Normal Pressure Hydrocephalus Associated with COVID-19 Infection: A Case Report

doi:10.21203/rs.3.rs-654791/v1

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Normal Pressure Hydrocephalus Associated with COVID-19 Infection: A Case Report

https://doi.org/10.21203/rs.3.rs-654791/v1

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published 03 Mar, 2022

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COVID-19 is a pandemic disease responsible for a large number of deaths worldwide. Many neurological manifestations have been described. We report a case of normal pressure hydrocephalus (NPH) two months after acute COVID19 infection, in a patient without other risk factors. A 45-year-old male patient presented an 8-month history of progressive gait disorder and cognitive impairment after being hospitalized for SARS-CoV-2 infection. Magnetic resonance imaging (MRI) was compatible with NPH. A spinal tap test was positive and there was progressive improvement after shunting, with complete resolution of symptoms. Other infections such Syphilis, cryptococcosis and Lyme disease have been associated with NPH. Possible mechanisms for NPH after COVID include disruption of choroid plexus cells by direct viral invasion or as a result of neuroinflammation and cytokine release and hypercoagulability leading to venous congestion and abnormalities of CSF flow. Given the significance of NPH as a cause of reversible dementia, it is important to consider the possibility of a causal association with COVID19 and understand the mechanisms behind this association.

Neurology

Cellular & Molecular Neuroscience

Normal Pressure Hydrocephalus

SARS-CoV-2

Coronavirus

COVID-19

Neurologic Manifestations.

COVID-19 is a pandemic disease initially reported in Wuhan, China, in 2019, which has been responsible for a large number of deaths worldwide [1]. It is caused by an RNA virus named SARS-CoV-2 and is primarily a respiratory disease involving lower and upper airways, although many systemic manifestations have been described. Similarly to what has been reported with other coronaviruses, such as MERS-CoV and SARS-CoV-1, this pathogen has shown neurotropic and neuro invasive properties resulting in a wide range of neurologic manifestations [2].

The viral mechanism of cell invasion involves interaction of viral spike proteins with the angiotensin converting enzyme 2 (ACE2) receptor which is largely distributed in human tissues, including the central nervous system [3]. Recent studies indicate that these receptors are highly expressed in the olfactory tract, substantia nigra, posterior cyngulate córtex and choroid plexus of lateral ventricles[4], leading to many neurologic manifestations.

Normal pressure hidrocephalus (NPH) is a condition characterized by a triad of cardinal symptoms composed by gait disorder, urinary incontinence and cognitive decline associated with dilated ventricles, in the absence of intracranial hypertension [5]^. Initially described in 1965, it has been extensively studied as a potential cause of reversible cognitive decline [6]

Herein, we report a case of Normal Pressure Hydrocephalus, occurring two months after acute COVID19 infection.

A 45-year-old male patient presented with a history of imbalance and progressive gait disorder for the last 8 months. During this period, his family also reported memory impairment and behavior changes. He had a previous history of bipolar disorder and type II diabetes mellitus and reported a COVID19 infection 2 months before initial presentation of neurologic symptoms.

Initial symptoms of SARS-Cov-2 infection were fever, anosmia, disgeusia and anorexia. A real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay (Allplex™ SARS-CoV-2 Assay (N/RdRP/S genes) from nasopharyngeal swab confirmed the diagnosis of COVID19. In the tenth day of infection, he had respiratory distress and hypoxemia (SO2 87%), was admitted to a hospital and received oxygen via nasal cannula. He was hospitalized for seven days and treated with dexamethasone and antibiotics for suspected bacterial pneumonia. At discharge he was able to walk unassisted.

Two months after acute COVID19 infection the patient started a progressive gait disorder, complaining that he felt like his feet were glued to the ground. After a few weeks, he started forgetting recent facts and his family complained of excessive daytime sleepiness and blunted affect. They also reported a change in his personality, previously active and extroverted, became apathic and introverted. He progressed to executive dysfunction and difficulty in performing his labor activities, which led to him leaving his job. There was no history of head trauma, previous stroke or subarachnoid hemorrhage, meningitis, blood transfusions or substance abuse. There was also no family history of neurologic diseases.

Neurologic examination revealed short-term memory loss, slow processing speed, inattention, difficulty in planning and executive dysfunction. A mild tetraparesis was also perceived, with brisk deep tendon reflexes in four limbs. There was no clonus and flexor plantar responses were observed. There was mild rigidity of the upper limbs, without cogwheeling. Gait was slow and magnetic, with short steps, feet close to the ground and postural instability.

Laboratory evaluation did not reveal any abnormalities (Table1). Complete blood count, renal, hepatic and thyroid function were normal. Serology was negative for Syphilis and HIV. Vitamin B12 levels were also normal.

Brain magnetic resonance imaging (MRI) disclosed moderately dilated supratentorial ventricular system with callosal angle reduction, sulcal effacement near the interhemispheric fissure and aqueduct flow-void (Figure 1). A high-volume (40ml) diagnostic lumbar tap test was performed and revealed an opening pressure of 100mmH2O. There was marked improvement of gait and balance after the procedure. CSF analysis was entirely normal (Table2).

A diagnosis of Normal Pressure Hydrocephalus was made and a ventriculoperitoneal shunt was placed. Thirty days after the procedure there was significant improvement of cognitive functions with a Montreal Cognitive Assessment (MoCA) score of 28/30. Gait also improved substantially, now presenting normal speed and step and stride length. The patient returned to his previous work activities.

We have described a previously healthy patient who developed NPH two months after a case of COVID19 infection of moderate severity, presenting with apraxic gait and cognitive impairment. Urinary incontinence was not reported, possibly because our patient was submitted to a ventriculoperitoneal shunt early in the disease course and urinary symptoms may present later in NPH [7].

Normal pressure hydrocephalus has been classified as idiopathic or secondary [8]. Many diseases have been implicated in its etiology, such as subarachnoid hemorrhage (SAH), traumatic brain injury (TBI), meningitis, stroke and intracranial neoplasms [8]. Outcomes in patients with secondary NPH (sNPH) tend to be better than in those with idiopathic NPH (iNPH), with improvement after shunt in 50-70% in sNPH and only 30-50% in iNPH[9]. Some specific infectious diseases have also been reported as possible etiologies for NPH, including Lyme disease [10], neurosyphilis [11] and cryptococcosis[12], but as far as we know it hasn’t been associated with COVID-19 infection.

Some mechanisms could explain CNS invasion in COVID19. The main theory is that SARS-CoV-2 uses the olfactory nerves as a main input port through interaction of the viral S protein with the ACE2 receptor expressed on olfactory epithelium, invasion and transsynaptic retrograde transmission through the olfactory nerve into the brain [13]. Another proposed mechanism is infection of cerebral endothelium by viral particles in the bloodstream, leading to blood-brain-barrier dysfunction and viral invasion into the CNS [2]. The spatial distribution of ACE2 receptors in the CNS was studied using brain transcriptome databanks and high concentrations of these receptors were found in the choroid plexus of lateral ventricles suggesting that the choroid plexus could be a pathway for SARS-CoV-2 to enter the CNS [4]. It is possible that this interaction between the virus and the choroid plexus could alter the dynamics of CSF flow, contributing to NPH. An animal model study of hydrocephalus after SAH has demonstrated that inflammation of choroid plexus cells marked by increase in NF-kB results in dysfunction of these barrier cells leading to the production of increased abnormal protein-rich CSF, and consequentially in hydrocephalus due to excess CSF production [14].

Many neuroinvasive viruses such influenza A and B can initially trigger an innate immune response by activating microglia [15]. Ramified microglia (M0) are constantly scanning the neuropil through their highly motile processes and after encountering an insult signal change to an ameboid activated state and release cytokines. Short or moderate signals lead to a neuroprotective M2 phenotype, whereas intensive acute (such as a neurotropic viral infection) activation renders a proinflammatory M1 phenotype producing reactive oxygen species, nitric oxide, proteases, and proinflammatory cytokines, such as IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) [16]. Microglia also activates astrocytes that can modulate the recruitment and activation of additional microglial and other immunocompetent cells [17]. Microglial and astrocyte activation as well as massive cytokine release might lead to inflammation of arachnoid villi resulting in fibrosis and adhesion of these structures, reduction in CSF reabsorption, and consequently to hydrocephalus [18]. Another possible factor in the etiology of COVID19-associated NPH is a hypercoagulable state induced by the systemic response to SAR-CoV-2 [19], which could lead to venous congestion and CSF flow abnormalities [20].

In a case series of patients with persistent headache after COVID-19 infection 84.6% had an increased ICP in the absence of meningitis or encephalitis. A pro-thrombotic state was implicated in the disruption of normal CSF flow resulting in increased ICP in these patients [20]. It is possible that in patients with an increased intracranial compliance the same abnormalities might lead to an increase in CSF volume (resulting in normal pressure hydrocephalus), instead of raising ICP [21]. Another possibility is that some of these patients with initially elevated ICP might progress to NPH over time as the CSF compartment rearranges itself in a larger volume to maintain physiologic ICP according to Laplace´s law [22].

We have described the first case of normal pressure hydrocephalus possibly associated with COVID19 infection. Although pathophysiological mechanisms are still unclear and we cannot be certain that NPH occurred because of COVID19, there was a temporal correlation and the patient did not have other risk factors for NPH. Given the significance of this condition as a cause of reversible dementia, it is important to consider the possibility of a causal association with COVID19, as well as understand the mechanisms behind this association, leading to possible measures for preventing this complication in patients with initially elevated ICP. More reports, longer follow-up and perhaps histopathology of arachnoid granulation specimens are necessary to confirm this association and clarify its mechanisms.

Funding

The research was funded by the researchers.

Competing interests

The authors report that they have no competing interests.

Ethics Approval

The study was approved by the local ethics committee under the number 4092933

Consent for publication

The manuscript contains no any individual person’s data in any form.

Availability of data and material

All materials used in this study will be made available subject to a material transfer agreement.

Code availability

Not applicable

Consent to participate

The patient has given informed consent to this report.

Author’s contribution

Conception, Organization, and design of the work: MASN, PBN and PRN

Acquisition, analysis, or interpretation of data for the work: TMFV, GMF, MLPS, ASV, PRN, PBN and MASN

Writing the first draft: TMFV and PRN

Review and critique: MASN, PBN, GMF, JDVC

Acknowledgments

The author Pedro Braga Neto received funding from the Brazilian National Council for Scientific and Technological Development (CNPq) and Fundação de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP) as research grant funding. We also acknowledge that the author Pedro Braga Neto received the brazilian funding number 88881.505364/2020-01 from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) and FUNCAP.

1- ( https://www.who.int/emergencies/diseases/novel-coronavirus-2019)

2-Zubair AS, McAlpine LS, Gardin T, Farhadian S, Kuruvilla DE, Spudich S (2020) Neuropathogenesis and Neurologic Manifestations of the Coronaviruses in the Age of Coronavirus Disease 2019: A Review. JAMA Neurol 77(8):1018-1027. https://doi.org/10.1001/jamaneurol.2020.2065

3- Hoffmann M, Kleine-Weber H, Schroeder S, et al (2020) SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 181(2):271-280.e8. https://doi.org/10.1016/j.cell.2020.02.052

4- Chen R, Wang K, Yu J, et al (2021) The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains. Front Neurol 11:573095. https://doi.org/10.3389/fneur.2020.573095

5- Gallia GL, Rigamonti D, Williams MA (2006) The diagnosis and treatment of idiopathic normal pressure hydrocephalus. Nat Clin Pract Neurol 2(7):375-381. https://doi.org/10.1038/ncpneuro0237

6- Trenkwalder C, Schwarz J, Gebhard J, et al (1995) Starnberg trial on epidemiology of Parkinsonism and hypertension in the elderly. Prevalence of Parkinson's disease and related disorders assessed by a door-to-door survey of inhabitants older than 65 years. Arch Neurol 52(10):1017-1022. https://doi.org/10.1001/archneur.1995.00540340109020

7- Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH (1965) Symptomatic occult hydrocephalus with "normal" cerebrospinal-fluid pressure. A treatable syndrome. N Engl J Med 273:117-126 https://doi.org/10.1056/NEJM196507152730301

8- Daou B, Klinge P, Tjoumakaris S, Rosenwasser RH, Jabbour P (2016) Revisiting secondary normal pressure hydrocephalus: does it exist? A review. Neurosurg Focus41(3):E6. https://doi.org/10.3171/2016.6.FOCUS16189

9- Vanneste JA (2000) Diagnosis and management of normal-pressure hydrocephalus. J Neurol 247(1):5-14. https://doi.org/10.1007/s004150050003

10- Abdool K, Seegobin K, Ramcharan K, et al (2016) Neurosyphilis With Normal Pressure Hydrocephalus and Dementia Paralytica: Serial Clinical, Laboratory and Radiological Correlations in the 21st Century. Neurol Int 8(3):6812. https://doi.org/10.4081/ni.2016.6812

11- Gimsing LN, Hejl AM (2020) Normal pressure hydrocephalus secondary to Lyme disease, a case report and review of seven reported cases. BMC Neurol 20(1):347. https://doi.org/10.1186/s12883-020-01917-8

12- Dhitinanmuang W, Chongtrakool P, Jitmuang A (2018) Undiagnosed Cryptococcus gattii meningitis leading to subsequent ventriculoperitoneal shunt infection in a patient with symptoms of normal pressure hydrocephalus: case report and literature review. BMC Infect Dis 18(1):257. https://doi.org/10.1186/s12879-018-3165-y

13- Armocida D, Palmieri M, Frati A, Santoro A, Pesce A (2020) How SARS-Cov-2 can involve the central nervous system. A systematic analysis of literature of the department of human neurosciences of Sapienza University, Italy. J Clin Neurosci 79:231-236. https://doi.org/10.1016/j.jocn.2020.07.007

14- Simard PF, Tosun C, Melnichenko L, Ivanova S, Gerzanich V, Simard JM (2011) Inflammation of the choroid plexus and ependymal layer of the ventricle following intraventricular hemorrhage. Transl Stroke Res 2(2):227-231. https://doi.org/10.1007/s12975-011-0070-8

15- Tse H, To KK, Wen X, et al (2011) Clinical and virological factors associated with viremia in pandemic influenza A/H1N1/2009 virus infection. PLoS One6(9):e22534. https://doi.org/10.1371/journal.pone.0022534

16- Nisticò R, Salter E, Nicolas C, et al (2017) Synaptoimmunology - roles in health and disease. Mol Brain 10(1):26. https://doi.org/10.1186/s13041-017-0308-9

17- Liu W, Tang Y, Feng J (2011) Cross talk between activation of microglia and astrocytes in pathological conditions in the central nervous system. Life Sci 89(5-6):141-146. https://doi.org/10.1016/j.lfs.2011.05.011

18- Kibler RF, Couch RS, Crompton MR (1961) Hydrocephalus in the adult following spontaneous subarachnoid haemorrhage. Brain 84:45-61. https://doi.org/10.1093/brain/84.1.45 19- Wichmann D, Sperhake JP, Lütgehetmann M, et al (2020) Autopsy Findings and Venous Thromboembolism in Patients With COVID-19: A Prospective Cohort Study. Ann Intern Med 173(4):268-277. https://doi.org/10.7326/M20-2003 20- Silva MTT, Lima MA, Torezani G, et al (2020) Isolated intracranial hypertension associated with COVID-19. Cephalalgia 40(13):1452-1458. https://doi.org/10.1177/0333102420965963

21- Czosnyka M, Whitehouse H, Smielewski P, Simac S, Pickard JD (1996) Testing of cerebrospinal compensatory reserve in shunted and non-shunted patients: a guide to interpretation based on an observational study. J Neurol Neurosurg Psychiatry 60(5):549-558. https://doi.org/10.1136/jnnp.60.5.549

22- Hakim S, Adams RD (1965) The special clinical problem of symptomatic hydrocephalus with normal cerebrospinal fluid pressure. Observations on cerebrospinal fluid hydrodynamics. J Neurol Sci2(4):307-327. https://doi.org/10.1016/0022-510x(65)90016-x

Table 1 – Results of laboratory and cerebrospinal fluid analysis in a patient with normal pressure hydrocephalus after COVID19

Variables	COVID Symptoms Onset	Neurological Symptoms Onset	Reference values
Serum tests
Hemoglobin (g/dL)	15,9	14,5	13 – 17,5
Leukocytes (cells/mm³)	7640	5600	4000 –11000
Lymphocytes (cells/mm³)	770	2420	1000-3500
Platelets (number/mm³)	259.000	255.000	150.000 - 450000
C-Reative Protein (mg/dL)	6,37	-	< 0,3
ESR (mm/Hr)	27	-
D-Dimer (ng/ml)	300		<600
Sodium (mMol/L)	-	142	136 – 146
Potassium (mMol/L)	-	4,3	3,5 – 5,1
Calcium (mg/dl)	-	9,3	1,16 – 1,32
Magnesium (mg/dL)	-	2,3	1,6 – 2,6
Blood Urea Nitrogen (mg/dL)	21	14	7-20
Creatinine (mg/dL)	1,1	0,92	0,5 – 1,3
AST (U/L)	39
ALT (U/L)	49
TSH (µlU/ml)	-	1,542	0,550 – 4,780
HIV I, II	-	Negative	Negative
Syphilis	-	Negative	Negative
Analysis of cerebrospinal fluid
Cell count (cells/mm³)	-	2	0-4
Differential cell count	-	100% lymphocytes	-
Protein (mg/dL)	-	26	15-45
Glucose (mg/dL)	-	74	-
VDRL	-	Negative	Negative
Gram stain	-	Negative	Negative
Fungal stain (India-ink)	-	Negative	Negative

PT- Prothrombin time; aPTT- Activated partial thromboplastin time; VDRL- Venereal Disease Research Laboratory; PCR- Polymerase chain reaction

Table 2 – Results of a spinal tap test in a patient with normal pressure hydrocephalus after COVID19

Test parameter	Before spinal tap	After spinal tap
Timed up and go (10 meters)	18,4 seg	16,7 seg
Number of steps	32 steps	29 steps

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Normal Pressure Hydrocephalus Associated with COVID-19 Infection: A Case Report

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