COVID-19-associated polyneuritis cranialis

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Main article: COVID-19

For COVID-19 frequently asked outpatient questions, click here
For COVID-19 frequently asked inpatient questions, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Javaria Anwer M.D.[2]

Synonyms and keywords: covid19 associated polyneuritis cranialis, SARS Cov2 associated polyneuritis cranialis, nCOV associated polyneuritis cranialis, coronavirus linked polyneuritis cranialis, covid linked polyneuritis cranialis, polyneuritis cranialis and coronavirus, polyneuritis cranialis and covid19, COVID-19 linked PNC.

Overview

Polyneuritis cranialis (PNC) literally means inflammation of the cranial nerves. It is a rare neurological disorder characterized by multiple cranial nerve palsies sparing the spinal cord. The novel coronavirus is also emerging as a neurotropic virus. The disease is a Guillain-Barré syndrome-Miller Fisher syndrome interface. The pathogenesis of polyneuritis cranials is characterized by demyelination of lower cranial nerves. COVID-19-associated polyneuritis cranials must be differentiated from other diseases that cause bulbar weakness, facial weakness, and ophthalmoparesis. The diagnosis of PNC is clinical and confirmed by NCS. Fixation nystagmus, bilateral abducens palsy, impaired visual acuity and gaze palsy abnormality and loss of deep tendon reflexes has been observed with no gait pathology. Treatment with acetaminophen caused complete recovery within 2 weeks. The disease itself is associated with COVID-19 infection as believed to be an immune response so prevention of the infection itself is the most promising primary prevention strategy at the moment.

Historical Perspective

• In 1937 French physicians Guillain G. et al. first described a postinfectious syndrome affecting the cranial nerves, associated with albumino-cytological dissociation. The syndrome did not involve the limbs unlike Guillain-Barré syndrome and was called 'polyneuritis cranialis'.
• The first COVID-19 outbreak news was first published by WHO on 5th January 2020.
• Since mid-January 2020, right after the start of COVID-19 outbreak neurological symptoms including the peripheral nervous system (PNS) symptoms have been reported in China (the first epicenter of the pandemic).
• WHO declared the COVID-19 outbreak a pandemic on March 12, 2020.
• Polyneuritis cralialis associated with COVID-19 was first reported in a patient by Consuelo Gutiérrez-Ortiz et al. from Madrid, Spain on April 17th, 2020. The team reported both Miller Fisher syndrome (MFS) and polyneuritis cranialis in patients with confirmed oropharyngeal RT PCR COVID-19 test.

Classification

• There is no established system for the classification of COVID-19 associated polyneuritis cranialis.
• Basis of phenotypic appearance, the disease itself is a Guillain-Barré syndrome-Miller Fisher syndrome interface.

Pathophysiology

• The exact pathogenesis of COVID-19-associated polyneuritis cranials is not fully understood.
• The pathogenesis of polyneuritis cranials is characterized by demyelination of lower cranial nerves. Since polyneuritis cranials lies at the interface of GBS and Miller Fisher syndrome the pathogenesis involved in Miller Fisher syndrome can help understand the dynamics.
• Novel coronavirus is usually transmitted via respiratory droplets, direct contact with infected persons, or with contaminated objects and surfaces.
• Neuro-pathogenic mechanism: The olfactory nerves are thought to be the primary site of direct viral inoculation in patients with neurological manifestations. Following transmission, COVID-19's spike protein interacts with sialic acids linked to the patient's cell surface gangliosides to invade the neuron. The neurotropism of the novel human coronavirus is explained by the interaction between host cell proteases and Novel coronavirus's S protein spikes.
• Immune mechanism:The presence of neurological symptoms in patients with severe COVID-19 disease and correlation of IL-6 with disease severity points towards the immune cause of neurological damage. novel human coronavirus being a neurotropic virus can induce a pro-inflammatory state in glial cells causing a rise in inflammatory factors such as interleukins as proved in vitro.
• The absence of novel human coronavirus in the CSF in a patient reported, potentially clouds the possible passage through the blood-brain barrier or direct infection injury which have been included among the reasons for neurological manifestations.
• The progression to polyneuritis cranials usually involves the nerve demyelination.

Causes

• COVID-19-associated polyneuritis cranialis (PNC) is caused after the infection with novel human coronavirus (a pan-betacoronavirus).
• PNC, in general, is caused by different viral or bacterial infections and in different disease states such as:
  • Lyme disease
  • Herpes zoster
  • Thyrotoxicosis
  • Idiopathic

Differentiating COVID-19-associated polyneuritis cranialis from other Diseases

• For further information about the differential diagnosis, click here.
• To view the differential diagnosis of COVID-19, click here.

Epidemiology and Demographics

Incidence

• Till date (July 25th, 2020) as the first six months pass since the COVID-19 outbreak, a single case report of COVID-19 associated PNC narrates the rarity of the disease.

Age

• COVID-19 associated PNC was reported in a 39-year-old patient.
• In general the age of patients reported of having PNC due to other reasons ranges from 10 - 40 years.

Race

• There is no racial predilection to COVID-19 associated with PNC. Having a single case reported to date makes it difficult to comment on the racial predilection.
• The only case of COVID-19 associated with PNC was reported from Madrid, Spain. The race of the patient has not been mentioned clearly in the report.

Gender

• The only patient with COVID-19 associated PNC was a male.
• Data regarding gender distribution for PNC, in general, is not available. Most of the cases of PNC that have been reported clearly show a predilection for male gender.

Risk Factors

• In general more severe patients are likely to have neurologic symptoms.
• There are no established risk factors for COVID-19-associated polyneuritis cranials (PNC).

Screening

• Currently, there are no recommended guidelines in place for the routine screening for COVID-19-associated polyneuritis cranials or coronavirus disease 2019 (COVID-19). Some countries use temperature monitoring as a screening tool. Certain companies have launched the Screening Tool but there are no formal guidelines. Click here for more information on COVID-19 screening.

Natural History, Complications, and Prognosis

• About 80% patients with polyneuritis cranislis (PNC) present with preceding infection such as diarrhea or upper respiratory tract infection. In COVID-19 associated case, diarrhea and fever preceded the neurological symptoms. The disease develops within days. On average, 3-6 cranial nerves can be involved.
• Prognosis of PNC is good and disease course is mono-phasic. Clinical improvement occurs within weeks or months. COVID-19 associated PNC case improved in 2 weeks.
• No complications have been reported.

Diagnosis

Diagnostic Study of Choice

• The diagnosis of GBS and MFS is confirmed by Nerve conduction studies (NCS).
• A decreased amplitude shows nerve conduction pathology.
• Although other reports mention decreased nerve conduction in PNC patients, COVID-19 associated PNC report did not show NCS studies and consider that a limitation.

History and Symptoms

• The hallmark of polyneuritis cranialis (PNC) is bulbar weakness, facial weakness and ophthalmoparesis. Ocular symptoms occur in 73% and bulbar in 33% patients.
• COVID-19 associated polyneuritis cranialis is preceded by COVID-19 infection symptoms such as diarrhea, fever which can be low-grade, and ageusia.
• Patient with polyneuritis cranialis may have the following symptoms as reported previously in literature:

Common Symptoms

• Unpleasant sensations in the tongue and oral cavity (may last a few days)
• Dysphagia
• Asymmetrical facial weakness or diplegia
• Dysarthria
• Diplopia

Less Common Symptoms

• Headache

Physical Examination

Neuromuscular

• The presence of ophthalmoparesis with bulbar and facial weakness on physical examination is highly suggestive of polyneuritis cranialis (PNC). The disease is sometimes referred to as an oculo-pharyngeal variant of GBS and the early diagnosis essentially relies on physical exam findings.
• According to the data from 15 polyneuritis cranialis cases asymmetric weakness with ocular signs (93% cases) such as ophthalmoplegia, ptosis, pupillary changes and bulbar signs such as dysarthria or dysphagia have been most commonly reported. facial palsy or numbness 73% cases has been reported.
• The patient with OVID-19 associated polyneuritis cralialis has been describe to have following findings on physical exam:
  • On Central nervous system exam:
  1. Patient is well oriented to place, time, and person.
  2. Mental status examination is normal.
  3. Intracranial pressure is roughly estimated by fundoscopy has been reported normal.
  • On Peripheral nervous system exam:
  1. Cranial nerve (CN)-1: Ageusia
  2. CN II: Visual acuity may be decreased such as in the COVID-19 associated polyneuritis cranialis patient had an acuity of 20/25 in both eyes
  3. CN III, IV, VI: Ophthalmoparesis, esotropia (abduction deficits), fixation nystagmus and Ptosis can also be present.
  4. CN V: Facial sensory deficit was not reported but has been reported in other cases.
  5. CN VII: COVID-19 associated PNC did not show facial palsy
  6. CN VIII-XII: Normal.
  7. Deep tendon reflexes: All deep tendon reflexes are absent. Globally, brisk reflexes suggest an abnormality of the UMN or pyramidal tract, while decreased reflexes suggest abnormality in the anterior horn, LMN, peripheral nerve or motor end plate.
  8. Muscle strength (typically graded on the MRC scale I-V) was normal.
  9. Sensory system( fine touch, pain, temperature): Normal.
  10. Muscle tone was normal and no signs of rigidity were observed.
  • Motor system exam: There was no ataxia or hypersomnolence.
  • Finger-to-nose test or heel-to-shin test did not show dysmetria or decomposition.

Laboratory Findings

• A positive qualitative real-time oropharyngeal swab RT PCR COVID-19 test.
• Cerebrospinal fluid (CSF) examination reveals:
  1. Opening pressure is normal (normal range 8-15 mm Hg).
  2. WBC count was reported normal with all monocytes (normal range 0 - 5 WBCs all monocytes).
  3. CSF protein was a little high i.e, 62 mg/dl (normal range 15 to 60 mg/dl). CSF protein can be normal as in other cases of polyneuritis cranialis (PNC) due t other etiologies. A high CSF protein and normal cell counts can be described as albumino-cytologic dissociation and is seen in 67% PNC cases.
  4. CSF glucose is normal (normal range 50-80 mg/dl).
  5. CSF cytology was normal.
  6. CSF cultures and serology were sterile and negative respectively.
  7. CSF RT PCR for COVID-19 was found negative in the patient.
• Anti-ganglioside GM-1 IgM and IgG antibody levels ( antiganglioside GQ1b and GD1b) should be checked. The COVID-19 associated PNC patient reported could not get the planned laboratory tests done due to hospital saturation.
• CBC and differential, ESR, CRP, Basic Metabolic Panel, cardiac enzymes were all normal expect leukopenia was observed.

Electrocardiogram

• There are no ECG findings associated with COVID-19-associated polyneuritis cranials (PNC).
• ECG shows significant findings in other manifestations or complications of COVID-19 infection such as COVID-19-associated myocardial injury, COVID-19-associated myocardial infarction, COVID-19-associated arrhythmia and conduction system disease, or COVID-19-associated pericarditis.
• The electrocardiogram findings on COVID-19 can be viewed by clicking here.

X-ray

• There are no x-ray findings associated with COVID-19-associated polyneuritis cranialis (PNC).
• However, an x-ray may be helpful in the diagnosis of complications of COVID-19 such as COVID-19-associated pneumonia which is the most common finding associated with COVID-19 infection.
• The x-ray findings on COVID-19 can be viewed by clicking here.

Echocardiography or Ultrasound

• There are no echocardiography/ultrasound findings associated with COVID-19-associated polyneuritis cranialis.
• However, echocardiography may be helpful in the diagnosis of cardiac complications of COVID-19 which include COVID-19-associated heart failure, or COVID-19-associated pericarditis. An abdominal ultrasound may be helpful in the case of COVID-19-associated abdominal pain.
• The echocardiographic findings on COVID-19 can be viewed by clicking here.
  

CT scan

Axial postcontrast T1 weighted MRI sequence, with yellow arrow showing contrast enhancement of CN VI - Case courtesy of Dr Bruno Di Muzio, Radiopaedia.org, rID: 37607

• There are no CT scan findings associated with COVID-19-associated polyneuritis cranialis.
• Chest CT scan may be helpful in suggesting other organ involvement in the COVID-19 which is a multi-organ disease.
• The CT scan findings in COVID-19 can be viewed by clicking here.

MRI

• There are no MRI findings reported in COVID-19-associated polyneuritis cranialis but the writer consider it a limitation to the study.
• MRI in such neuropathies demonstrates nerve enhancement. The MRI shown is not a case of COVID-19 related PNC but is to give an example of nerve enhancement.
• MRI may be helpful in suggesting other organ involvement in the COVID-19 which is a multi-organ disease.
• The MRI findings in COVID-19 can be viewed by clicking here.

Other Imaging Findings

There are no other imaging findings associated with COVID-19-associated polyneuritis cranialis.

Other Diagnostic Studies

There diagnostic studies associated with COVID-19-associated polyneuritis cranialis (PNC) that can help in the diagnosis include:

• Electromyography (EMG) in a patient with PNC will show neuropathic pattern helping differentiate neurological causes from primary muscle weakness. The case report on COVID-19 associated PNC considers not conducting [[EMG a limitation.
• Lyme (B.burgdorferi) IgG and IgM. (to rule out other commoner causes).
• TSH and T4 (rule out thyrotoxicosis especially in a patient with hyperthyroidism)

Treatment

Medical Therapy

• The mainstay of therapy for COVID-19-associated polyneuritis cranialis is the administration of acetaminophen per oral (report does not mention the dose).
• It can be started after the neurological symptoms develop.
• The treatment can be continued on the outpatient basis depending upon the patient's condition, co-morbidities, and complications.
• Acetaminophen works primarily as an analgesic, antipyretic and may work to ameliorate inflammation.
• It acts by inhibiting COX enzymes and eventually decreasing prostaglandin and prostacyclin production.
• COVID-19 associated MFS patient treated with intravenous immunoglobulin 0.4 g/kg for 5 days caused complete resolution of neurological pathologies.
• The patient with COVID-19 linked PNC was not administered immunoglobulins, cases of full recovery after intravenous immunoglobulin in same dosage have been reported.
• Randomized control trials are required to consider a definitive treatment of the disease.
• COVID-19 medical therapy is as important as treating the associated polyneuritis cranialis.
• A few patients with COVID-19-associated polyneuritis cranialis may require physical therapy for residual muscle weakness.

Surgery

• Surgical intervention is not recommended for the management of COVID-19-associated polyneuritis cranialis.

Primary Prevention

• The disease itself is associated with COVID-19 infection as believed to be an immune response so prevention of the infection itself is the most promising primary prevention strategy at the moment.
• There have been rigorous efforts in order to develop a vaccine for novel coronavirus and several vaccines are in the later phases of trials.
• The only prevention for COVID-19 associated PNC is the prevention and early diagnosis of the coronavirus-19 infection itself. According to the CDC, the measures include:
  • Frequent hand-washing with soap and water for at least 20 seconds or using a alcohol based hand sanitizer with at least 60% alcohol. Alcohol means ethanol here not methanol/ wood alcohol, as FDA warns against the use of methanol containing hand-wash.
  • Staying at least 6 feet (about 2 arms’ length) from other people who do not live with you.
  • Covering your mouth and nose with a cloth face cover when around others and covering sneezes and coughs.
  • Cleaning and disinfecting.

Secondary Prevention

• Contact tracing helps reduce the spread of the disease.

References

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