How should a 47-year-old man develop multiple cranial nerve palsy and dural enhancement?

How to distinguish between primary headache and secondary headache? What are the differential diagnoses of dura materitis? The latest issue of the Journal of Neurology Clinical Reasoning Series reported on a 47-year-old man with multiple cranial nerve palsy and dural enhancement.
Let’s take a look at the clinical reasoning process.

1 Man with acute dizziness for 2 days.
The patient is a 47-year-old man of Spanish nationality.
He has a history of isolated, severe and recurrent scleritis in his left eye and has been treated with adalimumab and methotrexate for 2 years.

Seeing a doctor for "emergency dizziness for 2 days".

Two days after the onset of vertigo, the patient felt a mild headache in the back of his right eye and continued to worsen for 5 days.
Valsalva movements and lying down would aggravate the headache.

The patient denied a history of nausea, vomiting, sensitivity to light and sound, or headache.

On the 5th day of the onset of symptoms, the patient develops diplopia, and the right vision becomes worse.

Physical examination showed normal vital signs and no fever; right vision was slightly restricted; pupil response was sensitive and no papilledema was seen on fundus examination; finger nose test was normal; mental state, muscle strength, sensation and reflexes were normal.

 Questions to ponder 1.
What are the differential diagnoses? 2.
What tests are needed to help narrow the scope of the differential diagnosis? 2 What differential diagnosis should be performed? SNNOOP10 helps to distinguish between primary headache and secondary headache: systemic symptoms, tumor history, neurological symptoms, sudden onset, old age (> 65 years old), pattern changes, posture-related, Valsalva aggravation, papilledema , Progressive atypical symptoms, pregnancy, eye pain, post-traumatic, central nervous system disease, and excessive use of painkillers are red flags for secondary headaches.

The patient's sudden onset, worsening of Valsalva's movements, and related neurological symptoms indicate a secondary headache.

Right gaze palsy indicates cranial nerve involvement, which can be located in any part of the abducens nerve, including the brainstem, subarachnoid space, cavernous sinus, or supraorbital fissure.

The causes of secondary headaches include vascular events (such as stroke), infections (such as meningitis), inflammation (such as neurosarcoidosis or vasculitis), traumatic injuries, and neoplastic causes (such as brain tumors or leptomeningeal spread).

The patient has no history of coagulation disorders, trauma, cancer, or known autoimmune diseases.

MRI of the head showed thickening of the right dura mater and enhanced meninges of the cerebellopontine angle (Figure 1A and B); no substantial lesions, and normal angiography.

Lumbar puncture showed normal initial pressure, 3 nucleated cells (mainly lymphocytes), 1 red blood cell, protein 80mg/dl and glucose 88mg/dl.

One week after the initial symptoms appeared, the patient developed peripheral facial nerve palsy on the right side.

After otolaryngology consultation, the right sensorineural hearing loss was considered.

Figure 1 MRI results of the patient's head.

A and B: Enhanced MRI scans of the head showed thickening and enhancement of the right dura mater and cerebellopontine angle.

 Questions to ponder 1.
Based on imaging and multiple cranial neuropathy, what is the most likely diagnosis? 2.
Which tests are helpful for diagnosis? 3 What inspections should be performed next? There are many diagnostic possibilities for patients with multiple cranial nerve palsy and thickening and strengthening of the dura mater.

Although the cerebrospinal fluid cells are normal, patients who use immunosuppression may not be able to develop an immune response to the underlying infection.
Therefore, infectious diseases need to be considered, such as neuro tuberculosis, Lyme disease, and fungal infection.

Re-examination of the lumbar puncture one week after the onset of symptoms showed 6 nucleated cells (78% lymphocytes), 16 red blood cells, 114 mg/dl protein and 91 mg/dl glucose.

Tests for specific viral, fungal and bacterial infections in CSF were all negative.

Studies have shown that cancer accounts for 30% of patients with multiple cranial neuropathy.

Although there is no space-occupying tumor, the spread of the pia mater is still possible.

Lymphoma requires important consideration, especially in patients with weakened immune functions.

However, the results of CSF cytology are all negative, and the possibility of malignant cells including lymphoma is unlikely.

The two most common inflammatory diseases that cause multiple cranial neuropathy and dural thickening include neurosarcoidosis and vasculitis.

Serum angiotensin-converting enzyme (ACE), CSF ACE and CSF IL-2 receptor antibodies were all negative, and hilar lymphadenopathy was not seen, so the possibility of neurosarcoidosis is small.

Serum vasculitis including rheumatoid factor, hepatitis B, hepatitis C, HIV, IgG4, anti-Smith antibody, anti-Ro antibody, anti-La antibody and anti-double-stranded DNA antibody were all negative.

The full set of cerebrospinal fluid paratumor was negative.

The serum anti-p-ANCA and anti-MPO antibodies were negative.

Serum anti-c-ANCA and anti-PR3 antibodies are positive, which supports the diagnosis of PR3-related vasculitis.

It should be noted that adalimumab and methotrexate are not standard treatments for scleritis.

Recurrent scleritis requires further study of its systemic causes.

Reviewing the medical history, the patient's recurrent scleritis may be part of an autoimmune disease, and now it appears to be PR3-related vasculitis.

The patient started treatment with methylprednisolone.

After treatment, her headache was relieved, dizziness and facial nerve palsy were improved.

 Questions 1.
How to manage PR3-related vasculitis? 4How to treat? A biopsy of the dura mater on the right showed mixed inflammation of the dura.
Chronic inflammatory cells infiltrated the blood vessel wall.
Scattered necrotic foci containing basophilic debris, neutrophil inflammatory foci, and extravascular epithelioid and multinucleated tissue cell aggregation (Figure 1C and 1D).

Based on medical history, examination, serum markers, and histopathology, the patient was formally diagnosed as hypertrophic meningitis (HP) with granulomatous polyangiitis (GPA).

Figure 1 Histopathological characteristics of the dura mater.

C: Histopathological section shows small vessel lumen (asterisk), with chronic inflammatory cell infiltration in the vessel wall.
Arrows indicate necrotic foci with basophilic debris (scale bar = 100 µm). D: Features of granulomatous polyangiitis: accumulation of extravascular epithelium and multinucleated tissue cells (long arrow), neutrophil infiltration (short arrow) (scale bar = 50 µm).

 Next, the patient began to receive rituximab induction therapy (375 mg/m2, once a week for 4 weeks).

However, after several months of treatment, there was almost no clinical improvement, and imaging showed that the dura mater was thickened and enhanced.

For patients with worsening meningeal thickening and refractory clinical symptoms, cyclophosphamide combined with prednisone is the standard treatment.

Therefore, the patient began to receive prednisone (60mg/day) combined with cyclophosphamide (500mg/m2/month for 6 consecutive months).

Since the start of the program, the patient's symptoms have improved significantly.

Once the disease resolves, the patient will switch to azathioprine as maintenance therapy.

 5What is hypertrophic meningitis (HP) with granulomatous polyangiitis (GPA)? GPA, formerly known as Wegener’s granulomatosis, is an autoimmune vasculitis that affects small and medium blood vessels, including the upper respiratory tract, lower respiratory tract, and kidneys.

GPA includes the following features: nosebleeds (+3), cartilage involvement (+2), conductive or sensorineural hearing loss (+1), pauci immune glomerulonephritis (+1), c-ANCA or PR3- Antibody positive (+5), p-ANCA or MPO antibody positive (-1), eosinophil count ≥1×109/L (-4), granuloma or giant cells (+2) visible on biopsy, chest imaging Nodules (+2) and paranasal sinusitis (+1) are visible.

The sensitivity of the score ≥ 5 to GPA diagnosis is 93%, and the specificity is 94%.

Neurological complications of GPA are seen in 22-54% of patients, including cerebral small vessel vasculitis or extracranial granuloma infiltration.

Peripheral neuropathy is the most common neurological complication, and only 8% of cases report central nervous system involvement.

HP is a chronic fibrous inflammation of the dura mater, mostly idiopathic, or it may be caused by immune mediated.

HP accounts for 33% of GPA neurological complications, and is characteristic in up to 60% of cases.

The most common clinical feature of HP is headache (seen in 73% of patients), followed by cranial neuropathy (seen in 50% of patients), of which cranial nerves II, V, VI, and VII are the most commonly affected cranial nerves.

Epilepsy, ataxia, and encephalopathy may also be complications of GPA-related HP.

However, the diagnosis of GPA-related HP is more difficult because the patient has fewer systemic manifestations, and vasculitis is usually not considered first.

In addition, clinical manifestations can mimic other diseases, including neurosarcoidosis, spontaneous intracranial hypotension, infectious meningitis, Erdheim-Chester disease, IgG4-related diseases, and idiopathic meningitis.

C-ANCA/PR3 has high specificity for GPA.

In addition to being used as a diagnostic tool, the titer of PR3-ANCA is also related to disease activity, and an increase in PR3 indicates recurrence.

MPO-ANCA is not specific for GPA, but up to 20% of GPA-related HP patients can be positive for MPO.

These patients may actually be a unique clinical entity called CNS-limited GPA, with lesions confined to the dura mater and upper respiratory tract.

Although these serum markers help support the diagnosis of GPA, biopsy of the affected tissue is usually required to confirm the diagnosis.

Early application of cyclophosphamide or rituximab combined with glucocorticoid therapy can improve the clinical outcome and reduce the recurrence rate.

Patients with dura meningitis have poor efficacy on rituximab, and patients with positive PR3 antibodies have a higher annual recurrence rate.
This case has the above two characteristics.

This case emphasizes the importance of early identification of GPA-related HP, highlights the diagnostic significance of c-ANCA/PR3-antibody and biopsy, and the importance of immunomodulatory therapy.

 Original index: Jessica Frey, Joshua Kramer, Rudolph Castellani, et al.
Clinical Reasoning: A 47-Year-Old With Headache, Vertigo, and Double Vision.
Neurology published online April 30, 2021.
DOI 10.
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