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 (CNS) – the brain and the 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?

By September 2016, 69 cases of NSD had 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 is most common in East Asians, and affects males (46 cases) more than females (23 cases) (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. 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 and memory disorders (Drago et al, 2016). There are lots of other potential symptoms too, depending on which part of the spinal cord or brain have been affected. Reported symptoms of NSD include:

  • A change in mental state or level of consciousness. This can lead to disorientation, confusion, drowsiness, and potentially semi-consciousness or loss of conciousness (Hisanaga et al, 1999; Makimoto et al, 2012; Singh et al, 2011: 989).
  • Headaches or migraines (Drago et al, 2014: 192; Makimoto et al, 2012: 20). Can also be a symptom of SS.
  • Memory disorders and disturbances (Drago et al, 2016).
  • Meningitis, encephalitis or meningoencephalitis (non-infectious) (Akiba et al, 2011: 142; Drago et al, 2014: 192; Hisanaga et al, 1999; Makimoto et al, 2012; Singh et al, 2011: 990). This may cause a change in mental state, headaches, affect memory, and other symptoms.
  • Generalized seizures (fits) (Hisanaga et al, 1999). Also, epilepsy (Drago et al, 2014: 192).
  • 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).
  • Double vision or abnormal eye movements (Hisanaga et al, 1999; Makimoto et al, 2012: 20; Singh et al, 2011: 989-90).
  • Psychiatric disorders (Drago et al, 2014: 192).
  • Ataxia – a group of disorders that affect co-ordination, balance and speech (Singh et al, 2011: 990). Ataxia is usually caused by damage to a part of the brain called the cerebellum, but can also be caused by damage to other parts of the nervous system. Symptoms depend on what kind of ataxia you have, but your gait or how you walk is often affected. Some patients may also experience tremors.
  • 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 – difficulty speaking (Akiba et al, 2011: 141; Makimoto et al, 2012: 20; Singh et al, 2011: 990). Also, total loss of speech (Mariën et al, 2012).
  • 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, e.g. hand (Akiba et al, 2011: 141).
  • Dysaesthesia, i.e. unusual or unpleasant sensations (Akiba et al, 2011: 141; Makimoto et al, 2012: 20). Dysaesthesia is caused by lesions of the nervous system, and can include pain, and sensations such as burning, wetness, itching, electric shock, tingling or pins and needles.
  • 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).

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 (steroids).
  • 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 (unlike Behcet’s syndrome). See below, ‘Additional information: problems with diagnosis’.
  • 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). Therefore, NSD should not be automatically ruled-out even when skin lesions are absent.
  • Lumbar puncture showing a higher concentration of proteins and an increased number of white blood cells – particularly lymphocytes or neutrophils in cerebrospinal fluid (Hisanaga et al, 1999; Makimoto et al, 2012: 20; Singh et al, 2011: 989-990).
  • Magnetic resonance imaging (MRI) scan of the brain showing lesions (Makimoto et al, 2012: 20). Computerised tomography (CT) scans are not always 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).

Find general info here.

How is it treated?

The most common and preferred treatment for NSD is oral steroid medication, e.g. prednisone. Intravenous (via a drip into a vein) steroids, e.g. methylprednisolone, will sometimes be given before starting oral steroids (Akiba et al, 2011: 142). Sometimes, other medications such as dapsone, or less commonly, colchicine will be considered. Read more here.

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 meningitis (not NSD-related); acute viral encephalitis; brain tumours; multiple sclerosis; neuro-Behcet’s disease (NBD), or 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, or sarcoidosis (Makimoto et al, 2012: 22).

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

Both NSD and NBD are forms of neutrophilic dermatosis. They 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 much less common than NBD and is acute in nature, ie. 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 Behcet’s disease (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 (Akiba et al, 2011: 142; Hisanaga et al, 1999). It is more common in SS, but rare in BD.
  • HWL-B51 is the genetic marker for BD.

Paraneoplastic and paraneoplastic neurologic syndromes.

In 15-20% of patients with SS their condition can be malignancy-associated or paraneoplastic, i.e. the SS develops secondary to cancer, and in 2016, a unique case of malignancy-associated SS was reported in a 69-year-old man with CNS lymphoma (Salam et al, 2016). His condition mimicked motor neurone disease; difficulty swallowing, weakness and weight loss.

Due to the possibility of underlying malignancy, it is important that cancer is ruled out as a cause for SS or NSD, and in patients with suspected NSD, paraneoplastic neurologic syndromes (PNS) may also 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 (cancer) 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 immunosuppression (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 extremely rare occasions, it may be possible for PNS to be mistaken for NSD in patients with SS who have developed neurological problems. Symptoms of PNS can be similar to those of NSD 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 can occur.

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 (online).

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 (online). 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 (online).

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 (online).

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 (online).

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 (online).

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 (online).

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).

Further information.

Kidd, D. (2013) Fact sheet: Behçet’s Disease and the Brain. Behçet’s Syndrome Society.

NHS Choices (2013) Lumbar puncture (online).

NHS Choices (2013) MRI scan (online).

NORD (2012) Paraneoplastic Neurologic Syndromes (online).

© 2012-2017 Sweet’s Syndrome UK

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