Transient headaches and neurologic deficits with cerebrospinal fluid lymphocytosis (HaNDL syndrome)

The Syndrome of transient Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL) (also known as pseudomigraine with lymphocytic pleocytosis or migraine – or migrainous syndrome – with CSF pleocytosis, or pseudomigraine with inflammatory CSF) is characterized by (transient) headaches, fluctuating neurological symptoms, and cerebrospinal fluid (CSF) lymphocytosis. A small proportion of patients develop intracranial hypertension as a consequence of the illness. Confusional state may be also observed.


The syndrome is self-limiting and typically lasts under three months but may rarely recur over the space of many years. It generally affects adults aged 30–40 years, though can occur at any age, including children.


HaNDL is characterised by episodes (from 1 to >20) of headache, which is usually severe,  neurologic deficits involving different neurovascular territories, and CSF lymphocytic pleocytosis. The attacks last from a few hours to 3 days and are separated by symptom-free intervals. The onset of headache is often preceded by symptoms suggestive of a viral infection and/or fever in about a third of the cases. Interestingly, unlike migraine, it has a slight predilection for males. Moreover, most patients do not have a previous history of migrainous headaches. The neurological symptoms, which can develop before, during or after the headache, entails sensory symptoms (78% of cases), aphasia (66%) and motor deficits (56%), while visual symptoms appear to be significantly rarer (18%). Blood tests show occasional leucocytosis. On CSF sampling, there is raised opening pressure (100–400 mm H 2O) in >50% of cases, high protein levels (20–250 mg/dl) in >90%, lymphocytosis (10–760 cells/ml), normal glucose and no oligoclonal bands are observed.  The CSF pleocytosis resolves with time, although its global duration has not been established. Both CSF and serum-based microbiological tests are normal (although there are exceptions to this). Conventional brain MRI is, as a rule, normal. 


The aetiopathogenesis of HaNDL has not been fully elucidated, but three major hypotheses have come to the fore. HaNDL has been regarded by some authors as an atypical form of migraine. However, several of its features militate against this view. First, unlike migraine, it is a monophasic illness and is more frequent in men. Second, the duration of the deficits is longer than in classical migraine and their characteristics are different from typical aura, where visual symptoms usually dominate the picture. Finally, although no systematic studies have addressed the composition of CSF in migraine, the general consensus (based on clinical experience, single case reports and a few case series) is that significant lymphocytic pleocytosis is distinctly unusual, even in hemiplegic forms. The model of HaNDL as a conventional meningoencephalitic illness is unconvincing, because of the universal absence of signs of meningeal irritation and the publication of only three reports implicating an infectious aetiology. It seems instead plausible that the primary pathogenetic mechanism in HaNDL is the activation of cortical spreading depression (probably by viral infection), which in turn incites sterile inflammation in the cortex and meninges through trigemino-vascular activation

opening pressure of cerebrospinal fluid in HaNDL syndrome