our patient, hydrocephalus was deemed to be a major etiology of HT based on timing of peak tremor onset with worsening of ventriculomegaly (Fig. 3) and amelioration of tremor with CSF drainage. It is also possible that disseminated tumor or chemotherapy may have contributed to his tremor, though we believed this was less likely given that the tumor had not changed during this time and that the patient was on chemotherapy holiday. Furthermore, the identification of subatmospheric ICP upon externalization of our patient’s shunt suggests that the mechanical distention of the neural tissue related to elevated ICP was unlikely to be a major contributor to his tremor. Somewhat counterintuitively in this condition, symptomatic ventriculomegaly is associated with low or negative pressures inside the ventricles, implying a change in brain stiffness or compliance.

As with many other cases of HT, our patient also appeared to have some parkinsonian features, such as hypomimia and the resting component of his tremor, and appeared to be responsive to levodopa therapy. It is of note that the resting tremor in HT is exacerbated by movement, in contrast to parkinsonian resting tremor, in which it disappears with movement.38 Of importance in this patient and others who have had a response to therapy, all components of the tremor improved (resting, postural, and intention).1 Other reported treatments, such as trihexyphenidyl, topiramate,1 zonisamide,8 DBS,39 and MR-guided focused ultrasound,40 were not tried.

Conclusions

HT is a rare and sometimes late complication of hydrocephalus. HT, along with other movement disorders, can respond to treatment of hydrocephalus, either by treating the underlying cause or through CSF diversion, and bilateral or symmetrical deficits may have a greater chance of responding. However, there are little robust data to provide guidance on questions such as which patients are most likely to respond well to treatment, if there are optimal time frames in which to treat, or even what the best endpoints for treatment should be. Recent advances in imaging modalities such as MR elastography may provide some important insights into the pathophysiological changes taking place in acute and chronic hydrocephalus and therefore how to best treat these conditions.41,42 Low-pressure hydrocephalus appears to be a risk factor for the development of HT. Management of low-pressure hydrocephalus remains complex, but current principles include negative CSF drainage to reduce ventriculomegaly, followed by interventions such as neck wrapping aimed at increasing venous pressures and brain stiffness, and placement of a VPS with an adjustable or low-pressure valve.43

HT has a good chance of responding to a trial of levodopa, and the patient may be able to be weaned off the agent after successful treatment of the hydrocephalus. The anticholinergic medication trihexyphenidyl has also been used with some success according to the literature, as have various antiepileptic medications. Trials of these agents as second-line or adjunct medications with levodopa would be reasonable in the management of these movement disorders.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Singhal, Chang. Acquisition of data: Singhal, Chang. Analysis and interpretation of data: Singhal, Chang. Drafting the article: Chang. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Singhal. Statistical analysis: Chang. Administrative/technical/material support: Chang. Study supervision: Singhal.

Supplemental Information

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    Mascalchi M, Salvi F, Godano U, et al. Expanding lacunae causing triventricular hydrocephalus. Report of two cases. J Neurosurg. 1999;91(4):669674.

  • 22

    Racette BA, Esper GJ, Antenor J, et al. Pathophysiology of parkinsonism due to hydrocephalus. J Neurol Neurosurg Psychiatry. 2004;75(11):16171619.

  • 23

    Hertel F, Züchner M, Decker C, et al. Unilateral Holmes tremor, clearly responsive to cerebrospinal fluid release, in a patient with an ischemic midbrain lesion and associated chronic hydrocephalic ventricle enlargement. Case report. J Neurosurg. 2006;104(3):448451.

    • Search Google Scholar
    • Export Citation
  • 24

    Prashantha DK, Netravathi M, Ravishankar S, Panda S, Pal PK. Reversible parkinsonism following ventriculoperitoneal shunt in a patient with obstructive hydrocephalus secondary to intraventricular neurocysticercosis. Clin Neurol Neurosurg. 2008;110(7):718721.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Boelmans K, Gerloff C, Münchau A. Long-lasting effect of levodopa on Holmes’ tremor. Mov Disord. 2012;27(9):10971098.

  • 26

    Hatt A, Cheng S, Tan K, Sinkus R, Bilston LE. MR Elastography can be used to measure brain stiffness changes as a result of altered cranial venous drainage during jugular compression. AJNR Am J Neuroradiol. 2015;36(10):19711977.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Yang SH, Kulkarni AV. Successful treatment of tremor by endoscopic third ventriculostomy in an adolescent with obstructive hydrocephalus due to tectal glioma: case report. Childs Nerv Syst. 2011;27(6):10071010.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Keough MB, Isaacs AM, Urbaneja G, Dronyk J, Lapointe AP, Hamilton MG. Acute low-pressure hydrocephalus: a case series and systematic review of 195 patients. J Neurosurg. 2020;135(1):300308.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Keane JR. Tremor as the result of shunt obstruction: four patients with cysticercosis and secondary parkinsonism: report of four cases. Neurosurgery. 1995;37(3):520522.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Lee TT, Uribe J, Ragheb J, Morrison G, Jagid JR. Unique clinical presentation of pediatric shunt malfunction. Pediatr Neurosurg. 1999;30(3):122126.

  • 31

    Krauss JK, Regel JP, Droste DW, Orszagh M, Borremans JJ, Vach W. Movement disorders in adult hydrocephalus. Mov Disord. 1997;12(1):5360.

  • 32

    Grant GA, Avellino AM, Loeser JD, Ellenbogen RG, Berger MS, Roberts TS. Management of intrinsic gliomas of the tectal plate in children. A ten-year review. Pediatr Neurosurg. 1999;31(4):170176.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Curran T, Lang AE. Parkinsonian syndromes associated with hydrocephalus: case reports, a review of the literature, and pathophysiological hypotheses. Mov Disord. 1994;9(5):508520.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Pang D, Altschuler E. Low-pressure hydrocephalic state and viscoelastic alterations in the brain. Neurosurgery. 1994;35(4):643656.

  • 35

    Strand A, Balise S, Leung LJ, Durham S. Low-pressure hydrocephalus: a case report and review of the literature. World Neurosurg. 2018;109:e131e135.

  • 36

    Akins PT, Guppy KH, Axelrod YV, Chakrabarti I, Silverthorn J, Williams AR. The genesis of low pressure hydrocephalus. Neurocrit Care. 2011;15(3):461468.

  • 37

    Kinugawa K, Itti E, Lepeintre JF, et al. Subacute dopa-responsive Parkinsonism after successful surgical treatment of aqueductal stenosis. Mov Disord. 2009;24(16):24382440.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Bhatia KP, Bain P, Bajaj N, et al. Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society. Mov Disord. 2018;33(1):7587.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Ramirez-Zamora A, Okun MS. Deep brain stimulation for the treatment of uncommon tremor syndromes. Expert Rev Neurother. 2016;16(8):983997.

  • 40

    Yang AI, Chaibainou H, Wang S, et al. Focused ultrasound thalamotomy for essential tremor in the setting of a ventricular shunt: technical report. Oper Neurosurg (Hagerstown). 2019;17(4):376381.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Streitberger KJ, Wiener E, Hoffmann J, et al. In vivo viscoelastic properties of the brain in normal pressure hydrocephalus. NMR Biomed. 2011;24(4):385392.

  • 42

    Wagshul ME, McAllister JP, Limbrick DD Jr, et al. MR Elastography demonstrates reduced white matter shear stiffness in early-onset hydrocephalus. Neuroimage Clin. 2021;30:102579102579.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Michael AP, Elkouzi A, Elble RJ. Pearls & Oy-sters: Low-pressure hydrocephalus and inadequate shunting. Neurology. 2017;88(17):e174e177.

  • 44

    Horn A, Li N, Dembek TA, et al. Lead-DBS v2: Towards a comprehensive pipeline for deep brain stimulation imaging. Neuroimage. 2019;184:293316.

  • 45

    Meola A, Comert A, Yeh FC, Sivakanthan S, Fernandez-Miranda JC. The nondecussating pathway of the dentatorubrothalamic tract in humans: human connectome-based tractographic study and microdissection validation. J Neurosurg. 2016;124(5):14061412.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

Diagram from Behbahani et al. (pp 488–496).

  • View in gallery

    PRISMA-style flowchart of studies.

  • View in gallery

    T2-weighted, FLAIR, and postcontrast T1-weighted brain imaging before (A, B, and C, respectively) and after (D, E, and F, respectively) CSF diversion reversing signs of HT. White arrows show the primary tectal lesion (C, F). White arrowheads indicate disseminated deposits, including a left hippocampal deposit (A, D) and a third ventricle deposit obstructing the ETV site (C).

  • View in gallery

    A 3D schematic of DRTT pathways. Posterior (A) and posterior oblique (B) views of standardized brain atlas reconstructions of the DRTT pathways using publicly available subcortical maps in Lead-DBS.44,45 Both the decussating (cyan) and nondecussating (fuchsia) fiber tracts are shown. In panel B the red nucleus (RN), substantia nigra (SN), and STN are depicted for reference. Coronal T2-weighted MRI slices obtained before (C) and after (D) CSF diversion reversing HT, depicting the region of the red nuclei (white arrows) in our patient. Figure is available in color online only.

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    Mascalchi M, Salvi F, Godano U, et al. Expanding lacunae causing triventricular hydrocephalus. Report of two cases. J Neurosurg. 1999;91(4):669674.

  • 22

    Racette BA, Esper GJ, Antenor J, et al. Pathophysiology of parkinsonism due to hydrocephalus. J Neurol Neurosurg Psychiatry. 2004;75(11):16171619.

  • 23

    Hertel F, Züchner M, Decker C, et al. Unilateral Holmes tremor, clearly responsive to cerebrospinal fluid release, in a patient with an ischemic midbrain lesion and associated chronic hydrocephalic ventricle enlargement. Case report. J Neurosurg. 2006;104(3):448451.

    • Search Google Scholar
    • Export Citation
  • 24

    Prashantha DK, Netravathi M, Ravishankar S, Panda S, Pal PK. Reversible parkinsonism following ventriculoperitoneal shunt in a patient with obstructive hydrocephalus secondary to intraventricular neurocysticercosis. Clin Neurol Neurosurg. 2008;110(7):718721.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Boelmans K, Gerloff C, Münchau A. Long-lasting effect of levodopa on Holmes’ tremor. Mov Disord. 2012;27(9):10971098.

  • 26

    Hatt A, Cheng S, Tan K, Sinkus R, Bilston LE. MR Elastography can be used to measure brain stiffness changes as a result of altered cranial venous drainage during jugular compression. AJNR Am J Neuroradiol. 2015;36(10):19711977.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Yang SH, Kulkarni AV. Successful treatment of tremor by endoscopic third ventriculostomy in an adolescent with obstructive hydrocephalus due to tectal glioma: case report. Childs Nerv Syst. 2011;27(6):10071010.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Keough MB, Isaacs AM, Urbaneja G, Dronyk J, Lapointe AP, Hamilton MG. Acute low-pressure hydrocephalus: a case series and systematic review of 195 patients. J Neurosurg. 2020;135(1):300308.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Keane JR. Tremor as the result of shunt obstruction: four patients with cysticercosis and secondary parkinsonism: report of four cases. Neurosurgery. 1995;37(3):520522.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Lee TT, Uribe J, Ragheb J, Morrison G, Jagid JR. Unique clinical presentation of pediatric shunt malfunction. Pediatr Neurosurg. 1999;30(3):122126.

  • 31

    Krauss JK, Regel JP, Droste DW, Orszagh M, Borremans JJ, Vach W. Movement disorders in adult hydrocephalus. Mov Disord. 1997;12(1):5360.

  • 32

    Grant GA, Avellino AM, Loeser JD, Ellenbogen RG, Berger MS, Roberts TS. Management of intrinsic gliomas of the tectal plate in children. A ten-year review. Pediatr Neurosurg. 1999;31(4):170176.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Curran T, Lang AE. Parkinsonian syndromes associated with hydrocephalus: case reports, a review of the literature, and pathophysiological hypotheses. Mov Disord. 1994;9(5):508520.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Pang D, Altschuler E. Low-pressure hydrocephalic state and viscoelastic alterations in the brain. Neurosurgery. 1994;35(4):643656.

  • 35

    Strand A, Balise S, Leung LJ, Durham S. Low-pressure hydrocephalus: a case report and review of the literature. World Neurosurg. 2018;109:e131e135.

  • 36

    Akins PT, Guppy KH, Axelrod YV, Chakrabarti I, Silverthorn J, Williams AR. The genesis of low pressure hydrocephalus. Neurocrit Care. 2011;15(3):461468.

  • 37

    Kinugawa K, Itti E, Lepeintre JF, et al. Subacute dopa-responsive Parkinsonism after successful surgical treatment of aqueductal stenosis. Mov Disord. 2009;24(16):24382440.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Bhatia KP, Bain P, Bajaj N, et al. Consensus Statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society. Mov Disord. 2018;33(1):7587.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Ramirez-Zamora A, Okun MS. Deep brain stimulation for the treatment of uncommon tremor syndromes. Expert Rev Neurother. 2016;16(8):983997.

  • 40

    Yang AI, Chaibainou H, Wang S, et al. Focused ultrasound thalamotomy for essential tremor in the setting of a ventricular shunt: technical report. Oper Neurosurg (Hagerstown). 2019;17(4):376381.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    Streitberger KJ, Wiener E, Hoffmann J, et al. In vivo viscoelastic properties of the brain in normal pressure hydrocephalus. NMR Biomed. 2011;24(4):385392.

  • 42

    Wagshul ME, McAllister JP, Limbrick DD Jr, et al. MR Elastography demonstrates reduced white matter shear stiffness in early-onset hydrocephalus. Neuroimage Clin. 2021;30:102579102579.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Michael AP, Elkouzi A, Elble RJ. Pearls & Oy-sters: Low-pressure hydrocephalus and inadequate shunting. Neurology. 2017;88(17):e174e177.

  • 44

    Horn A, Li N, Dembek TA, et al. Lead-DBS v2: Towards a comprehensive pipeline for deep brain stimulation imaging. Neuroimage. 2019;184:293316.

  • 45

    Meola A, Comert A, Yeh FC, Sivakanthan S, Fernandez-Miranda JC. The nondecussating pathway of the dentatorubrothalamic tract in humans: human connectome-based tractographic study and microdissection validation. J Neurosurg. 2016;124(5):14061412.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation

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