Idiopathic hypertrophic pachymeningitis has been described in humans as a rare, chronic progressive non-specific inflammatory and fibrotic disease of the dura mater. This is a case series of six canine cases of presumptive or confirmed intracranial idiopathic hypertrophic pachymeningitis. These dogs were included in this retrospective study, based on magnetic resonance imaging findings. All presented with pachymeningeal thickening and enhancement without involvement of the leptomeninges on magnetic resonance imaging and no underlying cause identified on cerebrospinal fluid analysis, complete blood count, serum biochemistry and infectious disease titres. Histopathological examination was available in one case. Response to immunomodulatory treatment (corticosteroids and cytosine arabinoside) was achieved in five cases. Idiopathic hypertrophic pachymeningitis should be considered as a possible differential diagnosis for dogs with pachymeningeal thickening on magnetic resonance imaging and no identified underlying cause. The prognosis appears to be fair to poor.
In humans, cranial idiopathic hypertrophic pachymeningitis (IHP) is a rare disorder affecting both females and males at various ages (Rudnik and others 2007). The most common clinical signs are headaches (focal or diffuse) and multiple cranial nerve (CN) deficits (Oiwa and others 2004). Magnetic resonance imaging (MRI) features are characterised by thickened dura mater lesions markedly hyperintense on T2-weighted images, iso- to hypointense on T1-weighted images with marked contrast enhancement (Tuncel and others 2005). In the absence of histopathology, the diagnosis in humans is based on MRI appearance and exclusion of other diseases by cerebrospinal fluid (CSF) analysis. In the authors’ opinion, this case series represents the first MRI-documented report of several cases of canine cranial IHP.
Six cases were included on the basis of common MRI findings: variable diffuse thickening of the dura mater with marked -hyperintensity on T2-weighted images, hyperintensity on fluid attenuated inversion recovery (FLAIR) images, iso- to hypointensity on T1-weighted images and contrast enhancement after gadolinium administration. The signalment and clinical presentation of the six cases are summarised in Table 1. Five dogs presented with abnormal mental status (obtunded or demented). Trigeminal nerve deficit was the most frequent CN deficit (cases 4, 5 and 6). Other CN deficits observed were CN VII for cases 3 and 6 and possible CN II for case 1. All cases underwent complete blood count (CBC), full blood chemistry, MRI of the brain, cisternal CSF analysis and infectious disease titres. Histopathology was available in case 2. Treatment and follow-up are summarised in Table 2.
Table 1. Signalment, neurological signs and diagnostic tests results
MRI Magnetic resonance imaging, CSF Cerebrospinal fluid, FS Female spayed, FLAIR Fluid attenuated inversion recovery, MN Male neutered, ME Male entire, PLR Pupillary light reflex, NCC Nucleated cell count
8 YO, FS, Lurcher
Acute onset of blindness (bilateral mydriasis, no PLR nor menace response), obtunded mental status
Marked generalised dural thickening, T2 hyperintense not suppressing on FLAIR, T1 iso- to hypointense, marked generalised dural contrast enhancement
Major diffuse dural thickening with mass effect on right parietal and temporal lobes, T2 hyperintense (FLAIR not performed), T1 iso- to hypointense, two layers of marked contrast enhancement -surrounding a hypointense centre
Cisternal: within reference limits
6 YO, FS, Labrador retriever
Bilateral facial paralysis, right head tilt (primary epilepsy diagnosed 1 year before)
Moderate localised dural thickening (main lesion on left frontal lobe), T2 hyperintense not suppressing on FLAIR, T1 hypointense, contrast enhancement of superficial dural layer
Marked diffuse dural thickening (main lesion on right parietal lobe), T2 hyperintense not suppressing on FLAIR, T1 hypointense, two layers of marked contrast enhancement surrounding a hypointense centre
Cisternal: protein=0·55 g/L; NCC=10/μL (mononuclear pleocytosis primarily lymphoid) Lumbar: protein=0·56 g/L; no cells seen
6 YO, MN, Greyhound
Obtunded mental status, bilateral trigeminal paralysis, protruded third eyelids, anisocoria
Moderate diffuse dural thickening, T2 hyperintense not suppressing on FLAIR, T1 iso- to hypointense, diffuse dural contrast enhancement
Obtunded mental status, tetra-ataxia, tetraparesis, left head tilt, left facial paralysis, bilateral trigeminal paralysis, anisocoria, spontaneous nystagmus fast phase to the right
Marked generalised dural thickening, T2 hyperintense not suppressing on FLAIR, T1 iso- to hypointense, marked generalised dural contrast enhancement, two layers of contrast enhancement surrounding a hypointense centre
Initial: Mannitol 1 g/kg iv, dexamethasone 0·2 mg/kg iv, Ara-C 50 mg/m2iv+50 mg/m2intrathecal.
Ara-C 100 mg/m2 SC q12h for four injections, then standard course, prednisolone 1 mg/kg q12h (tapered progressively)
3 weeks: left facial paralysis and bilateral partial trigeminal paralysis still present
7 months: euthanased after relapse
Bloodwork and infectious disease titres
CBC and blood chemistry were unremarkable in all cases. All dogs tested negative for toxoplasma, neospora and distemper on blood and CSF; cases 3, 4 and 5 were also negative for Borellia and case 2 was also negative for fungal agents on blood and CSF.
Pachymeningeal thickening was the common MRI feature in all six cases. A variable proportion of the dural surface was involved, from generalised (cases 1 and 6) to more localised thickening and contrast enhancement (case 3). Cases 1 and 5 showed symmetrical lesions and only case 2 showed unilateral lesions (Figs 1 to 3).
Pleocytosis was present in five cases with lymphocytic pleocytosis in four. Four cases had elevated protein in the CSF and two cases were within the reference limits (<0·003 g/L for cerebellomedullary cistern) (Di Terlizzi and Platt 2006, 2009) (Table 1).
The lesion from case 2 was described as severe chronic, fibrotic, lymphoplasmacytic pachymeningitis resembling IHP in humans (Kupersmith and others 2004).
All dogs were treated with a progressively tapering dose of glucocorticoids. Five dogs (cases 1, 3, 4, 5 and 6) received cytosine arabinoside either at presentation or following relapse. One dog (case 2) received anticonvulsant therapy and antibiotherapy (Table 2).
Five dogs initially presented with abnormal mental status and two of the three cases that experienced relapse were depressed. It is the authors’ opinion that more attention to pain-related behaviour changes (e.g. depression, reaction on head palpation) could help provide an earlier diagnosis at first onset and in case of relapse. Indeed, headache is the most frequent clinical sign associated with human IHP, encountered in 92% of cases, followed by CN neuropathy in approximately 75% of cases, visual deficit in up to 50% of cases and cerebellar ataxia in 11% of cases. Seizures (8%), hypopituitarism (2%) and cortical signs are also described (Oiwa and others 2004). CN deficits are mainly related to the thickening of the dura matter covering the nerve roots (Deprez and others 1997).
The various degrees of pachymeningeal thickening in these six cases correlate with findings in human cranial IHP: from 75% of the cranial dural surface involved to localised, nodular, mass-like and infiltrative lesions mimicking meningiomas (Park and others 2001, Osborn and others 2004, Kazem and others 2005). In all six cases, on T1-weighted images post-gadolinium injection, the main layer of dural enhancement was contrasted by an underlying area of low signal, at least in one site. Many cases showed lesions characterised by two layers of contrast enhancement surrounding a centre iso- to hypointense to the grey matter on T1-weighted images after gadolinium injection. Two hypotheses are proposed: a dilation of the subarachnoid space with fluid and separation between the dural and pial layer or inflamed lesion edges surrounding a fibrotic centre. The finding of hyperintense edges surrounding a hypointense centre on T2-weighted images in case 4 could favour the second hypothesis, as reported in humans (Deus-Silva and others 2003). The images obtained with FLAIR sequence in cases 1, 4 and 6 rule out the presence of pure fluid, as the corresponding lesions did not suppress on FLAIR sequence and still appeared hyperintense to the grey -matter (Fig 3). The histological analysis of the fibrotic lesion in case 2 also supports this hypothesis.
In all cases presented, the meningeal enhancement and thickening were characteristic of dural enhancement, limited to the pachymeninges without extension into the sulci (Mellema and others 2002). The most common site for meningeal enhancement was the dorso-lateral part of each cerebral hemisphere present in all dogs in either the parietal or frontal cortex. The falx cerebri was involved in four cases and the tentorium cerebellum in three cases. Human literature also reports those three sites as the most frequently affected (Chang Lee and others 2003). Meningeal enhancement in veterinary MRI has been reported in conditions such as B-cell lymphoblastic leukaemia (Vernau and others 2000), primary encephalic plasma cell tumour (Sheppard and others 1997), experimentally induced bacterial meningitis (Runge and others 1995, Mathews and others 1989), bacterial meningitis, plasmacytic meningitis, cryptococcal meningitis, otitis interna with extension to brainstem, granulomatous meningoencephalomyelitis, lymphoma/leukaemia, hystiocytic sarcoma (Mellema and others 2002), meningioma or other neoplasias (Cherubini and others 2005) and other inflammatory conditions of the CNS such as steroid responsive meningitis-arteritis (Lamb and others 2005) with several of the aforementioned causing thickened meningeal lesions. Chronic non-suppurative meningeal inflammation has been anecdotally reported to produce meningeal thickening and enhancement in cases of neosporosis (De Lahunta and Glass 2009). However, serology, anatomic distribution of the lesions and MRI features differed significantly in comparison to the present case series. The lack of supporting history and adjacent structure changes on MRI also helps to rule out intracranial extension of infectious processes (e.g. otitis interna/media and bite wound would demonstrate other changes).
Two cases benefited from MRI follow-up with correlation between MRI findings and clinical status. Case 5 had an unremarkable MRI at 4 months, after resolution of clinical signs. Case 1 had marked worsening of the dural thickening and contrast enhancement following neurological deterioration at 14 months. After clinical improvement at 22 months, the dura mater remained thickened with decreased enhancement limited to the edges, likely to represent a more chronic lesion with -fibrotic centre (Fig 2). This correlation between disease evolution and MRI findings is highlighted in human literature (Riku and Kato 2003), hence the interest of repeated follow-up MRIs.
CSF lymphocytosis and increased proteins concentration are variably present in humans but cases can also present with normal CSF (Rojana-Udomsart and others 2008). CSF analysis should not be used as a sole diagnostic test to monitor the progression of the disease, but remains part of the baseline work-up to rule out other aetiologies. Indeed some abnormalities would not be in favour of IHP (e.g. highly neutrophilic or eosinophilic pleocytosis, presence of neoplastic cells).
The association of human IHP with immunological disorders such as arthritis, synovitis (Deprez and others 1997), myocarditis (Tanaka and others 1996) and diabetes (Claus and others 2005) highlights the possibility of an immunologic underlying cause. Furthermore, as in human medicine, the response to the immunosuppressive treatment is in favour of a possible immunologic aetiology for canine IHP.
In humans, IHP is treated with glucocorticoids and other immunomodulating drugs such as azathioprine, cytosine arabinoside, methotrexate and cyclophosphamide (Riku and Kato 2003, Kleiter and others 2004). Treatment used by the authors is adapted from the treatment of CNS immune-mediated diseases and consists of the use of corticosteroids and cytosine arabinoside. Further studies are needed to evaluate other protocols and other immunomodulatory drugs (e.g. cyclosporine, procarbazine). None of the dogs underwent surgery as a treatment, although it has been advised and used with success in some human cases, particularly to relieve the pressure on vital structures (Van Toorn and others 2008).
In humans, despite reported spontaneous resolution (Nishio and others 1995), the need for early and long-term treatment is emphasised, with a high rate of recurrence with corticosteroid tapering (Rudnik and others 2007). In the present case series, cases 1, 3 and 6 were euthanased because of relapse and deterioration after prednisolone tapering, cases 4 and 5 were lost to follow-up after initial improvement and case 2 died from another disease unrelated to IHP.
In conclusion, it is suggested that a presumptive diagnosis of cranial IHP can be made on the basis of MRI appearance after excluding other causes of pachymeningeal thickening through CSF analysis and screening for infectious diseases. Treatment with corticosteroids, cytosine arabinoside and possibly other immunomodulating drugs should be started and continued for long term. The prognosis appears to be fair to poor.
Conflict of interest
None of the authors of this article has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper.
The authors would like to thank Ann Bilderback, DVM, DACVIM-Neurology, for her precious help in the preparation of this manuscript.