Neuro-Sweet’s disease: a neurological variant

Sometimes, Sweet’s syndrome (SS) can occur in an unusual form. This is called a disease variant.

What is neuro-Sweet’s disease?

Neuro-Sweet’s disease (NSD) is a rare neurological variant of SS that can affect the central nervous system (brain and spinal cord). It was first reported in 1999 in a 37-year-old Japanese man who was experiencing repeat episodes of encephalitis, and had the genetic marker HLA-B54 (Hisanaga et al, 1999).

How many cases of neuro-Sweet’s disease have been reported?

There have been more than 70 cases of NSD, and by September 2016, 69 cases had already been reported in medical literature, including the first case of radiation therapy-induced NSD in a patient receiving treatment for an oral squamous cell carcinoma (Drago et al, 2016; Wallet et al, 2016). It’s most common in East Asians, and affects males more than females (Drago et al, 2016). The average age of onset for NSD is approximately 49-years-old (Hisanaga et al, 1999).

Is neuro-Sweet’s disease more likely to affect some parts of the brain than others?

Yes, and the most commonly affected parts of the brain are the basal ganglia, thalamus and brain stem (Singh et al, 2011: 990).

What are the symptoms of neuro-Sweet’s disease?

A change in mental state is often associated with NSD, followed by headaches or migraines and memory disorders (Drago et al, 2016). NSD can also cause other symptoms, and symptoms experienced will depend on which part of the central nervous system has been affected. Other symptoms include:

  • Non-infectious meningitis, encephalitis or meningoencephalitis (Akiba et al, 2011: 142; Drago et al, 2014: 192; Hisanaga et al, 1999; Makimoto et al, 2012; Singh et al, 2011: 990).
  • Generalized seizures, also epilepsy (Drago et al, 2014: 192; Hisanaga et al, 1999).
  • Dizziness (Makimoto et al, 2012: 20). Can also be a symptom of SS when there is bilateral sensorineural hearing loss (Sweet’s Syndrome UK, 2016).
  • Eye and vision problems. Includes double vision or abnormal eye movements (Hisanaga et al, 1999; Makimoto et al, 2012: 20; Singh et al, 2011: 989-90). Eye problems can also be a symptom of SS.
  • Psychiatric disorders (Drago et al, 2014: 192).
  • Ataxia – a group of disorders that affect co-ordination, balance and speech (Singh et al, 2011: 990).
  • Hemiparesis or weakness of the entire left or right side of the body (Makimoto et al, 2012: 21). Symptoms may persist, even after treatment.
  • No gag reflex; tongue sticking out; problems swallowing (Akiba et al, 2011: 141).
  • Speech problems. Includes difficulty speaking or total loss of speech (Akiba et al, 2011: 141; Makimoto et al, 2012: 20; Mariën et al, 2012; Singh et al, 2011: 990).
  • Numbness in hands or feet (Akiba et al, 2011: 141). Can also be a symptom of SS-associated polyneuropathy (Sweet’s Syndrome UK, 2016).
  • Motor weakness of limbs or extremities (Akiba et al, 2011: 141).
  • Dysaesthesia – unusual or unpleasant sensations (Akiba et al, 2011: 141; Makimoto et al, 2012: 20).
  • Facial palsy – weakness of the facial muscles, mainly resulting from temporary or permanent damage to the facial nerve (Akiba et al, 2011: 141).
  • Urinary incontinence (Singh et al, 2011: 989).
  • Syndrome of inappropriate antidiuretic hormone secretion (SIADH). This occurred in a 66-year-old Japanese woman with myelodysplastic syndrome (MDS). Read more about this case here.

How is it diagnosed?

Medical information.

Main diagnostic criteria for neuro-Sweet’s disease (Cruz-Velasquez et al, 2016).

  • Neurological symptoms that respond quickly to corticosteroids.
  • Skin lesions, particularly plaques or painful nodules located on the face, neck, trunk or upper extremities, with neutrophilic infiltrate in the dermis and absence of vasculitis.
  • No uveitis or cutaneous vasculitis.
  • Exclusion of other reasons for central nervous system involvement.

Other.

  • Recurrent history of meningitis or encephalitis (Akiba et al, 2011: 142; Hisanaga et al, 1999).
  • Skin lesions not always present (Makimoto et al, 2012: 20; Singh et al, 2011: 989-990).
  • A sample of cerebrospinal fluid (CSF) via lumbar puncture. CSF normally shows a higher concentration of proteins, and an increased number of white blood cells, commonly lymphocytes or neutrophils (Hisanaga et al, 1999; Makimoto et al, 2012: 20; Singh et al, 2011: 989-990). Lymphocytes and neutrophils less likely to be found in MDS (click on link to SIADH blog post).
  • MRI scan of the brain showing lesions (Makimoto et al, 2012: 20). CT scans are not an effective diagnostic tool as they may not show abnormalities even when lesions are present (Singh et al, 2011: 990).
  • Biopsy of a brain lesion is of possible value, but not usually necessary (Akiba et al, 2011: 141).

Read more here. Includes both medical and patient information.

How is it treated?

The most common and preferred treatment for NSD is the oral steroid medication, prednisone. Intravenous (via a drip into a vein) steroids, e.g. methylprednisolone, are sometimes given before starting prednisone (Akiba et al, 2011: 142). Other medications include dapsone, colchicine, and ciclosporin has been used in low-risk MDS.

Read more here and click on link to SIADH blog post.

Additional information: problems with diagnosis.

Sometimes, NSD can be difficult to diagnose as it may be confused with other conditions.

Conditions that are often confused with neuro-Sweet’s disease.

NSD is often confused with infectious meningitis; acute viral encephalitis; brain tumours; multiple sclerosis; neuro-Behcet’s disease (NBD) which is a neurological variant of Behcet’s disease (BD). Both BD and SS are forms of neutrophilic dermatosis; lupus affecting the central nervous system (Drago et al, 2014: 192; Singh et al, 2011: 990).

Conditions that are sometimes confused with neuro-Sweet’s disease.

NSD is sometimes confused with Hashimoto’s encephalopathy; Sjögren’s syndrome; sarcoidosis (Makimoto et al, 2012: 22).

Neuro-Sweet’s and neuro-Behcet’s disease.

Both NSD and NBD share many signs and symptoms, and can look the same on MRI despite being different (Singh et al, 2011: 991; Tsunemi et al, 2006; 1317.).

Differences between the two conditions.

  • NSD is rarer than NBD and is acute in nature, i.e. it flares-up then settles down with treatment. Outcomes are usually good.
  • NBD is progressive, so can get worse over time.
  • Vasculitis (inflammation of the blood vessels) is a symptom of BD, but normally absent in SS.
  • The eye condition uveitis is common in BD, but rare in SS.
  • HWL-B54 is the genetic marker for SS, and is most commonly found in Japanese patients (Akiba et al, 2011: 142; Hisanaga et al, 1999). It’s more common in SS than BD.
  • HWL-B51 is the genetic marker for BD.

Paraneoplastic and paraneoplastic neurologic syndromes.

In 15-20% of patients with SS their condition can develop secondary to cancer (malignancy-associated), and in 2016, a case of malignancy-associated SS was reported in a 69-year-old man with central nervous system lymphoma (Salam et al, 2016). His condition mimicked motor neurone disease, and he experienced difficulty swallowing, weakness and weight loss.

Due to the possibility of underlying malignancy, it’s important that cancer is ruled out as a cause for SS or NSD, and in patients with neurological symptoms or suspected NSD, paraneoplastic neurologic syndromes (PNS) may need to be considered.

What are paraneoplastic (neurologic) syndromes?

Paraneoplastic syndromes.

Paraneoplastic syndromes are rare, and can be defined as a set of signs and symptoms that are caused by a substance that is produced by a tumour or in response to a tumour. This can happen because of :

  • Substances, e.g. hormones or other biologically active products, made by the tumour.
  • Blockade of the effect of a normal hormone, i.e. a normal hormone or uptake of a hormone is blocked.
  • Autoimmunity.
  • Immune-complex production, i.e. what happens when an antibody binds to an antigen, and a suppressed or weakened immune system.

Paraneoplastic neurologic syndromes.

Paraneoplastic neurologic syndromes (PNS) are a group of conditions that affect the nervous system in less than 1% of patients with cancer, mainly those with small cell lung cancer, lymphoma, and myeloma (Pelosof and Gerber, 2010). They are often mistaken for multiple sclerosis, stroke, or degenerative disorders. On very rare occasions, it could be possible for PNS to be mistaken for NSD. PNS and NSD symptoms can be similar and include:

  • Encephalitis (Pelosof and Gerber, 2010).
  • Cognitive changes, e.g. problems with memory, concentration and processing information.
  • Personality changes.
  • Problems with coordination, balance, and speech, or other symptoms of ataxia.
  • Cranial nerve deficits, e.g. facial palsy.
  • Weakness or numbness.
  • Other symptoms (Ibid).

I decided to add this PNS information as a result of the case of a SS patient who had suspected PNS or NSD. Details of the case were passed on by a family member of the patient, and this family member hoped that these details could be used to help another SS patient with neurological symptoms or their family – Michelle Holder, Sweet’s Syndrome UK.

Further information.

Kidd, D. (2016) Fact sheet: Behçet’s Disease and the Brain. Behçet’s Syndrome Society (PDF).

NHS Choices (2015) Lumbar puncture (online).

NHS Choices (2015) MRI scan (online).

NORD (2016) Paraneoplastic Neurologic Syndromes (online).

References.

Akiba, C., Esaki, T., Ando, M., Furuya, T., Noda, K., Nakao, Y., Yamamoto, T. Okuma, Y. and Mori, K. (2011) Possible neuroSweet disease mimicking brain tumor in the medulla oblongata-case report. Neurologia Medico-Chirurgica (Tokyo);51(2):140-3 (J-Stage).

Cruz -Velásquez, G., Pac Sha, J., Simal Gil, E. and Gazulla, J. (2016). Aseptic meningitis and anti-β2-glycoprotein 1 antibodies in Sweet syndrome. Neurologia (Barcelona, Spain), Jul 21 (Elsevier). Article in Spanish, use translate.

Drago, F., Ciccarese, G., Agnoletti, A., Sarocchi, F. and Parodi, A. (2016) Neuro sweet syndrome: a systematic review. A rare complication of Sweet syndrome. Acta Neurologica Belgica, Sept 22 (PubMed).

Drago, F., Ribizzi, G., Ciccarese, G., Agnoletti, A. and Parodi, A. (2014) Recurrent episodes of neuro-Sweet syndrome in a Caucasian patient. Journal of the American Academy of Dermatology, Jul; 71(1): 192-193 (PubMed).

Hisanaga, K., Hosokawa, M., Sato, N., Mochizuki, H., Itoyama, Y. and Iwasaki, Y. (1999) “Neuro-Sweet Disease”: Benign Recurrent Encephalitis With Neutrophilic Dermatosis. Archives of Neurology;56(8):1010-1013 (JAMA).

Makimoto, G., Manabe, Y., Yamakawa, C., Fujii, D., Ikeda-Sakai, Y., Narai, H., Omori, N. and Abe, K. (2012) Two cases of possible neuro-Sweet disease with meningoencephalitis as the initial manifestation. Neurology International, Jan 9;4(1):e5, 20-23 (PDF).

Mariën, P., Tops, W., Crols, R., Jonkers, R., De Deyn, P. and Verhoeven, J. (2012) Grammar disruption in a patient with Neuro-Sweet syndrome. Neurocase: The Neural Basis of Cognition, 18:3, 235-247 (PDF).

Pelosof, L. and Gerber, D. (2010) Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment. Mayo Clinic Proceedings, Sep; 85(9): 838–854 (PMC).

Salam, S., Fardoom, P. and Milahova, T. (2016) Take the Bitter with the Sweet. Journal of Neurology, Neurosurgery and Psychiatry, Dec; 87(12) (BMJ).

Singh, J., Costello, F., Nadeau, J., Witt, S., Trotter, M. and Goyal, M. (2011) Case 176: Neuro-Sweet Syndrome. Radiology, Dec; 261(3): 989-993 (PDF).

Sweet’s Syndrome UK (2016) Bilateral Sensorineural Hearing Loss and Polyneuropathy in Sweet’s Syndrome (online).

Tsunemi, T., Sakai, Y., Tsunoda, K., Irie, Y. and Wada, Y. (2006) Neuro-Behçets/neuro-Sweets disease presents simultaneously with severe tonsillitis, and features mimicking bacterial meningitis with skin lesions. Internal Medicine; 45 (22): 1315-1317 (J-Stage).

Wallett, A., Newland, K. and Foster-Smith, E. (2016) Radiation therapy-induced neuro-Sweet disease in a patient with oral squamous cell carcinoma. The Australasian Journal of Dermatology, Jan 28th (PubMed).

2012-2018 Sweet’s Syndrome UK

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